uniQure N.V. (Form: 10-Q, Received: 05/09/2017 16:10:06)

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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington D.C. 20549

FORM 10-Q

(Mark One)

x QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

For the quarterly period ended March 31, 2017

o TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

For the transition period from to

Commission file number: 001-36294

uniQure N.V.

(Exact name of Registrant as specified in its charter)

The Netherlands		Not applicable
(State or other jurisdiction of incorporation or organization)		(I.R.S. Employer Identification No.)

Paasheuvelweg 25a,

1105 BP Amsterdam, The Netherlands
(Address of principal executive offices) (Zip Code)

+31-20-240-6000

(Registrant’s telephone number, including area code)

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes x No o

Indicate by check mark whether the registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive Data File required to be submitted and posted pursuant to Rule 405 of Regulation S-T (§ 232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit and post such files). Yes x No o

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company or an emerging growth company. See the definitions of “large accelerated filer” “accelerated filer” and “smaller reporting company” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer o		Accelerated filer x

Non accelerated filer o		Smaller reporting company o
(do not check if smaller reporting company)
		Emerging growth company x

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13 (a) of the Exchange Act Yes x No o

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act.) Yes o No x

As of May 1, 2017, the registrant had 25,475,894 shares of common shares, par value €0.05, outstanding.

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PART I — FINANCIAL INFORMATION

Item 1	Financial Statements	4

Item 2	Management’s Discussion and Analysis of Financial Condition and Results of Operations	23

Item 3	Quantitative and Qualitative Disclosures About Market Risk	32

Item 4	Controls and Procedures	32

PART II — OTHER INFORMATION

Item 1	Legal Proceedings	33

Item 1A	Risk Factors	33

Item 2	Unregistered Sales of Equity Securities and Use of Proceeds	55

Item 3	Defaults Upon Senior Securities	55

Item 4	Mine Safety Disclosures	55

Item 5	Other Information	55

Item 6	Exhibits	56

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SPECIAL CAUTIONARY NOTICE REGARDING FORWARD-LOOKING STATEMENTS

This Quarterly Report on Form 10-Q contains “forward-looking statements” as defined under federal securities laws. Forward-looking statements are based on our current expectations of future event and many of these statements can be identified by the use of terminology such as “believes,” “expects,” “anticipates,” “plans,” “may,” “will,” “projects,” “continues,” “estimates,” “potential,” “opportunity” and similar expressions. These forward-looking statements may be found in Part II, Item 1A “Risk Factors,” Part I, Item 2”Management’s Discussion and Analysis of Financial Condition and Results of Operations” and other sections of this Quarterly Report on Form 10-Q.

Forward-looking statements involve risks and uncertainties that could cause actual results to differ materially from those projected or implied. The most significant factors known to us that could materially adversely affect our business, operations, industry, financial position or future financial performance include those discussed in Part II, Item 1a”Risk Factors,” as well as those discussed in Part I, Item 2 “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and elsewhere in this report, as well as other factors which may be identified from time to time in our other filings with the Securities and Exchange Commission (“SEC”) , including our most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission, or SEC, on March 15, 2017, or in the documents where such forward-looking statements appear. You should carefully consider that information before you make an investment decision.

You should not place undue reliance on these statements, which speak only as of the date that they were made. Our actual results or experience could differ significantly from those anticipated in the forward-looking statements and from historical results, due to the risks and uncertainties described in this Quarterly Report on Form 10-Q for the quarter ended March 31, 2017 and in our Annual Report on Form 10-K for the year ended December 31, 2016, including in “ Part I, Item 1A. Risk Factors ,” as well as others that we may consider immaterial or do not anticipate at this time. These cautionary statements should be considered in connection with any written or oral forward-looking statements that we may make in the future or may file or furnish with the SEC. We do not undertake any obligation to release publicly any revisions to these forward-looking statements after completion of the filing of this Quarterly Report on Form 10-Q to reflect later events or circumstances or to reflect the occurrence of unanticipated events. All forward-looking statements attributable to us are expressly qualified in their entirety by these cautionary statements.

In addition, with respect to all of our forward-looking statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995.

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Part I — FINANCIAL INFORMATION

Item 1. Financial Statements

uniQure N.V.

UNAUDITED CONDENSED CONSOLIDATED BALANCE SHEETS

	March 31,			December 31,
	2017			2016
	in thousands, except share and per share amounts
Current assets
Cash and cash equivalents	$	120,271		$	132,496
Accounts receivable and accrued income	1,233			3,680
Accounts receivable and accrued income from related party	517			5,500
Prepaid expenses	1,129			996
Other current assets	579			1,274
Total current assets	123,729			143,946
Non-current assets
Property, plant and equipment, net	35,241			35,702
Intangible assets, net	8,357			8,324
Goodwill	471			465
Other non-current assets	1,837			1,828
Total non-current assets	45,906			46,319
Total assets	$	169,635		$	190,265
Current liabilities
Accounts payable	$	3,954		$	5,524
Accrued expenses and other current liabilities	7,154			9,766
Current portion of long-term debt	2,443			605
Current portion of deferred rent	697			684
Current portion of deferred revenue	6,225			6,142
Total current liabilities	20,473			22,721
Non-current liabilities
Long-term debt, net of current portion	17,920			19,631
Deferred rent, net of current portion	8,090			6,781
Deferred revenue, net of current portion	75,404			75,612
Contingent consideration	1,989			1,838
Other non-current liabilities	32			51
Total non-current liabilities	103,435			103,913
Total liabilities	123,908			126,634
Commitments and contingencies (see note 13)
Shareholders’ equity
Common shares, €0.05 par value: 60,000,000 shares authorized at March 31, 2017, and December 31, 2016, and 25,475,894 and 25,257,420 shares issued and outstanding at March 31, 2017, and December 31, 2016, respectively.	1,604			1,593
Additional paid-in-capital	466,688			464,653
Accumulated other comprehensive loss	(6,235		)	(6,557		)
Accumulated deficit	(416,330		)	(396,058		)
Total shareholders’ equity	45,727			63,631
Total liabilities and shareholders’ equity	$	169,635		$	190,265

The accompanying notes are an integral part of these unaudited condensed consolidated financial statements.

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uniQure N.V.

UNAUDITED CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS

	Three months ended March 31,
	2017			2016
	in thousands, except share and per share amounts
License revenues	$	234		$	241
License revenues from related party	949			978
Collaboration revenues	1,580			1,426
Collaboration revenues from related party	558			1,650
Total revenues	3,321			4,295
Operating expenses:
Research and development expenses	(16,994		)	(16,706		)
Selling, general and administrative expenses	(6,358		)	(7,298		)
Total operating expenses	(23,352		)	(24,004		)
Other income	316			445
Loss from operations	(19,715		)	(19,264		)
Interest income	11			22
Interest expense	(504		)	(629		)
Foreign currency gains, net	(93		)	(2,188		)
Other non-operating income, net	29			317
Loss before income tax expense	(20,272		)	(21,742		)
Income tax benefit / (expense)	—			(557		)
Net loss	$	(20,272	)	$	(22,299	)
Other comprehensive loss, net of income tax:
Foreign currency translation adjustments net of tax impact of nil for the three months ended March 31, 2017 (three months ended March 31, 2016: $(0.6) million)	322			4,680
Total comprehensive loss	$	(19,950	)	$	(17,619	)

Basic and diluted net loss per common share	$	(0.80	)	$	(0.90	)
Weighted average shares used in computing basic and diluted net loss per common share	25,443,609			24,696,643

The accompanying notes are an integral part of these unaudited condensed consolidated financial statements.

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uniQure N.V.

UNAUDITED CONDENSED CONSOLIDATED STATEMENTS OF SHAREHOLDERS’ EQUITY

	Common shares			Additional paid-in			Accumulated other comprehensive			Accumulated			Total shareholders’
	No. of shares	Amount		capital			income/(loss)			deficit			equity
	in thousands, except share and per share amounts
Balance at December 31, 2016	25,257,420	$	1,593	$	464,653		$	(6,557	)	$	(396,058	)	$	63,631
Loss for the period	—	—		—			—			(20,272		)	(20,272		)
Other comprehensive income	—	—		—			322			—			322
Exercise of share options	134,974	7		434			—			—			441
Shares distributed during the period	83,500	4		(4		)	—			—			—
Share-based compensation expense	—	—		1,605			—			—			1,605
Balance at March 31, 2017	25,475,894	$	1,604	$	466,688		$	(6,235	)	$	(416,330	)	$	45,727

The accompanying notes are an integral part of these unaudited condensed consolidated financial statements.

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uniQure N.V.

UNAUDITED CONDENSED CONSOLIDATED STATEMENTS OF CASH FLOWS

	Three months ended March 31,
	2017			2016
	in thousands
Cash flows from operating activities
Net loss	$	(20,272	)	$	(22,299	)
Adjustments to reconcile net loss to net cash used in operating activities:
Depreciation and amortization	1,794			1,480
Share-based compensation expense	1,605			2,648
Change in fair value of derivative financial instruments	105			(244		)
Unrealized foreign exchange results	174			2,304
Change in deferred taxes	—			557
Change in lease incentive	1,305			(149		)
Changes in operating assets and liabilities:
Accounts receivable, prepaid expenses and other current assets	8,154			449
Inventories	—			31
Accounts payable	(683		)	1,191
Accrued expenses and other liabilities	(2,584		)	(276		)
Deferred revenue	(1,268		)	(1,418		)
Net cash used in operating activities	(11,670		)	(15,726		)
Cash flows from investing activities
Restricted cash	—			(608		)
Purchase of property, plant and equipment	(1,969		)	(1,867		)
Net cash used in investing activities	(1,969		)	(2,475		)
Cash flows from financing activities
Proceeds from issuance of shares	441			820
Repayment of capital lease obligations	—			(48		)
Net cash generated from financing activities	441			772
Currency effect cash and cash equivalents	973			5,483
Net increase / (decrease) in cash and cash equivalents	(12,225		)	(11,946		)
Cash and cash equivalents at beginning of period	132,496			221,626
Cash and cash equivalents at end of period	$	120,271		$	209,680
Supplemental cash flow disclosures:
Cash paid for interest	$	413		$	521
Non-cash adjustments in purchases of intangible assets and property, plant and equipment	$	(949	)	$	150

The accompanying notes are an integral part of these unaudited condensed consolidated financial statements.

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1 General business information

uniQure N.V. (“uniQure” or the “Company”) was founded in 1998 by scientists at the Academic Medical Center of the University of Amsterdam. The Company is a leader in the field of gene therapy and seeks to deliver to patients suffering from rare and other devastating diseases single treatments with potentially curative results. The Company initially operated through its predecessor company, Amsterdam Molecular Therapeutics Holding N.V. (“AMT”). The Company was incorporated in January 2012 to acquire and continue the gene therapy business of AMT. Effective February 10, 2014, in connection with its initial public offering, the Company converted into a public company with limited liability and changed its legal name from uniQure B.V. to uniQure N.V. The Company is registered with the Dutch Trade Register of the Chamber of Commerce ( handelsregister van de Kamer van Koophandel en Fabrieken ) in Amsterdam, the Netherlands under number 54385229. The Company’s headquarters is in Amsterdam, the Netherlands, and its registered office is located at Paasheuvelweg 25a, Amsterdam 1105 BP, the Netherlands, and its telephone number is +31 20 240 6000.

Effective January 1, 2017, the Company ceased to qualify as a foreign private issuer. Since January 1, 2017, the Company files electronically with the Securities and Exchange Commission (“SEC”) its annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K, and any amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, which is referred to as the Exchange Act. Prior to this time, it filed its annual report on Form 20-F and furnished quarterly financial report as an exhibit on Form 6-K.

The Company’s common stock is listed on the NASDAQ Global Market and trades under the symbol “QURE”.

2 Summary of significant accounting policies

2.1 Basis of preparation

The Company prepared these unaudited condensed consolidated financial statements in compliance with generally accepted accounting principles in the United States of America (“U.S. GAAP”) and applicable rules and regulations of the SEC regarding interim financial reporting. Any reference in these notes to applicable guidance is meant to refer to authoritative U.S. GAAP as found in the Accounting Standards Codification (“ASC”) and Accounting Standards Update (“ASU”) of the Financial Accounting Standards Board (“FASB”).

The unaudited condensed consolidated financial statements are presented in U.S. dollars, except where otherwise indicated. Transactions denominated in currencies other than U.S. dollars are presented in the transaction currency with the U.S. dollar amount included in parenthesis, converted at the foreign exchange rate as of the transaction date.

2.2 Unaudited interim financial information

The accompanying interim condensed financial statements and related disclosures are unaudited, have been prepared on the same basis as the annual financial statements and, in the opinion of management, reflect all adjustments, which include only normal recurring adjustments, necessary for a fair statement of the financial position, results of operations and changes in financial position for the periods presented.

The year-end condensed balance sheet data was derived from audited financial statements, but does not include all disclosures required by U.S. GAAP. Certain information and footnote disclosures normally included in financial statements prepared in accordance with U.S. GAAP have been condensed or omitted. The condensed results of operations for the three months ended March 31, 2017, are not necessarily indicative of the results to be expected for the full year ending December 31, 2017, or for any other future year or interim period. The accompanying condensed financial statements should be read in conjunction with the audited financial statements and the related notes thereto included in the Company’s Annual Report on Form 10-K for the year ended December 31, 2016, filed with the SEC on March 15, 2017.

2.3 Use of estimates

The preparation of the financial statements in conformity with U.S. GAAP requires management to make estimates and assumptions that affect the reported amounts of assets and liabilities, disclosure of

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contingent assets and liabilities at the date of the financial statements and reported amounts of revenues and expenses during the reporting periods. Actual results could differ from those estimates.

2.4 Accounting policies

The principal accounting policies applied in the preparation of these unaudited condensed consolidated financial statements are described in the Company’s audited financial statements as of and for the year ended December 31, 2016, and the notes thereto, which are included in the Company’s Annual Report on Form 10-K for the year ended December 31, 2016, filed with the SEC on March 15, 2017. There have been no material changes in the Company’s significant accounting policies during the three months ended March 31, 2017.

2.5 Recent accounting pronouncements

There have been no new accounting pronouncements or changes to accounting pronouncements during the three months ended March 31, 2017, compared to the recent accounting pronouncements described in Note 2.3.22 of the Company’s Annual Report on Form 10-K for the year ended December 31, 2016, which would be expected to materially impact the Company’s unaudited condensed consolidated financial statements.

3 Fair value measurement

The Company measures certain assets and liabilities at fair value, either upon initial recognition or for subsequent accounting or reporting. U.S. GAAP, requires disclosure of methodologies used in determining the reported fair values, and establishes a hierarchy of inputs used when available. The three levels of the fair value hierarchy are described below:

· Level 1 - Valuations based on unadjusted quoted prices in active markets for identical assets or liabilities that the Company has the ability to access at the measurement date.

· Level 2 - Valuations based on quoted prices for similar assets or liabilities in markets that are not active or models for which the inputs are observable, either directly or indirectly.

· Level 3 - Valuations that require inputs that reflect the Company’s own assumptions that are both significant to the fair value measurement and are unobservable.

To the extent that valuation is based on models or inputs that are less observable or unobservable in the market, the determination of fair value requires more judgment. Accordingly, the degree of judgment exercised by the Company in determining fair value is greatest for instruments categorized as Level 3. A financial instrument’s level within the fair value hierarchy is based on the lowest level of any input that is significant to the fair value measurement.

Items measured at fair value on a recurring basis include financial instruments and contingent consideration (note 3, “Fair value measurement”). The carrying amount of cash and cash equivalents, accounts receivable from collaborators, prepaid expenses, other assets, accounts payable, accrued expenses and other current liabilities reflected in the consolidated balance sheets approximate their fair values due to their short-term maturities.

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The following table sets forth the Company’s assets and liabilities that are required to be measured at fair value on a recurring basis as of March 31, 2017, and December 31, 2016:

	Quoted prices in active markets (Level 1)		Significant other observable inputs (Level 2)		Significant unobservable inputs (Level 3)		Total		Classification in consolidated balance sheets
	in thousands
At December 31, 2016
Assets:
Cash and cash equivalents	$	132,496	$	—	$	—	$	132,496
Total assets	132,496		—		—		132,496
Liabilities:
Derivative financial instruments - debt	—		—		11		11		Accrued expenses and other current liabilities
Derivative financial instruments - related party	—		—		51		51		Other non-current liabilities
Contingent consideration	—		—		1,838		1,838
Total liabilities	$	—	$	—	1,900		$	1,900
At March 31, 2017
Assets:
Cash and cash equivalents	$	120,271	$	—	$	—	$	120,271
Total assets	120,271		—		—		120,271
Liabilities:
Derivative financial instruments - debt	—		—		2		2		Accrued expenses and other current liabilities
Derivative financial instruments - related party	—		—		32		32		Other non-current liabilities
Contingent consideration	—		—		1,989		1,989
Total liabilities	$	—	$	—	$	2,023	$	2,023

Changes in Level 3 items during the three months ended March 31, 2017, and 2016, are as follows:

	Contingent consideration		Derivative financial instruments			Total
	in thousands
Balance at December 31, 2015	$	2,926	$	837		$	3,763
(Gains) / losses recognized in profit or loss	60		(317		)	(257		)
Currency translation effects	127		30			157
Balance at March 31, 2016	$	3,113	$	550		$	3,663

	Contingent consideration		Derivative financial instruments			Total
	in thousands
Balance at December 31, 2016	$	1,838	$	62		$	1,900
(Gains) / losses recognized in profit or loss	124		(29		)	95
Currency translation effects	27		1			28
Balance at March 31, 2017	$	1,989	$	34		$	2,023

Contingent consideration

In connection with the Company’s acquisition of InoCard GmbH in 2014, the Company recorded a contingent consideration related to amounts potentially payable to InoCard’s former shareholders. The amounts payable are contingent upon realization of the following milestones:

· Successful completion of GLP safety and toxicology study;

· First patient dosed in a clinical study; and

· Full proof-of-concept of the product in human patients after finalization of a phase I/II study.

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The valuation of the contingent liability is based on significant inputs not observable in the market such as the probability of success (“POS”) of achieving certain research milestones (estimated as probable for the first two milestones as of the balance sheet date), the time at which the research milestones are expected to be achieved (ranging from 2018 to 2021), as well as the 30% discount rate applied, which represents a Level 3 measurement. Varying, next to the passing of time, the unobservable inputs results in the following fair value changes:

	March 31,			December 31,
	2017			2016
	in thousands
Change in fair value
Moving out of all milestones by 6 months	$	(226	)	$	(209	)
Increasing the POS for the first milestone by 20%	398			367
Decreasing the POS for the first milestone by 20%	(398		)	(367		)
Reducing the discount rate from 30% to 20%	636			638
Increasing the discount rate from 30% to 40%	(305		)	(309		)

Derivative financial instruments

The Company issued derivative financial instruments related to its collaboration with Bristol-Meyers Squibb Company (“BMS”) and in relation to the issuance of the Hercules Technology Growth Corp. (“Hercules”) loan facility. The fair value of these derivative financial instruments as of March 31, 2017, was $0.0 million (December 31, 2016: $0.1 million), both of which are described in more details below.

There were no significant changes in (un)observable inputs, nor in the sensitivity of the fair value from (un)observable inputs as at March 31, 2017, compared to December 31, 2016.

BMS collaboration

On April 6, 2015, the Company entered into a number of agreements with BMS (the “BMS Agreements”). Pursuant to the terms of the BMS Agreements the Company granted BMS two warrants:

· A warrant allowing BMS to purchase a specific number of uniQure common shares such that its ownership will equal 14.9% immediately after such purchase. The warrant can be exercised on the later of (i) the date on which the Company receives from BMS the Target Designation Fees (as defined in the collaboration agreements) associated with the first six New Targets (as defined in the collaboration agreements); and (ii) the date on which BMS designates the sixth New Target.

· A warrant allowing BMS to purchase a specific number of uniQure common shares such that its ownership will equal 19.9% immediately after such purchase. The warrant can be exercised on the later of (i) the date on which uniQure receives from BMS the Target Designation Fees associated with the first nine New Targets; and (ii) the date on which BMS designates the ninth New Target.

Pursuant to the terms of the BMS Agreements the exercise price, in respect of each warrant, is equal to the greater of (i) the product of (A) $33.84, multiplied by (B) a compounded annual growth rate of 10% and (ii) the product of (A) 1.10 multiplied by (B) the VWAP for the 20 trading days ending on the date that is five trading days prior to the date of a notice of exercise delivered by BMS.

Hercules loan facility

On June 14, 2013, the Company entered into a venture debt loan facility with (the “Original Facility”) with Hercules Technology Growth Capital, Inc. (“Hercules”) pursuant to a Loan and Security Agreement (the “Loan Agreement”) which included a warrant. The warrant was not closely related to the host contract and was accounted for separately as a derivative financial liability measured at fair value though profit or loss. The warrant included in the Original Facility remained in place following the 2014 and 2016 amendments of the loan.

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4 Collaboration arrangements and concentration of credit risk

The Company generates all of its collaboration and license revenues from its Collaboration and License Agreement with BMS, its Co-Development Agreement for AMT-060 with Chiesi Farmaceutici S.p.A. (“Chiesi”) and its Glybera Commercialization Agreement with Chiesi. The Company agreed to terminate the Glybera Commercialization Agreement. See note 14 for additional information regarding the termination of this agreement.

Since June 2015, BMS has been considered a related party given the significance of its equity investment in the Company (exceeding 5%).

Services to the Company’s two collaboration partners are rendered by the Dutch operating entity. Total collaboration and license revenue generated from these partners are as follows:

	Three months ended March 31,
	2017		2016
	in thousands
Bristol Myers Squibb	$	1,507	$	2,628
Chiesi Farmaceutici S.p.A	1,814		1,667
Total	$	3,321	$	4,295

Amounts owed by these partners in relation to the collaboration are as follows:

	March 31,		December 31,
	2017		2016
	in thousands
Bristol Myers Squibb	$	517	$	5,500
Chiesi Farmaceutici S.p.A	1,233		3,680
Total	$	1,750	$	9,180

BMS collaboration

In May 2015, the Company closed a Collaboration and License Agreement with BMS (the “BMS Collaboration Agreement”) that provides exclusive access to the Company’s gene therapy technology platform for multiple targets in cardiovascular (and other) diseases. The collaboration included the Company’s proprietary gene therapy program for congestive heart failure which aims to restore the heart’s ability to synthesize S100A1, a calcium sensor and master regulator of heart function, and thereby improve clinical outcomes for patients with reduced ejection fraction. Beyond cardiovascular diseases, the agreement also included the potential for a target exclusive collaboration in other disease areas. In total, the companies may collaborate on ten targets, including S100A1.

The Company is leading the discovery, non-clinical, analytical and process development effort and is responsible for manufacturing of clinical and commercial supplies using the Company’s vector technologies and industrial, proprietary insect-cell based manufacturing platform, while BMS leads the clinical development and regulatory activities across all programs and reimburses the Company for all research and development efforts. BMS will be solely responsible for commercialization of all products from the collaboration.

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The Company evaluated the BMS Collaboration Agreement and determined that it is a revenue arrangement with multiple elements. The Company’s substantive deliverables under the BMS Collaboration Agreement include an exclusive license to its technology in the field of cardiovascular disease, research and development services for specific targets chosen by BMS and general development of the Company’s proprietary vector technology, participation in the Joint Steering Committee, and clinical and commercial manufacturing. The Company concluded that the BMS Collaboration Agreement consists of three units of accounting, including (i) technology (license and target selections), know-how and manufacturing in the field of gene therapy and development and active contribution to the development through the Joint Steering Committee participations, (ii) provision of employees, goods and services for research activities for specific targets and (iii) clinical and commercial manufacturing. The Company determined that the license does not have stand-alone value to BMS without the Company’s know-how and manufacturing technology through the participation of the Joint Steering Committee and accordingly, they were combined into one unit of accounting.

License revenue — BMS

As of May 21, 2015, the effective date of the BMS Collaboration Agreement, the Company recorded deferred revenue of $60.1 million. On July 31, 2015, BMS selected the second, third and fourth collaboration targets, triggering a $15.0 million target designation payment to the Company. The Company is entitled to $16.5 million in aggregate of target designation payments upon selection of the fifth through tenth collaboration target. The Company will also be eligible to receive research, development and regulatory milestone payments of up to $254.0 million for the first target and up to $217.0 million for the other selected targets if and when achieved. The Company determined that the contingent payments under the BMS Collaboration Agreement relating to research, development and regulatory milestones do not constitute substantive milestones and will not be accounted for under the milestone method of revenue recognition. The events leading to these payments solely depend on BMS’ performance. Accordingly, any revenue from these contingent payments would be allocated to the first unit of accounting noted above and recognized over the expected performance period.

License revenue is recognized over an expected performance period of 19 years on a straight-line basis commencing on May 21, 2015. The expected performance period is reviewed quarterly and adjusted to account for changes, if any, in the Company´s estimated performance period. The estimated performance period did not change in the three months ended March 31, 2017.

The Company recognized $0.9 million license revenue for the three months ended March 31, 2017, and $1.0 million in the same period 2016.

Additionally, the Company is eligible to receive net sales-based milestone payments and tiered high single to low double-digit royalties on product sales. These revenues will be recognized when earned. The royalty term is determined on a licensed-product-by-licensed-product and country-by-country basis and begins on the first commercial sale of a licensed product in a country and ends on the expiration of the last to expire of specified patents or regulatory exclusivity covering such licensed product in such country or, with a customary royalty reduction, ten years after such first commercial sale if there is no such exclusivity.

Collaboration revenue — BMS

The Company provides target-specific research and development services to BMS. Collaboration revenue related to these contracted services is recognized when earned.

The Company generated $0.6 million collaboration revenue for the three months ended March 31, 2017, and $1.7 million in the same period 2016.

Manufacturing revenue — BMS

BMS and the Company also entered into a term sheet for the Company to supply gene therapy products during the clinical and commercial phase to BMS. Revenues from product sales will be recognized when earned. To date the Company has not supplied any commercial product to BMS.

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Chiesi collaboration

In 2013, the Company entered into two agreements with Chiesi, a family-owned Italian pharmaceutical company, one for the co-development and commercialization of the AMT-060 program (the “Collaboration Agreement”) and one for the commercialization of Glybera (the “Glybera Agreement”, and together with the Collaboration Agreement, the “Chiesi Agreements”). The Company has retained full rights in the United States, Canada and Japan under the Chiesi Agreements. The Company evaluated the Chiesi Agreements and determined that they are a revenue arrangement with multiple elements. The Company’s substantive deliverables under the Chiesi Agreements include an exclusive license to its technology, research and development services, and commercial manufacturing. The Company concluded that the Chiesi Agreements consists of three units of accounting, including (i) co-development and active contribution to the collaboration by providing technology access and know-how in the field of gene therapy, (ii) provision of employees, goods and services for research and development activities and (iii) commercial manufacturing.

License revenue — Chiesi

Upon closing of the Chiesi Agreements on June 30, 2013, the Company received €17.0 million ($22.1 million) in non-refundable up-front payments. The Company determined that the up-front payments received from Chiesi constituted a single unit of accounting. The up-front payments are amortized on a straight-line basis and presented as license revenue over a period from July 2013, through September 2032, the date of expiration of the last intellectual property protection related to the Company’s manufacturing process at such date.

The Company recognized $0.2 million license revenue for the three months ended March 31, 2017, and $0.2 million in the same period 2016.

Collaboration revenue — Chiesi

Chiesi reimburses the Company for 50% of the agreed research and development efforts related to AMT-060, which is presented as collaboration revenue. Once regulatory approval has been obtained, Chiesi will distribute AMT-060 and the Company is entitled to receive a fixed mid double digit royalty as a percentage of Chiesi sales. The Company estimates that the amount it would retain, net of manufacturing costs, third-party royalties and related amounts, will be between 25% and 35% of the revenues from sales realized by Chiesi, varying by country of sale.

The Company generated $1.6 million collaboration revenue for the three months ended March 31, 2017, and $1.4 million in the same period 2016 from the co-development of AMT-060.

Manufacturing revenue — Chiesi

Pursuant to the Glybera Agreement, the Company to supply Glybera to Chiesi. Revenues from product sales, presented as collaboration revenue, will be recognized when earned. In the three months ended March 31, 2017, the Company recognized no revenue from product sales to Chiesi and nil in the same period 2016.

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5 Property, plant and equipment

The following table presents the Company’s property, plant and equipment as of March 31, 2017, and December 31, 2016:

	March 31,			December 31,
	2017			2016
	in thousands
Leasehold improvements	$	31,286		$	30,582
Laboratory equipment	14,817			14,166
Office equipment	2,733			2,710
Construction-in-progress	140			313
Total property, plant, and equipment	48,976			47,771
Less accumulated depreciation	(13,735		)	(12,069		)
Property, plant and equipment, net	$	35,241		$	35,702

Total depreciation expense of $1.7 million for the three months ended March 31, 2017, and $1.4 million in the same period 2016 was charged to research and development expense to the extent it relates to the Company’s manufacturing facility and equipment, and the remainder was charged to selling, general and administrative expense.

6 Intangible assets

The Company’s intangible assets include acquired licenses and acquired research and development (“acquired R&D”) and are presented in the following table:

	March 31,			December 31,
	2017			2016
	in thousands
Licenses	$	7,910		$	7,799
Acquired research & development	4,977			4,908
Total intangible assets	12,887			12,707
Less accumulated amortization	(4,530		)	(4,383		)
Intangible assets, net	$	8,357		$	8,324

The amortization expense of $0.1 million for the three months ended March 31, 2017, and $0.1 million in the same period 2016 is included in research and development expenses.

7 Accrued expenses and other current liabilities

Accrued expenses and other current liabilities include the following items:

	March 31,		December 31,
	2017		2016
	in thousands
Accruals for services provided by vendors-not yet billed	$	3,775	$	4,150
Personnel related accruals	2,247		4,381
Social security and other taxes	1,102		1,178
Other current liabilities	30		57
Total	$	7,154	$	9,766

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In November 2016, the Company announced a plan to restructure its activities as a result of a company-wide strategic review with the aim of refocusing its pipeline, consolidating its manufacturing capabilities into its Lexington, Massachusetts site, reducing operating costs and enhancing overall execution. Following the announcement of the plan, the Company recognized an accrual for termination benefits contractually agreed with four executives of $1.1 million. In January 2017, the Company entered into termination agreements with certain non-executive employees and recognized related termination costs of $0.5 million for services rendered by these employees during 2017. The change in the accrual of termination benefits (recognized within research and development expenses) for the three months ended March 31, 2017 was:

	Accrued termination benefits
	in thousands
Balance at December 31, 2016	$	1,148
Accrued through profit and loss	241
Payments	(977		)
Currency translation effects	6
Balance at March 31, 2017	$	418

8 Long-term debt

On June 14, 2013, the Company entered into a venture debt loan facility with Hercules, which was amended and restated on June 26, 2014, and again on May 6, 2016 (“2016 Amended Facility”). The 2016 Amended Facility increased the total potential commitment from Hercules from $20.0 million to up to $40.0 million, of which $20.0 million was outstanding as of March 31, 2017, and December 31, 2016, and extended the maturity date from June 30, 2018, to May 1, 2020. The Company has not drawn down any additional amounts as of March 31, 2017, following the May 2016 amendment. The interest rate is adjustable and is the greater of (i) 8.25% or (ii) 8.25% plus the prime rate less 5.25%. Under the 2016 Amended Facility, the interest rate will initially be 8.25% per annum with a back-end fee of 4.85% and facility fee of 0.75% of the outstanding loan amounts. The interest-only payment period is set at November 2017, but can be extended to May 2018 upon the Company raising a cumulative $30.0 million in up-front corporate payments and/or proceeds from equity financings (“Raisings”), and further extended to November 2018 upon the Company raising a cumulative $50.0 million from the Raisings.

The amortized cost of the 2016 Amended Loan as of March 31, 2017, was $20.4 million and $20.2 million as of December 31, 2016, and is recorded net of discount and debt issuance costs. The foreign currency gain on the loan in the three months ended March 31, 2017, was $0.3 million and a gain of $0.9 million in the same period 2016. The fair value of the loan approximates its carrying amount, given the impact of discounting is insignificant as the loan is amortized at a market conforming interest rate.

In the three months ended March 31, 2017, an amount of $0.5 million and $0.6 million in the same period 2016 was recorded as interest expense in relation to the 2016 Amended Facility.

As a covenant in the 2016 Amended Facility, the Company has periodic reporting requirements and is required to keep a minimum cash balance deposited in bank accounts in the United States, equivalent to the lesser of the outstanding balance of principal due and 50% of worldwide cash reserves. This restriction on the cash reserves only relates to the location of the cash reserves, and such cash reserves can be used at the discretion of the Company. In combination with other convents, the 2016 Amended Facility restricts the Company’s ability to, among other things, incur future indebtedness and obtain additional debt financing, to make investments in securities or in other companies, to transfer assets, to perform certain corporate changes, to make loans to employees, officers and directors, and to make dividend payments and other distributions. The Company secured the facilities by pledging the shares in its subsidiaries, substantially all its receivables, moveable assets as well as the equipment, fixtures, inventory and cash of uniQure Inc.

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9 Share-based compensation

The Company recognized share-based compensation expense totaling $1.6 million and $2.6 million during the three months ended March 31, 2017, and 2016, respectively.

Share-based compensation expense recognized by classification included in the consolidated statements of operations and comprehensive loss was as follows:

	Three months ended March 31,
	2017		2016
	in thousands
Research and development - employees	$	687	$	859
Selling, general and administrative - employees	918		1,119
Research and development - non-employees	—		670
Total	$	1,605	$	2,648

Share-based compensation expense recognized by award type was as follows:

	Three months ended March 31,
	2017		2016
	in thousands
Award type
Share options	$	826	$	2,384
Restricted share units (“RSUs”)	516		152
Performance share units (“PSUs”)	263		112
Total	$	1,605	$	2,648

As of March 31, 2017, the unrecognized compensation costs related to unvested awards under the various share-based compensation plans were:

	Unrecognized compensation costs		Weighted-average remaining period for recognition (in years)
	in thousands
Award type
Stock options	$	8,324	2.85
Restricted stock units	3,369		2.22
Performance stock units	2,703		2.60
Total	$	14,396	2.66

The Company satisfies the exercise of share options and vesting of RSUs and PSUs through newly issued shares.

The Company’s share-based compensation plans include the 2014 Amended and Restated Share Option Plan (the “2014 Plan”) and inducement grants under Rule 5653(c)(4) of the NASDAQ Global Market with characteristics similar to the 2014 Plan (classified as “Other Plans”). The Company previously had a 2012 Equity Incentive Plan (the “2012 Plan”) and issued options to purchase common shares to the shareholders of 4D in connection with a collaboration and license agreement between the Company and 4D dated as of January 2014 (classified as Other Plans).

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2012 Plan

The following table summarizes option activity under the Company’s 2012 Plan for the three months ended March 31, 2017:

	2012 Plan
	Options		Weighted average exercise price

Outstanding at December 31, 2016	483,006		€	5.13
Exercised	(134,974	)	€	3.07
Outstanding, fully vested and exercisable at March 31, 2017	348,032		€	5.92

Options exercised during the three months ended March 31, 2017, resulted in total proceeds to the Company of $0.4 million.

2014 Plan

Share options

The following table summarizes option activity under the Company’s 2014 Plan for the three months ended March 31, 2017:

	2014 plan
	Options		Weighted average exercise price

Outstanding at December 31, 2016	1,812,766		$	12.47
Granted	508,500		$	5.63
Forfeited	(40,371	)	$	12.76
Expired	(12,952	)	$	18.30
Outstanding at March 31, 2017	2,267,943		$	10.90
Fully vested and exercisable	746,557		$	13.01
Outstanding and expected to vest	1,521,386		$	9.86

During the three months ended March 31, 2017, the Company granted options to purchase an aggregate of 508,500 common shares with an aggregate weighted average grant date fair value of $1.6 million. This included an option to purchase 175,000 options common shares the Company granted to its Chief Executive Officer and options to purchase an aggregate 69,000 common shares that the Company granted to its non-executive directors, each such option vesting after one year from the date of grant.

The fair value of each option issued was estimated at the date of grant using the Hull & White option pricing model with the following weighted-average assumptions:

	Three months ended March 31,
	2017	2016
Assumptions
Expected volatility	75%	75%
Expected terms (in years)	10 years	10 years
Risk free interest rate	2.53% - 2.70%	0.16% - 0.54%
Expected dividends	0%	0%

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Restricted Share Units (RSUs)

The following table summarizes the RSUs activity for the three months ended March 31, 2017:

	Number of shares		Weighted average grant-date fair value
Undistributed at December 31, 2016	307,063		$	9.11
Granted	285,500		$	5.95
Distributed	(25,000	)	$	18.21
Forfeited	(375	)	$	13.03
Undistributed at March 31, 2017	567,188		$	7.12

During the three months ended March 31, 2017, the Company granted an aggregate of 285,500 RSUs with an aggregate weighted average grant date fair value of $1.7 million. The grants include 69,000 RSUs granted to non-executive directors, each such grant to vest after one year, and 175,000 RSUs granted to the Company’s Chief Executive Officer, which vest in equal tranches on February 21, 2018, and February 21, 2019.

During the three months ended March 31, 2017, the Company distributed 25,000 common shares in connection with the settlement of vested RSUs.

Performance Share Units (PSUs)

The following table summarizes the PSUs activity for the three months ended March 31, 2017:

	Number of shares		Weighted average grant-date fair value
Undistributed at December 31, 2016	111,564		$	5.76
Distributed	(58,500	)	$	5.76
Undistributed at March 31, 2017	53,064		$	5.76

In January 2017, the Company awarded an aggregate of 423,500 PSUs to members of its senior management, including 162,500 PSUs to its Chief Executive Officer. As awarding these PSUs is discretionary based on the Board’s assessment of 2017 performance, these PSUs are not recorded in the above table.

In September 2016, the Company awarded 61,560 PSUs to its Chief Executive Officer, subject to the successful implementation of the strategic plan. As awarding thee PSUs is discretionary based on the Board’s assessment of the Chief Executive Officer’s 2017 performance, these PSUs are also not recorded in the above table.

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Other Plans

The following table summarizes option activity under the Company’s Other Plans for the three months March 31, 2017:

	Other plans
	Options	Weighted average exercise price

Outstanding at December 31, 2016	187,500	$	17.93
Granted	150,000	$	5.31
Outstanding at March 31, 2017	337,500	$	12.32
Fully vested and exercisable	62,500	$	27.82
Outstanding and expected to vest	275,000	$	8.80

Under Rule 5653(c)(4) of the NASDAQ Global Market, the Company grants share options to certain employees as a material inducement to enter into employment with the Company. During the three months ended March 31, 2017, the Company granted 150,000 options with an aggregate weighted average grant date fair value of $0.5 million. No options were exercised during the three months ended March 31, 2017.

The fair value of the inducement grant options was estimated at the date of grant using the Hull & White option pricing model with the same assumptions as used in determining the fair value of options issued under the 2014 Plan.

10 Income taxes

Deferred tax assets and deferred tax liabilities are recognized based on the expected future tax consequences temporary differences between the financial statement carrying amounts and the income tax basis of assets and liabilities, using current statutory rates. A valuation allowance is recorded against deferred tax assets if it is more likely than not that some or all of the deferred tax assets will not be realized. Due to the uncertainty surrounding the realization of the favorable tax attributes in future tax returns, the Company has recorded a full valuation allowance against the Company’s otherwise recognizable net deferred tax assets.

11 Basic and diluted earnings per share

Diluted earnings per share is calculated by adjusting the weighted average number of common shares outstanding, assuming conversion of all potentially dilutive common shares. As the Company has incurred a loss, all potentially dilutive common shares would have an antidilutive effect, if converted, and thus have been excluded from the computation of loss per share.

	March 31,	March 31,
	2017	2016
	common shares
BMS warrants	3,587,333	3,442,655
Warrants	37,175	37,175
Stock options under 2012 Plan	348,032	964,155
Stock options under 2014 Plan	2,267,943	1,567,236
Stock options (other)	337,500	1,000,000
RSUs and PSUs	620,252	195,940
Total potential dilutive common shares	7,198,235	7,207,161

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12 Leases

The Company leases various office space and laboratory space under operating lease agreements, expiring at various dates through 2032. These leases are described in more detail below.

Rent expense for the three months ended March 31, 2017, was $1.0 million and $0.8 million in the same period 2016. Rent expense is calculated on a straight-line basis over the term of the leases, and takes into account $11.8 million of lease incentives received.

Aggregate minimum lease payments for the calendar years ending December 31, 2017, 2018, 2019, 2020 and 2021 and beyond at March 31, 2017 were as follows:

	in thousands
2017 (nine months remaining)	$	1,746
2018	4,132
2019	3,675
2020	3,729
2021 and beyond	26,400
Total minimum lease payments	$	39,682

Lexington, Massachusetts

In July 2013, uniQure entered into a lease for a facility in Lexington, Massachusetts, United States. The term of the lease commenced in November 2013 and was set for 10 years and is non-cancellable. The lease for this facility terminates in 2024, and subject to the provisions of the lease, may be renewed for two subsequent five-year terms. The Company expects to complete the qualification of its approximately 53,000 square feet manufacturing facility in 2017. The future aggregate minimum lease payments under the non-cancellable term of the lease amount to $14.0 million. As of March 31, 2017, the Company recorded a total deferred rent of $6.1 million (December 31, 2016: $6.2 million), with a current element of $0.7 million (December 31, 2016: $0.7 million) related to lease incentives received. The lease provides for annual minimum increases in rent, based on a consumer price index.

Paasheuvelweg, Amsterdam

In March 2016, the Company entered into a 16-year lease for a facility in Amsterdam, the Netherlands, and amended this agreement in June 2016. The Company expects to consolidate its three Amsterdam sites into the new site by the end of May 2017. The lease for this facility terminates in 2032, with an option to extend for further periods of five years. Following the completion of its restructuring by the end of 2017, the Company will seek to sublease parts of the facility. The future aggregate minimum lease payments under the non-cancellable term of the lease amount to $24.8 million. The lease contract provides for annual minimum increases in rent, based on a consumer price index.

Meibergdreef, Amsterdam

In April 2015, uniQure entered into a lease with Jan Snel B.V. for a laboratory facility of approximately 9,300 square feet, located at the Meibergdreef in Amsterdam, the Netherlands. The minimum lease period terminates in September 2018. The future aggregate minimum lease payments under the non-cancellable term of the lease amount to $0.9 million.

13 Other commitments

The Company’s predecessor entity received a technical development loan from the Dutch government in relation to the development of Glybera. The Company is required to repay the grant through a percentage of revenue derived from product sales of Glybera up to December 31, 2019. Any grant balance remaining at this date will be forgiven. The Company decided not to renew its marketing authorization for Glybera in the European Union, which expires on October 25, 2017. The Company does not expect to derive any revenue from Glybera after that time.

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14 Subsequent event

On April 20, 2017, the Company announced that it will not pursue the renewal of the Glybera® (alipogene tiparvovec) marketing authorization in Europe when it is scheduled to expire on October 25, 2017. The Company will continue to supply product to Chiesi to treat any patients that are approved for treatment prior to October 25, 2017, and will be responsible for terminating the Phase IV post-approval study. According to the termination agreement executed in April 2017, the Company will be required to make installment payments to Chiesi totaling $2.2 million through January 2019. Additionally, the Company may owe up to an additional $1.8 million depending on the number of patients treated with Glybera prior to its withdrawal, if any. Any such payments related to additional patients treated will be payable no earlier than April 1, 2019, in accordance with a schedule to be agreed upon by the parties.

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Item 2. Management’s Discussion and Analysis of Financial Condition and Results of Operations

The following Management’s Discussion and Analysis of Financial Condition and Results of Operations (“MD&A”) is intended to help the reader understand our results of operations and financial condition. This MD&A is provided as a supplement to, and should be read in conjunction with, our unaudited condensed consolidated financial statements and the accompanying notes thereto and other disclosures included in this Quarterly Report on Form 10-Q, including the disclosures under Part II, Item 1A “Risk Factors”, and our audited financial information and the notes thereto included in our Annual Report on Form 10-K for the year ended December 31, 2016, which was filed with the Securities and Exchange Commission, or the SEC, on March 15, 2017. Our unaudited condensed consolidated financial statements have been prepared in accordance with generally accepted accounting principles in the US (“U.S. GAAP”) and unless otherwise indicated are presented in U.S. dollars.

Overview

We are a leader in the field of gene therapy, seeking to develop single treatments with potentially curative results for patients suffering from genetic and other devastating diseases. We are advancing a focused pipeline of innovative gene therapies that have been developed both internally and through partnerships, such as our collaboration with Bristol Myers-Squibb focused on cardiovascular diseases. We have established clinical proof-of-concept in our lead indication, hemophilia B, and achieved preclinical proof-of-concept in Huntington’s disease. We believe our validated technology platform and manufacturing capabilities provide us distinct competitive advantages, including the potential to reduce development risk, cost and time to market. We produce our AAV-based gene therapies in our own facilities with a proprietary, commercial-scale, consistent, manufacturing process. We believe our Lexington, Massachusetts-based facility is one of the world’s leading, most versatile, gene therapy manufacturing facilities.

Business Developments

Below is a summary of our significant business developments in the three months ended March 31, 2017:

· On January 25, 2017, we appointed Dr. Alexander Kuta as our Senior Vice President of regulatory affairs.

· On January 30, 2017, we received breakthrough therapy designation from the Food and Drug Administration (“FDA”) for our AMT-060 program in hemophilia B. The designation was based on results from the ongoing, dose-ranging Phase I/II study that show sustained increases in Factor IX (FIX), reductions in FIX replacement usage and a near cessation of spontaneous bleeding in patients with severe disease at up to 12 months follow-up. During the first quarter of 2017, the Company initiated discussions with the FDA regarding the data from its ongoing Phase I/II study and the design of a potential pivotal study.

· On March 3, 2017, our Lexington, Massachusetts gene therapy manufacturing facility was recognized by Frost & Sullivan as a 2017 Manufacturing Leadership Awards winner for outstanding achievement in Engineering & Production Technology Leadership. Our Lexington-based facility is one of the largest, most versatile gene therapy manufacturing facilities in the world. Over the past four years, we have invested more than $25 million in designing, constructing and equipping our 55,000 square foot facility with state-of-the-art laboratories and commercial-scale production capabilities. The facility offers 500-liter capacity with the ability to expand to up to 2,000 liters when needed.

· On April 4, 2017, we published data demonstrating widespread transduction in the central nervous system following direct injection of our AAV5 vector in a large animal model. The method of injection used was found to result in a controlled and accurate administration with no adverse events observed in non-human primates. Varying doses of AAV5 achieved predictable transduction of connected areas of the brain. The data demonstrate that AAV5 is an effective vector for the central nervous system and has potential for the treatment of a wide range of neurological pathologies. These data will help guide the clinical development of our gene therapy product candidate AMT-130, which consists of an AAV5 vector carrying an artificial micro-RNA that silences the huntingtin gene for the treatment of Huntington’s disease.

· On April 20, 2017, we announced that it will not pursue the renewal of the Glybera® (alipogene tiparvovec) marketing authorization in Europe when it is scheduled to expire on October 25, 2017.

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We will continue to supply product to Chiesi to treat any patients that are approved for treatment prior to October 25, 2017, and will be responsible for terminating the Phase IV post-approval study. According to the termination agreement executed in April 2017, we will be required to make installment payments to Chiesi totaling $2.2 million through January 2019. Additionally, we may owe up to an additional $1.8 million depending on the number of patients treated with Glybera prior to its withdrawal, if any. Any such payments related to additional patients treated will be payable no earlier than April 1, 2019, in accordance with a schedule to be agreed upon by the parties. As a result of the withdrawal of Glybera, we expect to reduce future expenses related to the product by approximately $10 million through 2021.

Financial Operations Overview

Key components of our results of operations include the following:

	Three months ended March 31,
	2017			2016
	in thousands
Total revenues	$	3,321		$	4,295
Research and development expenses	(16,994		)	(16,706		)
Selling, general and administrative expenses	(6,358		)	(7,298		)
Net loss	(20,272		)	(22,299		)

As of March 31, 2017, we had cash and cash equivalents of $120.3 million and $132.5 million as of December 31, 2016. We had a net loss of $20.3 million in the three months ended March 31, 2017, and $22.3 million for the same period in 2016. As of March 31, 2017, and December 31, 2016, we had accumulated deficits of $416.3 million and $396.1 million, respectively. We anticipate that our expenses will increase in the future as we:

· Advance our hemophilia B program, in collaboration with Chiesi, towards late-stage clinical development;

· Continue non-clinical and preclinical studies that are expected to support an IND filing for the S100A1 gene therapy program for the treatment of congestive heart failure, which is currently being developed with BMS;

· Continue IND-enabling studies for our proprietary Huntington’s disease gene therapy program and initiate a proof-of-concept clinical study;

· Advance multiple research programs related to gene therapy candidates targeting liver-directed and CNS disorders;

· Continue to enhance and optimize our technology platform, including our manufacturing capabilities, next-generation viral vectors and promoters, and other enabling technologies;

· Implement our strategic restructuring, including costs associated with consolidation of our manufacturing capabilities into our Lexington site and the termination or retention of certain employees;

· seek marketing approval for any product candidates that successfully complete clinical trials;

· acquire or in-license rights to new therapeutic targets or product candidates;

· enter into collaboration agreements with third parties to research, develop and/or manufacture potential product candidates;

· maintain, expand and protect our intellectual property portfolio, including in-licensing additional intellectual property rights from third parties;

· build-out our clinical, medical and regulatory capabilities in the U.S; and

· appoint additional executives, including a Chief Financial Officer and Chief Operating Officer.

See “Results of Operations” below for a discussion of the detailed components and analysis of the amounts above.

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Restructuring

Following the completion of our strategic review in November 2016, we announced a strategic restructuring plan aimed at refocusing our pipeline, consolidating our manufacturing operations and enhancing overall execution to drive shareholder value. As part of our plan, we intend to eliminate between 50 and 55 positions. In 2016, we accrued $1.1 million related to termination benefits offered to executive employees, expected to be paid in 2017. We also entered into termination agreements with non-executive employees in January 2017, for which the related termination benefits of $0.5 million in the aggregate will be recognized over the relevant remaining service period during 2017. These changes are expected to reduce annual operating expenses by $5.0 to $6.0 million from 2018 onwards.

Following our April 2017 decision not to seek extension of our European marketing authorization for Glybera after its expiration in October 2017, we will eliminate an additional 7 positions required for Glybera’s manufacturing at our Amsterdam site. We expect to incur additional termination costs of $0.3 million in 2017.

Critical Accounting Policies and Estimates

In preparing our consolidated financial statements in accordance with U.S. GAAP and pursuant to the rules and regulations promulgated by the Securities and Exchange Commission (“SEC”) we make assumptions, judgments and estimates that can have a significant impact on our net income/loss and affect the reported amounts of certain assets, liabilities, revenue and expenses, and related disclosures. On an ongoing basis, we evaluate our estimates and judgments, including those related to the BMS collaboration agreement, share-based payments, contingent consideration, valuation of derivative financial instruments, and research and development expenses. We base our estimates on historical experience, known trends and events and various other factors that are believed to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values of assets and liabilities that are not readily apparent from other sources. Actual results may differ from these estimates under different assumptions or conditions. In making estimates and judgments, management employs critical accounting policies. During the three months ended March 31, 2017, there were no material changes to our critical accounting policies as reported in our Annual Report on Form 10-K for the year ended December 31, 2016, which was filed with the SEC on March 15, 2017.

Results of Operations for the Three Months Ended March 31, 2017

The following table presents a comparison of the three months ended March 31, 2017, and 2016.

	Three months ended March 31,
	2017			2016			2017 vs 2016
	in thousands
Total revenues	$	3,321		$	4,295		$	(974	)
Operating expenses:
Research and development expenses	(16,994		)	(16,706		)	(288		)
Selling, general and administrative expenses	(6,358		)	(7,298		)	940
Total operating expenses	(23,352		)	(24,004		)	652
Other income	316			445			(129		)
Loss from operations	(19,715		)	(19,264		)	(451		)
Other non-operating items, net	(557		)	(2,478		)	1,921
Loss before income tax benefit / (expense)	(20,272		)	(21,742		)	1,470
Income tax benefit / (expense)	—			(557		)	557
Net loss	$	(20,272	)	$	(22,299	)	$	2,027

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Revenues

We recognize total collaboration revenues associated with development activities that are reimbursable by Chiesi and BMS under our respective collaboration agreements.

We recognize license revenues associated with the amortization of the non-refundable upfront payment, target designation fees and research and development milestone payments we received or might receive from Chiesi and BMS. The timing of these cash payments may differ from the recognition of revenue, as revenue is deferred and recognized over the duration of the performance period. We treat other revenue, such as sales milestone payments or service fees, as earned when receivable.

Our revenue for the three months ended March 31, 2017, and 2016 was as follows:

	Three months ended March 31,
	2017		2016		2017 vs 2016
	in thousands
License revenue	$	1,183	$	1,219	$	(36	)
Collaboration revenue Chiesi	1,580		1,426		154
Collaboration revenue BMS	558		1,650		(1,092		)
Total revenues	$	3,321	$	4,295	$	(974	)

We expect to continue to recognize $1.0 million in license revenue each quarter from upfront payments and target designation fees received from BMS in the second and third quarters of 2015. We also continue to recognize $0.2 million license revenue each quarter from upfront fees received from Chiesi in 2013.

Collaboration revenue generated from our research activities associated with the S100A1 heart failure program on behalf of BMS during the three months ended March 31, 2017 were $0.6 million, compared to $1.7 million for the same period in 2016. The reduction in the current year period was driven by the timing of various preclinical activities as well as activities related to the production of preclinical material during the prior year period.

Collaboration revenue generated from our co-development of AMT-060 with Chiesi for the three months ended March 31, 2017, were $1.6 million, compared to $1.4 million for the same period in 2016.

Research and development expenses

We expense research and development costs (“R&D”) as incurred. Our R&D expenses generally consist of cost incurred for the development of our target candidates, which include:

· Employee-related expenses, including salaries, benefits, travel and share-based compensation expense;

· Costs incurred for laboratory research, preclinical and nonclinical studies, clinical trials, statistical analysis and report writing, and regulatory compliance costs incurred with clinical research organizations and other third party vendors;

· Costs incurred to conduct consistency and comparability studies;

· Costs incurred for the start-up and validation of our Lexington facility;

· Costs incurred for the development and improvement of our manufacturing processes and methods;

· Costs associated with our research activities for our next-generation vector and promoter platform;

· Costs incurred, including share-based compensation expense, under our collaboration and license agreement with 4D Molecular Therapeutics;

· Changes in the fair value of the contingent consideration related to our acquisition of InoCard;

· Facilities, depreciation and other expenses, which include direct and allocated expenses for rent and maintenance of facilities, insurance and other supplies; and

· Amortization and impairments of intangible assets.

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Our research and development expenses primarily consist of costs incurred for the research and development of our product candidates, which include:

· AMT-060 ( Hemophilia B ). We initiated a Phase I/II clinical trial of AMT-060 for the treatment of hemophilia B in the first quarter of 2015 in collaboration with Chiesi. Under our co-development agreement, we and Chiesi will each bear half of the agreed development costs of this program;

· S100A1 ( congestive heart failure ). In the third quarter of 2014, we started to incur costs related to the preclinical development of product candidates targeting the S100A1 gene. Since May 2015, all costs related to the program are reimbursed by BMS under the collaboration agreement;

· AMT-130 ( Huntington’s disease ). We have incurred costs related to preclinical research for AMT-130;

· AMT-110 ( Sanfilippo B ). We have incurred costs related to the development and manufacture of clinical supplies of AMT-110 for the Phase I/II clinical trial. We suspended this program in late 2016;

· Preclinical research programs . We incur costs related to the research of multiple preclinical gene therapy product candidates with the potential to treat certain rare and other serious medical conditions; and

· Technology platform development and other related research . We incur significant research and development costs related to vector design, manufacturing and other aspects of our modular gene therapy technology platform that are applicable across all of our programs.

Our research and development expenses may vary substantially from period to period based on the timing of our research and development activities, including manufacturing campaigns, regulatory submissions and enrollment of patients in clinical trials. We expect that our research and development expenses will increase significantly as we progress our preclinical and clinical programs, advance the research and development of our other product candidates and transfer manufacturing to our facility in Lexington, Massachusetts. The successful development of our product candidates is highly uncertain. At this time, we cannot reasonably estimate the nature, timing or estimated costs of, or any cash inflows resulting from, the development of any of our product candidates. This is due to numerous risks and uncertainties associated with developing gene therapies, including the uncertainty of:

· the scope, rate of progress and expense of our research and development activities;

· our ability to successfully manufacture and scale-up production;

· clinical trial protocols, speed of enrollment and resulting data;

· the effectiveness and safety of our product candidates;

· the timing of regulatory approvals; and

· our ability to agree to ongoing development budgets with collaborators who share the costs of our development program.

A change in the outcome of any of these variables with respect to our product candidates that we may develop could mean a significant change in the expenses and timing associated with the development of such product candidate.

Research and development expenses for the three months ended March 31, 2017, were $17.0 million, compared to $16.7 million for the same period in 2016.

· We incurred $9.0 million in personnel, share-based compensation expenses and consulting cost in the three months ended March 31, 2017, compared to $8.8 million in the three months ended March 31, 2016. The increase in 2017 is driven by one-off expenses we incur related to terminations and retention benefits as well as the addition of personnel throughout 2016;

· We incurred $3.9 million in external services and cost related to the development of our product candidates in the three months ended March 31, 2017, compared to $3.9 million for the same period in 2016, as we advanced our efforts to drive hemophilia B towards late-stage clinical development;

· We incurred $3.8 million operating expenses and depreciation expenses related to our rented facilities in the three months ended March 31, 2017, compared to $3.0 million for the same period in 2016. The increase in 2017 is driven primarily by the additional costs associated with our new Amsterdam facility, the lease for which commenced in March 2016;

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· We incurred no share-based compensation expenses related to our collaboration with 4D Molecular Therapeutics in the three months ended March 31, 2017, compared to $0.7 million for the same period in 2016.

Selling, general and administrative expenses

Our general and administrative expenses consist principally of employee, office, consultancy, legal and other professional and administrative expenses. We incur expenses associated with operating as a public company, including expenses for personnel, legal, accounting and audit fees, board of directors costs, directors’ and officers’ liability insurance premiums, NASDAQ listing fees, expenses related to investor relations and fees related to business development and maintaining our patent and license portfolio. Following the initiation of the commercialization of Glybera in September 2015, we incurred selling and marketing costs related to maintaining a patient registry and conducting a post-approval, Phase IV study for Glybera. These costs were recorded as research and development expenses prior to the commercialization.

Selling, general and administrative expenses for the three months ended March 31, 2017, were $6.4 million, compared to $7.3 million for the same period in 2016.

· Our expenses related to employees, contractors and consultants in the three months ended March 31, 2017, were $2.2 million compared to $2.4 million for the same period in 2016. The decrease was primarily related to $0.6 million in one-time costs related to the CEO-transition during the prior year period;

· We incurred $0.9 million of share-based compensation expenses in the three months ended March 31, 2017, compared to $1.1 million for the same period in 2016. The decrease was related to the reduction in fair value of the equity instruments offered to employees;

· We incurred $1.8 million of professional fees in the three months ended March 31, 2017, compared to $1.6 million for the same period in 2016. We regularly incur accounting, audit and legal fees associated with operating as a public company; and

· We incurred $0.2 million of costs associated with the Glybera global registry and Phase IV study as selling cost in the three months ended March 31, 2017, compared to $0.9 million for the same period in 2016. The decrease was primarily related to one-time costs to implemented post-approval requirement incurred in the first quarter 2016.

Other non-operating items, net

Our other non-operating items, net, for the three months ended March 31, 2017, and 2016 were as follows:

	Three months ended March 31,
	2017			2016			2017 vs 2016
	in thousands
Interest income	$	11		$	22		$	(11	)
Interest expense Hercules long-term debt	(504		)	(629		)	125
Foreign currency gains / (losses)	(93		)	(2,188		)	2,095
Other non-operating income / (expense)	29			317			(288		)
Total other non-operating income / (expense), net	$	(557	)	$	(2,478	)	$	1,921

Our interest income consists of interest income earned on our cash and cash equivalents.

We hold monetary items and enter into transactions in foreign currencies, predominantly in euros and U.S. dollars. We recognize foreign exchange results related to changes in these foreign currencies. We recognized a net loss of $0.1 million in the three months ended March 31, 2017, compared to a net loss of $2.2 million for the same period in 2016 related to our borrowings from Hercules and our cash and cash equivalents.

We issued warrants to Hercules in 2013 and to BMS in 2015. We recognize changes in the fair value of these warrants within other non-operating income / (expense). In the three months ended March 31, 2017, we recognized a gain of $0.0 million compared to a gain of $0.3 million for the same period in 2016.

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Financial Position, Liquidity and Capital Resources

As of March 31, 2017, we had cash and cash equivalents of $120.3 million. We currently expect that our cash and cash equivalents will be sufficient to fund operations into 2019. The table below summarizes our consolidated cash flow data for the three months ended March 31, 2017, and 2016.

	Three months ended March 31,
	2017			2016
	in thousands
Cash and cash equivalents at the beginning of the period	$	132,496		$	221,626
Net cash (used in) / provided by operating activities	(11,670		)	(15,726		)
Net cash used in investing activities	(1,969		)	(2,475		)
Net cash generated from financing activities	441			772
Foreign exchange impact	973			5,483
Cash and cash equivalents at the end of the period	$	120,271		$	209,680

We have incurred losses and cumulative negative cash flows from operations since our business was founded by our predecessor entity AMT Therapeutics (“AMT”) Holding N.V. in 1998. We had a net loss of $20.3 million in the three months ended March 31, 2017, compared to a loss of $22.3 million in the same period 2016. As of March 31, 2017, we had an accumulated deficit of $416.3 million.

Sources of liquidity

From our first institutional venture capital financing in 2006 through March 31, 2017, we funded our operations primarily through private and public placements of equity securities and convertible and other debt securities and to a much lesser extend upfront, target designation or similar payments from our collaboration partners as well as collaboration revenues.

We expect to continue to incur losses and to generate negative cash flows. We have no firm sources of additional financing other than our collaboration agreements with Chiesi and BMS and additional commitments that may be available under our Hercules loan facility. Until such time, if ever, as we can generate substantial cash flows from successfully commercializing our product candidates, we expect to finance our cash needs through a combination of equity offerings, debt financings, collaborations, strategic alliances and marketing, distribution and licensing arrangements.

We are subject to covenants under our Loan Agreement with Hercules, and may become subject to covenants under any future indebtedness that could limit our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends, which could adversely impact our ability to conduct our business. In addition, our pledge of assets as collateral to secure our obligations under the Hercules loan agreement may limit our ability to obtain debt financing. To the extent, we need to finance our cash needs through equity offerings or debt financings, such financing may be subject to unfavorable terms including without limitation, the negotiation and execution of definitive documentation, as well as credit and debt market conditions, and we may not be able to obtain such financing on terms acceptable to us or at all. If financing is not available when needed, including through debt or equity financings, or is available only on unfavorable terms, we may be unable to meet our cash needs. If we raise additional funds through collaborations, strategic alliances or marketing, distribution or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams or product candidates or grant licenses on terms that may not be favorable to us. If we are unable to raise additional funds through equity or debt financings when needed, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves, which could have a material adverse effect on our business, financial conditions, results of operations and cash flows.

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Net Cash (used in)/generated by operating activities

Net cash used in operating activities was $11.7 million for the three months ended March 31, 2017, a reduction of $4.0 million compared to the $15.7 million of cash used in the same period in 2016.

The reduction in 2017 is due to a $3.6 million reduction of our net working capital compared to a relatively flat net working capital position during the same period in 2016. In addition, in 2017, we collected $1.1 million in lease incentive payments related to our new Amsterdam facility.

Net cash used in investing activities

In the three months ended March 31, 2017, we used $2.0 million in our investing activities compared to $2.5 million for the same period in 2016.

	Three months ended March 31,
	2017			2016
	in thousands
Build out of Lexington site	$	(236	)	$	(691	)
Build out of Amsterdam sites	(1,733		)	(1,176		)
Restricted cash	—			(608		)
Total investments	$	(1,969	)	$	(2,475	)

In the three months ended March 31, 2017, we invested $1.7 million in our new facility in Amsterdam and $1.2 million in the same period 2016.

Net cash generated from financing activities

During the three months ended March 31, 2017, we received $0.4 million from the exercise of options to purchase common shares in relation to our share incentive plans, compared to $0.8 million in the same period 2016.

Funding requirements

We believe our cash and cash equivalents as of March 31, 2017, will enable us to fund our operating expenses including our debt repayment obligations as they become due and capital expenditure requirements, for at least the next twelve months. Our future capital requirements will depend on many factors, including but not limited to:

· the potential to receive future consideration pursuant to our collaboration with BMS, which is largely contingent on achieving certain research, development, regulatory and sales milestones;

· our collaboration agreements remaining in effect and our ability to enter into such new arrangements in the future;

· the scope, timing, and results and costs of our current and planned clinical trials, including those for hemophilia B and AMT-130 in Huntington’s Disease;

· the scope, timing, results and costs of preclinical development and laboratory testing of our additional product candidates, including those for the treatment of Huntington’s disease and other gene therapy product candidates;

· the timing and costs incurred in relation to the withdrawal of our marketing authorization for Glybera;

· the need for any additional tests, studies, or trials beyond those originally anticipated to confirm the safety or efficacy of our product candidates and technologies;

· the number of other product candidates that we pursue and their respective development requirements;

· the cost, timing and outcome of regulatory review of our product candidates;

· the cost and timing of future commercialization activities, including product manufacturing, marketing, sales and distribution, for any of our product candidates for which we receive marketing approval in the future;

· the amount and timing of revenue, if any, we receive from commercial sales of any product candidates for which we, or our collaboration partners, receive marketing approval in the future;

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· the costs and timing of preparing, filing, expanding, acquiring, licensing, maintaining, enforcing and prosecuting patents and patent applications, as well as defending any intellectual property-related claims;

· the repayments of the principal amount of our venture debt loan with Hercules, which will contractually start in December 2017 and will run through May 2020;

· the extent to which we acquire or in-license other businesses, products, product candidates or technologies;

· the costs associated with maintaining quality compliance and optimizing our manufacturing processes, including the operating costs associated with our Lexington, Massachusetts manufacturing facility;

· the costs associated with hiring additional senior management and other personnel, particularly in our clinical development, medical affairs and regulatory affairs groups;

· the timing, costs, savings and operational implications of the corporate restructuring we are implementing following the recent completion of our strategic review; and

· the costs associated with augmenting our corporate infrastructure, including the improvement of our information systems and addition of finance, human resource, legal and compliance personnel.

Contractual obligations and commitments

The table below sets forth our contractual obligations and commercial commitments as of March 31, 2017, that are expected to have an impact on liquidity and cash flows in future periods.

	Undefined		Less than 1 year		Between 1 and 2 years		Between 2 and 5 years		Over 5 years		Total
	in thousands
Debt obligations (including $4.4 million interest payments)	$	—	$	4,009	$	9,098	$	11,292	$	—	$	24,399
Operating lease obligations	—		2,773		4,016		11,226		21,668		39,683
Contingent consideration (nominal amount)	15,469		—		—		—		—		15,469
Total	$	15,469	$	6,782	$	13,114	$	22,518	$	21,668	$	79,551

Due to uncertainty of the timing of achieving milestones, the contingent consideration of $15.5 million related to our acquisition of InoCard (later renamed uniQure GmbH), is considered to have an undefined contractual maturity. As of March 31, 2017, we expect the milestone obligations will become payable between 2018 and 2021. When due, the obligations can be settled either in cash or in a variable number of our shares. As of March 31, 2017, we recorded this obligation at its fair value of $2.0 million.

We also have obligations to make future payments to third parties that become due and payable on the achievement of certain development, regulatory and commercial milestones (such as the start of a clinical trial, filing of a Biologics License Application, approval by the FDA or product launch). We have not included these commitments on our balance sheet or in the table above because the achievement and timing of these milestones is not fixed and determinable.

We enter into contracts in the normal course of business with CROs for preclinical research studies and clinical trials, research supplies and other services and products for operating purposes. These contracts generally provide for termination on notice, and therefore are cancelable contracts and not included in the table of contractual obligations and commitments.

The Company’s predecessor entity received a technical development loan from the Dutch government in relation to the development of Glybera. The Company needs to repay the grant through a percentage of revenue derived from product sales of Glybera up to December 31, 2019. Any grant balance remaining at this date will be forgiven. We have decided not to renew our marketing authorization for Glybera in the European Union, which expires on October 25, 2017. We do not expect to derive any revenue from Glybera after that time.

Off-Balance Sheet Arrangements

As of March 31, 2017, we did not have any off-balance sheet arrangements as defined in Item 303(a) (40) of Regulation S-K.

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Item 3. Quantitative and Qualitative Disclosures about Market Risk

We are exposed to a variety of financial risks in the normal course of our business, including market risk (including currency, price and interest rate risk), credit risk and liquidity risk. Our overall risk management program focuses on preservation of capital and the unpredictability of financial markets and has sought to minimize potential adverse effects on our financial performance and position.

Our market risks and exposures to such market risks during the three months ended March 31, 2017, has not materially changed from our market risks and our exposure to market risk discussed in Part II, Item 7A of our Annual Report on Form 10-K for the year ended December 31, 2016, which was filed with the SEC on March 15, 2017.

Item 4. Controls and Procedures

Evaluation of Disclosure Controls and Procedures

Our management, with the participation of our chief executive and interim finance officer (“CEO”), evaluated the effectiveness of our disclosure controls and procedures (as defined in Rules 13a-15(e) and 15d-15(e) under the Securities Exchange Act of 1934, as amended (the “Exchange Act”)) as of March 31, 2017. Based on such evaluation, our CEO has concluded that as of March 31, 2017, our disclosure controls and procedures were effective to ensure that information required to be disclosed by it in reports the Company files or submits under the Exchange Act is recorded, processed, summarized and reported within the time periods specified in the rules and forms of the SEC, and that such material information is accumulated and communicated to the Company’s management, including its Principal Executive Officer and Principal Financial Officer, to allow timely decisions regarding required disclosure. Because of the inherent limitations in all control systems, any controls and procedures, no matter how well designed and operated, can provide only reasonable assurance of achieving the desired control objectives, and management necessarily is required to apply its judgment in evaluating the cost-benefit relationship of possible controls and procedures. Furthermore, the Company’s controls and procedures can be circumvented by the individual acts of some persons, by collusion of two or more people or by management override of such control, and misstatements due to error or fraud may occur and not be detected on a timely basis.

Changes in Internal Control over Financial Reporting

During the three months ended March 31, 2017, there were no changes in our internal control over financial reporting (as defined in Rule 13a-15(f) under the Exchange Act) that materially affected, or are reasonably likely to affect, internal control over financial reporting.

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Part II — OTHER INFORMATION

Item 1. Legal Proceedings

None.

Item 1A. Risk Factors

An investment in our common shares involves a high degree of risk. You should carefully consider the following information about these risks, together with the other information appearing elsewhere in this Quarterly Report on Form 10-Q, including our financial statements and related notes thereto, and the risk factors discussed in Part I, Item 1A “Risk Factors” in our Annual Report on Form 10-K for the year ended December 13, 2016, field with the SEC on March 15, 2017, before deciding to invest in our common shares. We operate in a dynamic and rapidly changing industry that involves numerous risks and uncertainties. The risks and uncertainties described below are not the only ones we face. Other risks and uncertainties, including those that we do not currently consider material, may impair our business. If any of the risks discussed below actually occur, our business, financial condition, operating results or cash flows could be materially adversely affected. This could cause the value of our securities to decline, and you may lose all or part of your investment.

Those risk factors below denoted with a “*” are newly added or have been materially updated from our Annual Report on 10-K filed with the SEC on March 15, 2017.

Risks Related to the Development of Our Product Candidates

We may encounter substantial delays in and impediments to the progress of our clinical trials or fail to demonstrate the safety and efficacy of our product candidates.

Clinical and non-clinical development is expensive, time-consuming and uncertain as to outcome. Our product candidates are in early clinical or preclinical development, and there is a significant risk of failure or delay in each of these programs. We cannot guarantee that any preclinical tests or clinical trials will be completed as planned or completed on schedule, if at all. A failure of one or more preclinical tests or clinical trials can occur at any stage of testing. Events that may prevent successful or timely completion of clinical development include, but are not limited to:

· delays in reaching a consensus with regulatory agencies on study design;

· delays in reaching agreement on acceptable terms with prospective clinical research organizations (“CROs”) and clinical trial sites;

· delays in receiving regulatory authority to conduct the clinical trials or a regulatory authority decision that the clinical trial should not proceed;

· delays in obtaining required Institutional Review Board (“IRB”) approval at each clinical trial site;

· imposition of a clinical hold by regulatory agencies after an inspection of our clinical trial operations or trial sites;

· failure by CROs, other third parties or us to adhere to clinical trial requirements or otherwise properly manage the clinical trial process, including meeting applicable timelines, properly documenting case files, including the retention of proper case files, and properly monitoring and auditing clinical sites;

· failure of sites or clinical investigators to perform in accordance with good clinical practices (“GCP”) or applicable regulatory guidelines in other countries;

· difficulty or delays in patient recruiting into clinical trials;

· delays or deviations in the testing, validation, manufacturing and delivery of our product candidates to the clinical sites;

· delays in having patients complete participation in a study or return for post-treatment follow-up;

· clinical trial sites or patients dropping out of a study;

· occurrence of serious adverse events associated with a product candidate that are viewed to outweigh its potential benefits; or

· changes in regulatory requirements and guidance that require amending or submitting new clinical protocols, undertaking additional new tests or analyses or submitting new types or amounts of clinical data.

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Before obtaining marketing approval from regulatory authorities for the sale of our product candidates, we must conduct extensive clinical trials to demonstrate the safety and efficacy of the product candidates in humans. Such trials and regulatory review and approval take many years. It is impossible to predict when or if any of our clinical trials will demonstrate that product candidates are effective or safe in humans. If the results of our clinical trials are inconclusive, or fail to meet the level of statistical significance required for approval or if there are safety concerns or adverse events associated with our product candidates, we may:

· be delayed in or altogether prevented from obtaining marketing approval for our product candidates;

· obtain approval for indications or patient populations that are not as broad as intended or desired;

· obtain approval with labeling that includes significant use or distribution restrictions or safety warnings;

· be subject to changes with the way the product is administered;

· be required to perform additional clinical trials to support approval or be subject to additional post-marketing testing requirements;

· have regulatory authorities withdraw their approval of the product or impose restrictions on its distribution in the form of a modified risk evaluation and mitigation strategy;

· be subject to the addition of labeling statements, such as warnings or contraindications;

· be sued; or

· experience damage to our reputation.

Because of the nature of the gene therapies we are developing, regulators may also require us to demonstrate long-term gene expression or clinical efficacy, which may require additional or longer clinical trials and which may not be able to be demonstrated to the regulatory authorities’ standards.

Our ability to recruit patients for our trials is often reliant on third parties, such as the pharmacies at our clinical trial sites. These third parties may not have the adequate infrastructure established to handle gene therapy products or to support certain gene therapy product formulations, or may not agree to recruit patients on our behalf.

In addition, we or our collaborators may not be able to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA, the EMA or similar regulatory authorities outside the United States and the European Union. This may result in our failure to initiate or continue clinical trials for our product candidates, or may cause us to abandon one or more clinical trials altogether. In particular, because several of our programs are focused on the treatment of patients with rare, orphan or ultra-orphan diseases, our ability to enroll eligible patients in these trials may be limited or slower than we anticipate in light of the small patient populations involved and the specific age range required for treatment eligibility in some indications. In addition, our potential competitors, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions and governmental agencies and public and private research institutions, may seek to develop competing therapies, which would further limit the small patient pool available for our studies.

Any inability to successfully initiate or complete preclinical and clinical development could result in additional costs to us or impair our ability to receive marketing approval, to generate revenues from product sales or obtain regulatory and commercialization milestones and royalties. In addition, if we make manufacturing or formulation changes to our product candidates, including changes in the vector or manufacturing process used, we may need to conduct additional studies to bridge our modified product candidates to earlier versions. Clinical trial delays could also shorten any periods during which we may have the exclusive right to commercialize our product candidates or allow our competitors to bring products to market before we do, which could impair our ability to successfully commercialize our product candidates and may harm our business and results of operations.

Our progress in early-stage clinical trials may not be indicative of long-term efficacy in late-stage clinical trials, and our progress in trials for one product candidate may not be indicative of progress in trials for other product candidates.

The product candidates in our pipeline are at early-stages of development. Study designs and results from previous studies are not necessarily predictive of our future clinical study designs or results, and initial results may not be confirmed upon full analysis of the complete study data. Our product candidates may fail to show the required level of safety and efficacy in later stages of clinical development despite having successfully advanced through initial clinical studies.

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A number of companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical trials even after achieving promising results in early-stage clinical trials. If a larger population of patients does not experience positive results during clinical trials, if these results are not reproducible or if our products show diminishing activity over time, our products may not receive approval from the FDA or EMA. Data obtained from preclinical and clinical activities are subject to varying interpretations, which may delay, limit or prevent regulatory approval. In addition, we may encounter regulatory delays or rejections as a result of many factors, including changes in regulatory policy during the period of product development. Failure to confirm favorable results from earlier trials by demonstrating the safety and effectiveness of our products in late-stage clinical trials with larger patient populations could have a material adverse effect on our business that would cause our share price to decline.

Fast track product, breakthrough therapy, priority review, or Regenerative Advanced Therapy (“RAT”) designation by the FDA, or access to the PRIME scheme by the EMA, for our product candidates may not lead to faster development or regulatory review or approval process, and it does not increase the likelihood that our product candidates will receive marketing approval.

We may seek fast track, a breakthrough therapy designation, RAT designation, and priority review designation and PRIME scheme access for our product candidates if supported by the results of clinical trials. A fast track product designation is designed to facilitate the clinical development and expedite the review of drugs intended to treat a serious or life-threatening condition which demonstrate the potential to address an unmet medical need. A breakthrough therapy is defined as a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. A RAT designation is designed to accelerate approval for regenerative advanced therapies. Priority review designation is intended to speed the FDA marketing application review timeframe for drugs that treat a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. PRIME is a scheme provided by the EMA to enhance support for the development of medicines that target an unmet medical need.

For drugs and biologics that have been designated as fast track products or breakthrough therapies, or granted access to the PRIME schema, interaction and communication between the regulatory agency and the sponsor of the trial can help to identify the most efficient path for clinical development. Sponsors of drugs with fast track products or breakthrough therapies may also be able to submit marketing applications on a rolling basis, meaning that the FDA may review portions of a marketing application before the sponsor submits the complete application to the FDA, as long as the sponsor pays the user fee upon submission of the first portion of the marketing application. For products that receive a priority review designation, the FDA’s marketing application review goal is shortened to six months, as opposed to ten months under standard review. This review goal is based on the date the FDA accepts the marketing application for review, which typically adds approximately two months to the timeline for review and decision from the date of submission. RAT designations will accelerate approval but the exact mechanisms have not yet been announced by FDA.

Designation as a fast track product, breakthrough therapy, RAT, PRIME, or priority review product is within the discretion of the regulatory agency. Accordingly, even if we believe one of our product candidates meets the criteria for designation as a fast track product, breakthrough therapy, RAT, PRIME, or priority review product, the agency may disagree and instead determine not to make such designation. In any event, the receipt of such a designation for a product candidate may not result in a faster development process, review or approval compared to drugs considered for approval under conventional regulatory procedures and does not assure ultimate marketing approval by the agency. In addition, with regard to fast track products and breakthrough therapies, the FDA may later decide that the products no longer meet the conditions for qualification as either a fast track product, RAT, or a breakthrough therapy or, for priority review products, decide that the time period for FDA review or approval will not be shortened.

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We may not be successful in our efforts to use our gene therapy technology platform to build a pipeline of additional product candidates.

An element of our strategy is to use our gene therapy technology platform to expand our product pipeline and to progress these candidates through clinical development ourselves or together with our collaborators. Although we currently have a pipeline of programs at various stages of development, we may not be able to identify or develop product candidates that are safe and effective. Even if we are successful in continuing to build our pipeline, the potential product candidates that we identify may not be suitable for clinical development. Research programs to identify new product candidates require substantial technical, financial and human resources. We or our collaborators may focus our efforts and resources on potential programs or product candidates that ultimately prove to be unsuccessful. If we do not continue to successfully develop and commercialize product candidates based upon our technology, we may face difficulty in obtaining product revenues in future periods, which could result in significant harm to our financial position and adversely affect our share price.

Our strategy of obtaining rights to key technologies through in-licenses may not be successful.

We seek to expand our product pipeline in part by in-licensing the rights to key technologies, including those related to gene delivery, genes and gene cassettes. The future growth of our business will depend in significant part on our ability to in-license or otherwise acquire the rights to additional product candidates or technologies, particularly through our collaborations with academic research institutions. However, we may be unable to in-license or acquire the rights to any such product candidates or technologies from third parties on acceptable terms or at all. The in-licensing and acquisition of these technologies is a competitive area, and a number of more established companies are also pursuing strategies to license or acquire product candidates or technologies that we may consider attractive. These established companies may have a competitive advantage over us due to their size, cash resources and greater clinical development and commercialization capabilities. In addition, companies that perceive us to be competitors may be unwilling to license rights to us. Furthermore, we may be unable to identify suitable product candidates or technologies within our areas of focus. If we are unable to successfully obtain rights to suitable product candidates or technologies, our business, financial condition and prospects could suffer.

Negative public opinion and increased regulatory scrutiny of gene therapy and genetic research may damage public perception of our product candidates or adversely affect our ability to conduct our business or obtain marketing approvals for our product candidates. *

Public perception may be influenced by claims that gene therapy is unsafe, and gene therapy may not gain the acceptance of the public or the medical community. The risk of cancer remains a concern for gene therapy, and we cannot assure that it will not occur in any of our planned or future clinical studies. In addition, there is the potential risk of delayed adverse events following exposure to gene therapy products due to persistent biological activity of the genetic material or other components of products used to carry the genetic material.

As of December 31, 2016, a total of two serious adverse event reports in AMT-060-treated patients occurred in our Phase I/II hemophilia B trial, a transient elevation of liver transaminases and a fever, which were assessed as probably, and possibly related to AMT-060, respectively.

Adverse events in our clinical trials or those conducted by other parties (even if not ultimately attributable to our product candidates), and the resulting publicity, could result in increased governmental regulation, unfavorable public perception, failure of the medical community to accept and prescribe gene therapy treatments, potential regulatory delays in the testing or approval of our product candidates, stricter labeling requirements for those product candidates that are approved and a decrease in demand for any such product candidates.

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Risks Related to Our Manufacturing

Delays in qualifying our U.S. manufacturing facility for clinical production activities could delay our development and commercialization plans and thereby limit our revenues and growth. *

We have commenced consolidating all manufacturing at our facility in Lexington, Massachusetts, which is currently in the qualification process to enable production of clinical trial material. If qualification is delayed, we may not be able to manufacture sufficient quantities of our product candidates, which would limit our commercialization and development activities and our opportunities for growth. Cost overruns associated with this facility could also require us to raise additional funds from external sources, which may be unavailable on favorable terms or at all.

Our manufacturing facility is subject to significant government regulations and approvals. If we fail to comply with these regulations or maintain these approvals our business will be materially harmed. *

Our manufacturing facility in Lexington will be subject to ongoing regulation and periodic inspection by the EMA, FDA and other regulatory bodies to ensure compliance with current Good Manufacturing Practices (“cGMP”). Any failure to follow and document our adherence to such cGMP regulations or other regulatory requirements may lead to significant delays in the availability of products for commercial sale or clinical study, may result in the termination of or a hold on a clinical study, or may delay or prevent filing or approval of marketing applications for our products.

Failure to comply with applicable regulations could also result in the EMA, FDA or other applicable authorities taking various actions, including levying fines and other civil penalties; imposing consent decrees or injunctions; requiring us to suspend or put on hold one or more of our clinical trials; suspending or withdrawing regulatory approvals; delaying or refusing to approve pending applications or supplements to approved applications; requiring us to suspend manufacturing activities or product sales, imports or exports; requiring us to communicate with physicians and other customers about concerns related to actual or potential safety, efficacy, and other issues involving our products; mandating product recalls or seizing products; imposing operating restrictions; and seeking criminal prosecutions. Any of the foregoing could materially harm our business.

Gene therapies are complex and difficult to manufacture. We could experience production or technology transfer problems that result in delays in our development or commercialization schedules or otherwise adversely affect our business.

We manufacture our clinical and commercial supplies of our product candidates ourselves in our GMP certified facility in Amsterdam. We plan to decommission this facility in the second quarter of 2017 and have begun transferring all manufacturing to our facility in Lexington, Massachusetts, which will involve a complex process of technology transfer. The insect-cell based manufacturing process we use to produce our products and product candidates is highly complex and in the normal course is subject to variation or production difficulties. Issues with the manufacturing process, even minor deviations from the normal process, could result in insufficient yield, product deficiencies or manufacturing failures that result in lot failures, insufficient inventory, product recalls and product liability claims. We may encounter problems in completing our technology transfer or in achieving adequate or clinical-grade materials that meet EMA, FDA or other applicable standards or specifications with consistent and acceptable production yields and costs.

A number of factors common to the manufacturing of most biologics and drugs could also cause production interruptions, including raw materials shortages, raw material failures, growth media failures, equipment malfunctions, facility contamination, labor problems, natural disasters, disruption in utility services, terrorist activities, or acts of god beyond our control. We also may encounter problems in hiring and retaining the experienced specialized personnel needed to operate our manufacturing process, particularly as we transition manufacturing to Lexington, which could result in delays in our production or difficulties in maintaining compliance with applicable regulatory requirements.

Any problems in our manufacturing processes or facilities could make us a less attractive collaborator for academic research institutions and other parties, which could limit our access to additional attractive development programs, result in delays in our clinical development or marketing schedules and harm our business.

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Our use of viruses, chemicals and other hazardous materials requires us to comply with regulatory requirements and exposes us to significant potential liabilities.

Our development and manufacturing processes involve the use of viruses, chemicals, other (potentially) hazardous materials and produce waste products. Accordingly, we are subject to national, federal, state and local laws and regulations in the United States, the Netherlands and Germany governing the use, manufacture, distribution, storage, handling, treatment and disposal of these materials. In addition to ensuring the safe handling of these materials, applicable requirements require increased safeguards and security measures for many of these agents, including controlling access and screening of entities and personnel who have access to them, and establishing a comprehensive national database of registered entities. In the event of an accident or failure to comply with environmental, occupational health and safety and export control laws and regulations, we could be held liable for damages that result, and any such liability could exceed our assets and resources.

Risks Related to Regulatory Approval

We cannot predict when or if we will obtain marketing approval to commercialize a product candidate *

The development and commercialization of our product candidates, including their design, testing, manufacture, safety, efficacy, purity, recordkeeping, labeling, storage, approval, advertising, promotion, sale and distribution, are subject to comprehensive regulation by the FDA and other regulatory agencies in the United States, the EMA and other regulatory agencies of the member states of the European Union, and similar regulatory authorities in other jurisdictions. Failure to obtain marketing approval for a product candidate in a specific jurisdiction will prevent us from commercializing the product candidate in that jurisdiction.

The process of obtaining marketing approval for our product candidates in the European Union, the United States and other countries is expensive and may take many years, if approval is obtained at all. Changes in marketing approval policies during the development period, changes in or the enactment of additional statutes or regulations, or changes in regulatory review for each submitted product application, may cause delays in the approval or rejection of an application. Regulatory authorities have substantial discretion in the approval process and may refuse to accept any application, may decide that our data are insufficient for approval, may require additional preclinical, clinical or other studies and may not complete their review in a timely manner. Further, any marketing approval we ultimately obtain may be for only limited indications, or be subject to stringent labeling or other restrictions or post-approval commitments that render the approved product not commercially viable.

If we experience delays in obtaining marketing approval of any of our product candidates in the United States or other countries, the commercial prospects of our other product candidates may be harmed and our ability to generate revenues will be materially impaired.

The FDA will require us to conduct comparability studies evaluating the products manufactured at our Amsterdam facility with those to be manufactured at our new Lexington, Massachusetts facility. Those studies and their results could substantially delay or preclude our ability to commercialize our product candidates in the United States.

The FDA maintains strict requirements governing the manufacturing process for biologics. When a manufacturer seeks to modify or change that process, or begin manufacturing at a new facility, the FDA typically requires the applicant to conduct non-clinical and, depending on the magnitude of the changes, potentially clinical comparability studies that evaluate the potential differences in the product resulting from the change in the manufacturing process or facility. In connection with any application for marketing approval in the United States, we will be required to conduct comparability studies assessing product manufactured at our facility in Amsterdam with product to be manufactured at our new facility in Lexington, Massachusetts.

Delays in designing and completing a comparability study to the satisfaction of the FDA could delay or preclude our development and commercialization plans and, thereby, increase the risk and time to achieve regulatory approval. For example, we may attempt to show comparability of the product manufactured at our Amsterdam and Lexington facilities through the use of non-clinical data, such as potency assays and animal studies. In the event that the FDA does not accept such non-clinical comparability data, we may need to conduct additional studies involving dosing of animals or patients. These potential studies may result in a delay of the approval or launch of product in the United States.

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The risks associated with the marketing approval process are heightened by the status of our products as gene therapies.

We believe that all our current product candidates will be viewed as gene therapy products by the applicable regulatory authorities. Gene therapies are relatively new treatments for which regulators do not have extensive experience or standard review and approval processes. The FDA unlike the EMA, does not have an exceptional circumstances approval pathway.

Both the FDA and EMA have demonstrated caution in their regulation of gene therapy treatments, and ethical and legal concerns about gene therapy and genetic testing may result in additional regulations or restrictions on the development and commercialization of our product candidates that are difficult to predict. The FDA and the EMA have issued various guidance documents pertaining to gene therapy products, with which we likely must comply to gain regulatory approval of any of our product candidates in the United States or European Union, respectively. The close regulatory scrutiny of gene therapy products may result in delays and increased costs, and may ultimately lead to the failure to obtain approval for any gene therapy product.

Regulatory requirements affecting gene therapy have changed frequently and may continue to change, and agencies at both the U.S. federal and state level, as well as congressional committees and foreign governments, have sometimes expressed interest in further regulating biotechnology. For example, the European Commission conducted a public consultation in early 2013 on the application of EU legislation that governs advanced therapy medicinal products, including gene therapy products, which could result in changes in the data we need to submit to the EMA in order for our product candidates to gain regulatory approval or change the requirements for tracking, handling and distribution of the products which may be associated with increased costs. In addition, divergent scientific opinions among the various bodies involved in the review process may result in delays, require additional resources and ultimately result in rejection. These regulatory agencies, committees and advisory groups and the new regulations and guidelines they promulgate may lengthen the regulatory review process, require us to perform additional studies, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of our product candidates or lead to significant post-approval limitations or restrictions. Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product to market could decrease our ability to generate sufficient product revenues to maintain our business.

Our failure to obtain or maintain orphan product exclusivity for any of our product candidates for which we seek this status could limit our commercial opportunity, and if our competitors are able to obtain orphan product exclusivity before we do, we may not be able to obtain approval for our competing products for a significant period of time.

Regulatory authorities in some jurisdictions, including the European Union and the United States, may designate drugs for relatively small patient populations as orphan drugs. Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the relevant indication, the product is entitled to a period of market exclusivity, which precludes the EMA or FDA from approving another marketing application for the same drug for the same indication for that time period. The EMA, however, may subsequently approve a similar drug for the same indication during the first product’s market exclusivity if the EMA concludes that the later drug is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care.

Orphan drug exclusivity may be lost if the EMA or FDA determines that the request for designation was materially defective, or if the manufacturer is unable to assure sufficient quantity of the drug to meet the needs of patients with the rare disease or condition or if the incidence and prevalence of patients who are eligible to receive the drug in these markets materially increase.

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As appropriate, we intend to seek all available periods of regulatory exclusivity for our product candidates. However, there is no guarantee that we will be granted these periods of regulatory exclusivity or that we will be able to maintain these periods of exclusivity.

The FDA grants product sponsors certain periods of regulatory exclusivity, during which the agency may not approve, and in certain instances, may not accept, certain marketing applications for competing drugs. For example, biologic product sponsors may be eligible for twelve years of exclusivity from the date of approval, seven years of exclusivity for drugs that are designated to be orphan drugs, and/or a six-month period of exclusivity added to any existing exclusivity period or patent life for the submission of FDA requested pediatric data. While we intend to apply for all periods of market exclusivity that we may be eligible for, there is no guarantee that we will receive all such periods of market exclusivity. Additionally, under certain circumstances, the FDA may revoke the period of market exclusivity. Thus, there is no guarantee that we will be able to maintain a period of market exclusivity, even if granted. In the case of orphan designation, other benefits, such as tax credits and exemption from user fees may be available. If we are not able to obtain or maintain orphan drug designation or any period of market exclusivity to which we may be entitled, we will be materially harmed, as we will potentially be subject to greater market competition and may lose the benefits associated with programs.

The termination of our Commercialization Agreement with Chiesi and our efforts to withdraw the marketing authorization for Glybera in Europe may expose us to financial and other risks*

On April 20, 2017, we announced that we agreed to terminate our Glybera Agreement with Chiesi and will not seek a marketing authorization renewal for Glybera in Europe. Under the terms of the termination of the Commercialization Agreement, we are obligated to make certain payments to Chiesi and are responsible for bearing all costs associated with certain activities associated with the winding down of the Glybera program. We are also obligated to continue to provide Glybera to Chiesi for the treatment of patients until October 25, 2017. While we believe that the financial obligations under the termination agreement are not material to the Company, the Company may be forced to incur additional costs in connection with the termination and our related obligations. We may also have to devote our resources to the winding down of the Glybera program in the period prior to termination, which may prevent us from applying our resources to other programs.

Risks Related to Commercialization

If we or our collaborators are unable to successfully commercialize our product candidates or experience significant delays in doing so, our business will be materially harmed.

Our ability to generate product revenues will depend on the successful development and eventual commercialization of our product candidates. The success of our product candidates will depend on a number of factors, including:

· successful completion of preclinical studies and clinical trials;

· receipt and maintenance of marketing approvals from applicable regulatory authorities;

· our ability to timely manufacture sufficient quantities according to required quality specifications;

· obtaining and maintaining patent and trade secret protection and non-patent, orphan drug exclusivity for our product candidates;

· obtaining and maintaining regulatory approval for our manufacturing facility in Lexington, Massachusetts;

· launch and commercialization of our products, if and when approved, whether alone or in collaboration with others;

· identifying and engaging effective distributors or resellers on acceptable terms in jurisdictions where we plan to utilize third parties for the marketing and sales of our product candidates;

· acceptance of our products, if and when approved, by patients, the medical community and third party payers;

· effectively competing with existing therapies and gene therapies based on safety and efficacy profile;

· achieve value based pricing levels based on durability of expression, safety and efficacy;

· obtaining and maintaining healthcare coverage and adequate reimbursement; and

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· complying with any applicable post-approval requirements and maintaining a continued acceptable overall safety profile.

Failure to achieve or implement any of these elements could result in significant delays or an inability to successfully commercialize our product candidates, which could materially harm our business.

The affected populations for our gene therapies may be smaller than we or third parties currently project, which may affect the size of our addressable markets.

Our projections of the number of people who have the diseases we are seeking to treat, as well as the subset of people with these diseases who have the potential to benefit from treatment with our therapies, are estimates based on our knowledge and understanding of these diseases. The total addressable market opportunities for these therapies will ultimately depend upon a number of factors, including the diagnosis and treatment criteria included in the final label, if approved for sale in specified indications, acceptance by the medical community, patient consent, patient access and product pricing and reimbursement. For example, after obtaining marketing authorization for Glybera from the EMA in 2013, various national European authorities denied reimbursement under national insurance schemes.

Prevalence estimates are frequently based on information and assumptions that are not exact and may not be appropriate, and the methodology is forward-looking and speculative. The use of such data involves risks and uncertainties and is subject to change based on various factors. Our estimates may prove to be incorrect and new studies may change the estimated incidence or prevalence of the diseases we seek to address. The number of patients with the diseases we are targeting may turn out to be lower than expected or may not be otherwise amenable to treatment with our products, or new patients may become increasingly difficult to identify or access, any of which would adversely affect our results of operations and our business.

The addressable market for AAV-based gene therapies are also impacted by the prevalence of neutralizing antibodies to the capsids, which are an integral component of our gene therapy constructs. Patients that have pre-existing antibodies to a particular capsid are generally not eligible for administration of a gene therapy that includes this particular capsid. For example, our AMT-060 gene therapy candidate for hemophilia B patients incorporates an AAV5 capsid. In our Phase I/II clinical study, we screened patients for preexisting anti-AAV5 antibodies in order to determine their eligibility for the trial. While none of the 10 patients screened for the study tested positive for anti-AAV5 antibodies, we have limited clinical and preclinical data on the prevalence of anti-AAV5 antibodies, and it is possible that future clinical studies may demonstrate a higher prevalence of anti-AAV5 antibodies in hemophilia B patients. This may limit the addressable market for AMT-060 and any future revenues derived from the sale of the product.

Any approved gene therapy we seek to offer may fail to achieve the degree of market acceptance by physicians, patients, third party payers and others in the medical community necessary for commercial success.

Doctors may be reluctant to accept a gene therapy as a treatment option or, where available, choose to continue to rely on existing symptomatic treatments. The degree of market acceptance of any of our product candidates that receive marketing approval in the future will depend on a number of factors, including:

· the efficacy and potential advantages of our therapies compared with alternative treatments;

· our ability to convince payers of the long-term cost-effectiveness of our therapies and, consequently, the availability of third party coverage and adequate reimbursement;

· the limitations on use and label requirements imposed by regulators;

· the convenience and ease of administration of our gene therapies compared with alternative treatments;

· the willingness of the target patient population to try new therapies, especially a gene therapy, and of physicians to administer these therapies;

· the strength of marketing and distribution support;

· the prevalence and severity of any side effects;

· limited access to site of service that can perform the product preparation and administer the infusion; and

· any restrictions on the use of our products.

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We face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully than we do.

The development and commercialization of new biotechnology and biopharmaceutical products, including gene therapies, is highly competitive. We may face competition with respect to our product candidates, as well as with respect to any product candidates that we may seek to develop or commercialize in the future, from large and specialty pharmaceutical companies and biotechnology companies worldwide, who currently market and sell products or are pursuing the development of products for the treatment of many of the disease indications for which we are developing our product candidates. Potential competitors also include academic institutions, government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative arrangements for research, development, manufacturing and commercialization. In recent years, there has been a significant increase in commercial and scientific interest and financial investment in gene therapy as a therapeutic approach, which has intensified the competition in this area.

We are aware of numerous companies focused on developing gene therapies in various indications, including AGTC, Abeona Therapeutics, Adverum Biotechnologies, Asklepios BioPharmaceutical, Audentes Therapeutics, Avalanche Biotech, AveXis, Bayer, BioMarin, Bioveratiy, bluebird bio, Dimension Therapeutics, Errant Gene Therapeutics, Expression Therapeutics, Freeline Therapeutics, Genethon, Genzyme, GlaxoSmithKline, Homology Medicines, Lysogene, Megenics, Milo Therapeutics, Nightstarx, Pfizer, REGENXBIO, Renova Therapeutics, Retrosense Therapeutics, Sangamo BioSciences, Shire, Solid Biosciences, Spark Therapeutics, Takara, and Voyager, as well as several companies addressing other methods for modifying genes and regulating gene expression. We may also face competition with respect to the treatment of some of the diseases that we are seeking to target with our gene therapies from protein pharmaceuticals under development at pharmaceutical and biotechnology companies such as Amgen, Bayer, Biogen, BioMarin, Genzyme, Novartis, Novo Nordisk, Pfizer, Shire, and numerous other pharmaceutical and biotechnology firms.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than the products that we develop. Our competitors also may obtain FDA, EMA or other regulatory approval for their products more rapidly than we do, which could result in our competitors establishing a strong market position before we are able to enter the market. Because we expect that gene therapy patients may generally require only a single administration, we believe that the first gene therapy product to enter the market for a particular indication will likely enjoy a significant commercial advantage, and may also obtain market exclusivity under applicable orphan drug regimes.

Many of the companies with which we are competing or may compete in the future have significantly greater financial resources and expertise than we do in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products. Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in more resources being concentrated among a smaller number of our competitors. Smaller and other early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These third parties compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

Risks Related to Our Dependence on Third Parties

If our collaboration with BMS is not successful or if BMS designates or develops fewer targets than permitted under our collaboration agreement, our development plans, financial position and opportunities for growth may be adversely affected.

In order to earn all milestone payments and royalties potentially due under our collaboration with BMS, we are dependent on BMS electing to designate and actively pursue target indications covered by the collaboration and our achievement of all development, clinical and regulatory milestones under the collaboration. If BMS designates or actively pursues fewer development targets, utilizes contract research organizations, instead of our organization, to conduct non-clinical and pre-clinical studies, or if we fail to

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achieve a significant number of the applicable milestones, the total payments we receive under this collaboration may be materially lower than are potentially payable.

In connection with our 2014 acquisition of the InoCard business (later renamed uniQure GmbH), we undertook certain obligations regarding the development of the acquired program pursuant to a plan to be agreed between us and the sellers. The acquisition agreement provides that, in the case of an unremedied breach by us of these development obligations, the sellers could be entitled, in defined circumstances, to repurchase the InoCard business from us. If we were to breach such development obligations and were not successful in remedying such breach, the sellers might seek to exercise this repurchase right or to claim other financial penalties. Although we are diligently pursuing the development of the acquired program through our collaboration with BMS, and believe that we have not breached and will not breach such development obligations, any claim of breach could result in distraction of management and staff attention. In the event that the sellers were successful in pursuing a claim of breach by us of such obligations, our financial position and our efforts to develop S100A1 together with our collaboration partner BMS could be materially adversely affected.

We rely on third parties for important aspects of our development programs. If these parties do not perform successfully or if we are unable to maintain any of our collaboration arrangements, or enter into new collaborations, our business could be adversely affected.

We have entered into, and expect in the future to enter into, collaborations with other companies and academic research institutions with respect to important elements of our commercial and development programs. For example, we have collaboration agreements with BMS for the development and commercialization of gene therapies for cardiovascular and potentially other diseases and with Chiesi, for the co-development and commercialization of our hemophilia B program in the European Union and certain other countries.

Our existing collaborations, and any future collaborations we enter, may pose several risks, including the following:

· collaborators have significant discretion in determining the efforts and resources that they will apply to these collaborations;

· we generally have limited or no control over the design or conduct of clinical trials sponsored by our current collaborators;

· we may be hampered from entering into collaboration arrangements if we are unable to obtain consent form our licensor to enter into sublicensing arrangements of technology we have licensed from such licensors;

· if our collaborators do not conduct the clinical trials they sponsor in accordance with regulatory requirements or stated protocols, we will not be able to rely on the data produced in such trials in our further development efforts;

· collaborators may not perform their obligations as expected;

· collaborators may also have relationships with other entities, some of which may be our competitors;

· collaborators may not pursue development and commercialization of any product candidates or may elect not to continue or renew development or commercialization programs based on clinical trial results, changes in the collaborators’ strategic focus or available funding, or external factors, such as an acquisition, that divert resources or create competing priorities;

· collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing;

· collaborators could develop, independently or with third parties, products that compete directly or indirectly with our products or product candidates, if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours;

· our collaboration arrangements may impose restrictions on our ability to undertake other development efforts that may appear to be attractive to us;

· product candidates discovered in collaboration with us may be viewed by our collaborators as competitive with their own product candidates or products, which may cause collaborators to cease to devote resources to the commercialization of our product candidates;

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· a collaborator with marketing and distribution rights that achieves regulatory approval may not commit sufficient resources to the marketing and distribution of such product or products;

· disagreements with collaborators, including over proprietary rights, contract interpretation or the preferred course of development, could cause delays or termination of the research, development or commercialization of product candidates, lead to additional responsibilities for us, delay or impede reimbursement of certain expenses or result in litigation or arbitration, any of which would be time-consuming and expensive;

· collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our rights or expose us to potential litigation;

· collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability; and

· collaborations may in some cases be terminated for the convenience of the collaborator and, if terminated, we could be required to expend additional funds to pursue further development or commercialization of the applicable product or product candidates.

If our collaborations do not result in the successful development and commercialization of products or if one of our collaborators terminates its agreement with us, we may not receive future research funding or milestone or royalty payments under the collaboration, and we may lose access to important technologies and capabilities of the collaboration. All of the risks relating to product development, regulatory approval and commercialization described herein also apply to the activities of our development collaborators.

Risks Related to Our Intellectual Property

We rely on licenses of intellectual property from third parties, and such licenses may not provide adequate rights or may not be available in the future on commercially reasonable terms or at all, and our licensors may be unable to obtain and maintain patent protection for the technology or products that we license from them.

We currently are heavily reliant upon licenses of proprietary technology from third parties that is important or necessary to the development of our technology and products, including technology related to our manufacturing process, our vector platform, our gene cassettes and the therapeutic genes of interest we are using. These and other licenses may not provide adequate rights to use such technology in all relevant fields of use. Licenses to additional third party technology that may be required for our development programs may not be available in the future or may not be available on commercially reasonable terms, which could have a material adverse effect on our business and financial condition.

In some circumstances, we may not have the right to control the preparation, filing and prosecution of patent applications, or to maintain the patents, covering technology that we license from third parties. In addition, some of our agreements with our licensors require us to obtain consent from the licensor before we can enforce patent rights, and our licensor may withhold such consent or may not provide it on a timely basis. Therefore, we cannot be certain that these patents and applications will be prosecuted and enforced in a manner consistent with the best interests of our business. In addition, if third parties who license patents to us fail to maintain such patents, or lose rights to those patents, the rights we have licensed may be reduced or eliminated.

Our intellectual property licenses with third parties may be subject to disagreements over contract interpretation, which could narrow the scope of our rights to the relevant intellectual property or technology or increase our financial or other obligations to our licensors.

The agreements under which we license intellectual property or technology from third parties are complex, and certain provisions in such agreements may be susceptible to multiple interpretations. The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology, or increase what we believe to be our financial or other obligations under the relevant agreement, either of which could have a material adverse effect on our business and financial condition.

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If we fail to comply with our obligations in our intellectual property licenses with third parties, we could lose rights that are important to our business.

We in-license intellectual property from third parties that is material to our product candidates, including technology related to our manufacturing process, our vector platform, and the therapeutic genes and gene cassettes we are using. Our licensing arrangements with third parties impose diligence, development and commercialization timelines, milestone payment, royalty, insurance and other obligations on us. If we fail to comply with these obligations, our counterparties may have the right to terminate these agreements, in which case we might not be able to develop, manufacture or market any product that is covered by these agreements or may face other penalties under the agreements. Such an occurrence could materially adversely affect the value of the product candidate being developed under any such agreement. Termination of these agreements or reduction or elimination of our rights under these agreements may result in our having to negotiate new or amended agreements with less favorable terms, or cause us to lose our rights under these agreements, including our rights to important intellectual property or technology.

If we are unable to obtain and maintain patent protection for our technology and products, or if the scope of the patent protection is not sufficiently broad, our ability to successfully commercialize our products may be impaired.

We rely upon a combination of in-licensed and owned patents, trade secret protection and confidentiality agreements to protect our intellectual property. Our success depends in a large part on our ability to obtain and maintain this protection in the European Union, the United States and other countries, in part by filing patent applications related to our novel technologies and product candidates. Our patents may not provide us with any meaningful commercial protection, prevent competitors from competing with us or otherwise provide us with any competitive advantage. Our competitors may be able to circumvent our owned or licensed patents by developing similar or alternative technologies or products in a non-infringing manner. Successful challenges to our patents may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated or held unenforceable, in whole or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our technology and products.

The patent prosecution process is expensive, time-consuming and uncertain, and we may not be able to file and prosecute all necessary or desirable patent applications at a reasonable cost or in a timely manner. It is also possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection. Additionally, given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, our owned and licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.

The patent position of biotechnology and pharmaceutical companies generally is highly uncertain, involves complex legal and factual questions and has in recent years been the subject of much litigation. In addition, the laws of foreign countries may not protect our rights to the same extent as the laws of the United States. For example, EU patent law with respect to the patentability of methods of treatment of the human body is more limited than U.S. law. Publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the United States and other jurisdictions are typically not published until 18 months after their priority date, or in some cases at all. Therefore, we cannot know with certainty whether we were the first to make the inventions or that we were the first to file for patent protection of the inventions claimed in our owned or licensed patents or pending patent applications. As a result, the issuance, scope, validity, enforceability and commercial value of our patent rights are highly uncertain. Our pending and future patent applications may not result in patents being issued that protect our technology or products, in whole or in part, or which effectively prevent others from commercializing competitive technologies and products. Changes in either the patent laws or interpretation of the patent laws in the European Union, the United States or other countries may diminish the value of our patents or narrow the scope of our patent protection.

We may become involved in lawsuits to protect or enforce our patents or other intellectual property or third parties may assert their intellectual property rights against us, which could be expensive, time consuming and unsuccessful.

Competitors may infringe our owned or licensed patents or other intellectual property. To counter infringement or unauthorized use, we may be required to file infringement claims, which can be expensive and

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time consuming. An adverse result in any litigation proceeding could put one or more of our patents at risk of being invalidated, maintained in more narrowly amended form or interpreted narrowly.

Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses, increase our operating losses, reduce available resources and could distract our technical and management personnel from their normal responsibilities. In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments, which could have an adverse effect on the price of our common shares.

Third parties may initiate legal proceedings alleging that we are infringing their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business. If we are found to infringe a third party’s intellectual property rights, we could be required to obtain a license from such third party to continue developing and marketing our products and technology. We may not be able to obtain the required license on commercially reasonable terms or at all. Even if we were able to obtain a license, it could be non-exclusive, thereby giving our competitors access to the same technologies licensed to us. We could be forced, including by court order, to cease commercializing the infringing technology or product or otherwise to cease using the relevant intellectual property. In addition, we could be found liable for monetary damages, including treble damages and attorneys’ fees if we are found to have willfully infringed a patent. A finding of infringement could prevent us from commercializing our product candidates or force us to cease or materially modify some of our business operations, which could materially harm our business. Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business.

For example, we are aware of patents owned by third parties that relate to some aspects of our programs that are still in development. In some cases, because we have not determined the final methods of manufacture, the method of administration or the therapeutic compositions for these programs, we cannot determine whether rights under such third party patents will be needed. In addition, in some cases, we believe that the claims of these patents are invalid or not infringed, or will expire before commercialization. However, if such patents are needed and found to be valid and infringed, we could be required to obtain licenses, which might not be available on commercially reasonable terms, or to cease or delay commercializing certain product candidates, or to change our programs to avoid infringement.

Our reliance on third parties may require us to share our trade secrets, which could increase the possibility that a competitor will discover them or that our trade secrets will be misappropriated or disclosed.

Because we collaborate with various organizations and academic research institutions on the advancement of our gene therapy platform, we must, at times, share trade secrets with them. We seek to protect our proprietary technology in part by entering into confidentiality agreements and, if applicable, materials transfer agreements, collaborative research agreements, consulting agreements or other similar agreements with our collaborators, advisors and consultants prior to beginning research or disclosing proprietary information. These agreements typically limit the rights of the third parties to use or disclose our confidential information, such as trade secrets. Despite the contractual provisions employed when working with third parties, the need to share trade secrets and other confidential information increases the risk that such trade secrets become known by our competitors, are inadvertently incorporated into the technology of others, or are disclosed or used in violation of these agreements. Given that our proprietary position is based, in part, on our know-how and trade secrets, a competitor’s discovery of our trade secrets or other unauthorized use or disclosure would impair our competitive position and may have a material adverse effect on our business.

In addition, these agreements typically restrict the ability of our collaborators, advisors and consultants to publish data potentially relating to our trade secrets. Our academic collaborators typically have rights to publish data, provided that we are notified in advance and may delay publication for a specified time in order to secure our intellectual property rights arising from the collaboration. In other cases, publication rights are controlled exclusively by us, although in some cases we may share these rights with other parties. We also conduct joint research and development programs that may require us to share trade secrets under the terms of our research and development partnerships or similar agreements.

Some courts inside and outside the United States are less willing or unwilling to protect trade secrets. If any of our trade secrets were to be lawfully obtained or independently developed by a competitor, we would

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have no right to prevent them, or those to whom they communicate it, from using that technology or information to compete with us.

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Risks Related to Pricing and Reimbursement

We face uncertainty related to insurance coverage of, and pricing and reimbursement for product candidates for which we may receive marketing approval.

We anticipate that the cost of treatment using our product candidates will be significant. We expect that most patients and their families will not be capable of paying for our products themselves. There will be no commercially viable market for our product candidates without reimbursement from third party payers, such as government health administration authorities, private health insurers and other organizations. Even if there is a commercially viable market, if the level of third party reimbursement is below our expectations, our revenues and gross margins will be adversely affected and our business will be harmed.

Government authorities and other third party payers, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels. Reimbursement systems vary significantly by country and by region, and reimbursement approvals must be obtained on a country-by-country basis. Government authorities and third party payers have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications and procedures. Increasingly, third party payers require drug companies to provide them with predetermined discounts from list prices, are exerting influence on decisions regarding the use of particular treatments and are limiting covered indications. Additionally, in the United States and some foreign jurisdictions, legislative and regulatory changes regarding the healthcare system and insurance coverage, particularly in light of the new U.S. presidential administration, could result in more rigorous coverage criteria and downward pressure on drug prices, and may affect our ability to profitably sell any products for which we obtain marketing approval.

The pricing review period and pricing negotiations for new medicines take considerable time and have uncertain results. Pricing review and negotiation usually begins only after the receipt of regulatory marketing approval, and some authorities require approval of the sale price of a product before it can be marketed. In some markets, particularly the countries of the European Union, prescription pharmaceutical pricing remains subject to continuing direct governmental control and to drug reimbursement programs even after initial approval is granted and price reductions may be imposed. Prices of medical products may also be subject to varying price control mechanisms or limitations as part of national health systems if products are considered not cost-effective or where a drug company’s profits are deemed excessive. In addition, pricing and reimbursement decisions in certain countries can lead to mandatory price reductions or additional reimbursement restrictions in other countries. As a result of these restrictions, any product candidates for which we may obtain marketing approval may be subject to price regulations that delay or prohibit our or our partners’ commercial launch of the product in a particular jurisdiction. In addition, we or our collaborators may elect to reduce the price of our products in order to increase the likelihood of obtaining reimbursement approvals. In the event that countries impose prices, which are not sufficient to allow us or our collaborators to generate a profit, we or our collaborators may refuse to launch the product in such countries or withdraw the product from the market. If pricing is set at unsatisfactory levels, or if the price decreases, our business could be harmed, possibly materially. If we fail to obtain and sustain an adequate level of coverage and reimbursement for our products by third party payers, our ability to market and sell our products would be adversely affected and our business would be harmed.

Due to the generally limited addressable market for our target orphan indications and the potential for our therapies to offer therapeutic benefit in a single administration, we face uncertainty related to pricing and reimbursement for these product candidates.

The relatively small market size for orphan indications and the potential for long-term therapeutic benefit from a single administration present particular challenges to pricing review and negotiation of our product candidates for which we may obtain marketing authorization. The patient populations of our product candidates targeted at orphan and ultra-orphan diseases are relatively small. If we are unable to obtain adequate levels of reimbursement relative to the small market size in our target orphan and ultra-orphan indications, our ability to support our development and commercial infrastructure and to successfully market and sell our product candidates for which we may obtain marketing approval will be adversely affected.

We also anticipate that many or all of our gene therapy product candidates may provide long-term, and potentially curative benefit, with a single administration. This is a different paradigm than that of other pharmaceutical therapies, which often require an extended course of treatment or frequent administration. As a result, governments and other payers may be reluctant to provide the significant level of reimbursement that we

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seek at the time of administration of our gene therapies or may seek to tie reimbursement to clinical evidence of continuing therapeutic benefit over time. Although we anticipate that our product candidates will need to be administered only once, there may be situations in which re-administration is required, which may further complicate the pricing and reimbursement for these treatments. In addition, in light of the anticipated cost of these therapies, governments and other payers may be particularly restrictive in making coverage decisions. These factors could limit our commercial success and harm our business.

Risks Related to Our Financial Position and Need for Additional Capital

We have incurred significant losses to date, expect to incur losses over the next several years and may never achieve or maintain profitability.*

We had a net loss of $20.3 million in the first quarter of 2017, $73.4 million in full year 2016 and $82.1 million in 2015. As of March 31, 2017, we had an accumulated deficit of $416.3 million. To date, we have financed our operations primarily through the sale of equity securities and convertible debt, venture loans, through upfront payments from our collaboration partners and, to a lesser extent, subsidies and grants from governmental agencies and fees for services. We have devoted substantially all of our financial resources and efforts to research and development, including preclinical studies and clinical trials. A significant portion of potential consideration under our agreement with BMS is contingent on achieving research, development, regulatory and sales milestones. We expect to continue to incur significant expenses and losses over the next several years, and our net losses may fluctuate significantly from quarter to quarter and year to year.

We anticipate that our expenses will increase substantially as we:

· prepare for a pivotal study for our gene therapy candidate in hemophilia B, in collaboration with Chiesi;

· advance the preclinical development and initiate a clinical study for our product candidate in Huntington’s disease;

· progress our research programs of additional product candidates targeting liver-directed and CNS disorders;

· conduct any additional trials or tests beyond those originally anticipated in order to confirm the safety or efficacy of our product candidates;

· seek marketing approval for any product candidates that successfully complete clinical trials;

· acquire or in-license rights to new therapeutic targets or product candidates;

· enter into collaboration agreements with third parties to collaborate on the research and development of potential product candidates;

· build clinical, medical, regulatory affairs, development and commercial infrastructure in the United States;

· maintain, expand and protect our intellectual property portfolio, including in-licensing additional intellectual property rights from third parties;

· hire additional executives to fill current vacancies, including a Chief Financial Officer and Chief Operating Officer; and

· incur cost to terminate or retain employees related to restructuring our operations.

We and our collaborators may never succeed in these activities and, even if we do, may never generate revenues that are sufficient to achieve or sustain profitability. Our failure to become and remain profitable would depress the value of our company and could impair our ability to expand our business, maintain our research and development efforts, diversify our product offerings or even continue our operations.

We will likely need to raise additional funding, which may not be available on acceptable terms, or at all. Failure to obtain capital when needed may force us to delay, limit or terminate our product development efforts or other operations which could have a material adverse effect on our business, financial conditions, results of operations and cash flows.

We expect to incur significant expenses in connection with our on-going activities and that we will likely need to obtain substantial additional funding in connection with our continuing operations. In addition, we have based our estimate of our financing requirements on assumptions that may prove to be wrong, and we could use our capital resources sooner than we currently expect.

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Adequate capital may not be available to us when needed or may not be available on acceptable terms. Our ability to obtain debt financing may be limited by covenants we have made under our Loan and Security Agreement with Hercules Technology Growth Capital, Inc. (“Hercules”) and our pledge to Hercules of substantially all of our assets as collateral. If we raise additional capital through the sale of equity or convertible debt securities, our shareholders’ ownership interest will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect the rights of holders of our common shares.

If we raise additional funds through collaborations, strategic alliances, or marketing, distribution or licensing arrangements with third parties, we may have to issue additional equity, relinquish valuable rights to our technologies, future revenue streams, products or product candidates, or grant licenses on terms that may not be favorable to us. If we are unable to raise capital when needed or on attractive terms, we could be forced to delay, reduce or eliminate our research and development programs or any future commercialization efforts, which would have a negative impact on our financial condition, results of operations and cash flows. If our collaborations with BMS and Chiesi are not successful, our development plans, financial position and opportunities for growth may be adversely affected.

Our existing and any future indebtedness could adversely affect our ability to operate our business.*

As of March 31, 2017, we had $20.4 million of outstanding borrowings under our Loan and Security Agreement with Hercules, which we are required to repay in monthly principal installments from December 2017 through May 2020. We could in the future incur additional debt obligations beyond our borrowings from Hercules. Our existing loan obligations, together with other similar obligations that we may incur in the future, could have significant adverse consequences, including:

· requiring us to dedicate a portion of our cash resources to the payment of interest and principal, reducing money available to fund working capital, capital expenditures, research and development and other general corporate purposes;

· increasing our vulnerability to adverse changes in general economic, industry and market conditions;

· subjecting us to restrictive covenants that may reduce our ability to take certain corporate actions or obtain further debt or equity financing;

· limiting our flexibility in planning for, or reacting to, changes in our business and the industry in which we compete; and

· placing us at a disadvantage compared to our competitors that have less debt or better debt servicing options.

We may not have sufficient funds, and may be unable to arrange for additional financing, to pay the amounts due under our existing loan obligations. Failure to make payments or comply with other covenants under our existing debt could result in an event of default and acceleration of amounts due. Under our agreement with Hercules, the occurrence of an event that would reasonably be expected to have a material adverse effect on our business, operations, assets or condition is an event of default. If an event of default occurs and the lender accelerates the amounts due, we may not be able to make accelerated payments, and the lender could seek to enforce security interests in the collateral securing such indebtedness, which includes substantially all of our assets.

We may be required to sublease space in excess of our requirements at our Amsterdam site.*

In March 2016, we entered into a lease for a new approximately 100,000 square feet facility in Amsterdam, and we amended this agreement in June 2016 in order to lease an additional 11,000 square feet. We intend to initiate the consolidation of our current three Amsterdam sites into the new site in the first half of 2017. The lease for this facility terminates in 2032. Following our restructuring announced in November 2016, we do not expect to utilize a significant portion of our new Amsterdam facility. We are contractually required to incur significant costs in relation to areas not utilized by us over the full contractual term. While we will seek to sublease any excess space, we may not be able to do so at commercially attractive terms.

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Risks Related to Other Legal Compliance Matters

Our relationships with customers and third party payers will be subject to applicable anti-kickback, anti-bribery, fraud and abuse and other laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.

Healthcare providers, physicians and third party payers will play a primary role in the recommendation and prescription of any products for which we obtain marketing approval. Our future arrangements with third party payers and customers may expose us to broadly applicable anti-bribery laws, including the Foreign Corrupt Practices Act, as well as fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute any products for which we obtain marketing approval.

Efforts to ensure that our business arrangements with third parties will comply with applicable laws and regulations will involve substantial costs. If our operations, or the activities of our collaborators, distributors or other third party agents are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, exclusion of products from government funded healthcare programs and the curtailment or restructuring of our operations.

If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could harm our business.

We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. Our operations involve the use of hazardous and flammable materials, including chemicals and biological materials. Our operations also produce hazardous waste products. We cannot eliminate the risk of contamination or injury from these materials. We also could incur significant costs associated with civil or criminal fines and penalties for failure to comply with such laws and regulations.

Although we maintain employer’s liability insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials, this insurance may not provide adequate coverage against potential liabilities. We do not maintain insurance for environmental liability or toxic tort claims that may be asserted against us in connection with our storage or disposal of biological, hazardous or radioactive materials.

In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. These current or future laws and regulations may impair our research, development or production efforts. Our failure to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions.

Product liability lawsuits could cause us to incur substantial liabilities and to limit commercialization of our therapies.

We face an inherent risk of product liability related to the testing of our product candidates in human clinical trials and in connection with product sales. If we cannot successfully defend ourselves against claims that our product candidates or products caused injuries, we will incur substantial liabilities. Regardless of merit or eventual outcome, liability claims may result in:

· decreased demand for any product candidates or products that we develop or sell;

· injury to our reputation and significant negative media attention;

· negative publicity or public opinion surrounding gene therapy;

· withdrawal of clinical trial participants;

· significant costs to defend the related litigation;

· substantial monetary awards to trial participants or patients;

· loss of revenue;

· reduced resources of our management to pursue our business strategy; and

· the inability to further develop or commercialize any products that we develop.

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Dependent upon the country where the clinical trial is conducted, we currently hold a maximum of €6,000,000 and minimum of €2,000,000 in clinical trial insurance coverage in the aggregate, with a per incident limit of €450,000 to €1,000,000 with respect to the clinical studies we conduct. Such coverage may not be adequate to cover all liabilities that we may incur. We may need to increase our insurance coverage as we expand our clinical trials. In addition, insurance coverage is increasingly expensive. We may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to satisfy any liability that may arise.

Risks Related to Employee Matters and Managing Growth

Our future success depends on our ability to retain key executives and technical staff and to attract, retain and motivate qualified personnel.

We are highly dependent on the research and development, clinical and business development expertise of our Chief Executive Officer, Mathew Kapusta; our Chief Medical Officer, Christian Meyer, M.D. and our Chief Scientific Officer, Harald Petry as well as the other principal members of our management, scientific and clinical team. Although we have entered into employment agreements with our senior management, each of them may terminate their employment on relatively short notice. We do not maintain key person insurance for any of our senior management or employees.

The loss of the services of our senior management or other key employees could impede the achievement of our research, development and commercialization objectives and seriously harm our ability to successfully implement our business strategy. Furthermore, replacing senior management and key employees may be difficult and may take an extended period of time because of the limited number of individuals in our industry with the breadth and depth of skills and experience required to successfully develop, gain regulatory approval of and commercialize gene therapy products. Competition to hire from this limited pool is intense, and we may be unable to hire, train, retain or motivate these key personnel on acceptable terms.

If we are unable to continue to attract and retain high quality personnel, our ability to pursue our growth strategy will be limited.

We have initiated a significant restructuring of our operations that will include a sizable reduction in headcount in our Amsterdam facility and expansion of personnel in our Lexington facility, and as a result, we may encounter challenges managing the associated organizational change.*

In November 2016, we announced plans to restructure and refocus our business, which will result in the elimination of approximately 50 to 55 positions, as well as the transition of certain operations to our Lexington, Massachusetts facility. We will incur expenses related to the reduction in staff as well as the retention of key personnel. We may also experience operational disruptions as we implement our new organizational structure and transfer certain functions to Lexington. This process may distract the attention of management and staff and may cause disruption in our operations.

At the same time, we continue to expand the scope of certain of our operations in the United States, particularly in the areas of clinical operations, medical and regulatory affairs and product development. To manage our operations and new organizational structure, we will be required to implement and improve our managerial, operational and financial systems and recruit and train additional qualified personnel. Due to our limited financial resources and the limited experience of our management team in implementing significant organizational change, we may not be able to effectively manage this process.

Risks Related to Our Common Shares

The price of our common shares has been and may in the future be volatile and fluctuate substantially.*

Our share price has been and may in the future be volatile. From the start of trading of our common shares on the NASDAQ Global Select Market on February 4, 2014 through May 1, 2017, the sale price of our common shares ranged from a high of $36.38 to a low of $4.91. The closing price on May 1, 2017, was $5.46 per common share. The stock market in general and the market for smaller biopharmaceutical companies in particular have experienced extreme volatility that has often been unrelated to the operating performance of particular companies. The market price for our common shares may be influenced by many factors, including:

· the success of competitive products or technologies;

· results of clinical trials of our product candidates or those of our competitors;

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· public perception of gene therapy;

· regulatory delays and greater government regulation of potential products due to adverse events;

· regulatory or legal developments in the European Union, the United States and other countries;

· developments or disputes concerning patent applications, issued patents or other proprietary rights;

· the recruitment or departure of key personnel;

· the level of expenses related to any of our product candidates or clinical development programs;

· the results of our efforts to discover, develop, acquire or in- license additional product candidates or products;

· actual or anticipated changes in estimates as to financial results, development timelines or recommendations by securities analysts;

· variations in our financial results or those of companies that are perceived to be similar to us;

· changes in the structure of healthcare payment systems;

· market conditions in the pharmaceutical and biotechnology sectors; and

· general economic, industry and market conditions.

An active trading market for our common shares may not be sustained.

Although our common shares are listed on The NASDAQ Global Select Market, an active trading market for our shares may not be sustained. If an active market for our common shares does not continue, it may be difficult for our shareholders to sell their shares without depressing the market price for the shares or sell their shares at all. Any inactive trading market for our common shares may also impair our ability to raise capital to continue to fund our operations by selling shares and may impair our ability to acquire other companies or technologies by using our shares as consideration.

Our directors and named executive officers and major shareholders, if they choose to act together, will continue to have a significant degree of control with respect to matters submitted to shareholders for approval. *

Our directors and named executive offices and major shareholders more than 5% of our outstanding common shares, in the aggregate, beneficially own approximately 31.5% of our issued shares as at March 31, 2017. As a result, if these shareholders were to choose to act together, they may be able, as a practical matter, to control many matters submitted to our shareholders for approval, as well as our management and affairs. For example, these persons, if they choose to act together, could control the election of board directors and approval of any merger, consolidation or sale of all or substantially all of our assets.

Provisions of our articles of association or Dutch corporate law might deter acquisition bids for us that might be considered favorable and prevent or frustrate any attempt to replace our board.

Certain provisions of our articles of association may make it more difficult for a third party to acquire control of us or effect a change in our board. These provisions include:

· staggered terms of our directors;

· a provision that our directors may only be removed at a general meeting of shareholders by a two-thirds majority of votes cast representing more than half of the issued share capital of the company (unless the removal was proposed by the board); and

· a requirement that certain matters, including an amendment of our articles of association, may only be brought to our shareholders for a vote upon a proposal by our board.

We do not expect to pay dividends in the foreseeable future.

We have not paid any dividends since our incorporation. Even if future operations lead to significant levels of distributable profits, we currently intend that earnings, if any, will be reinvested in our business and that dividends will not be paid until we have an established revenue stream to support continuing dividends. Accordingly, shareholders cannot rely on dividend income from our common shares and any returns on an investment in our common shares will likely depend entirely upon any future appreciation in the price of our common shares.

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We are an “emerging growth company,” and the reduced disclosure requirements applicable to emerging growth companies may make our common shares less attractive to investors.

We are an emerging growth company, as defined in the Jumpstart Our Business Startups Act of 2012 (“JOBS Act”) and may remain an emerging growth company for up to five years from our initial public offering. For so long as we remain an emerging growth company, we are permitted and intend to rely on exemptions from certain disclosure requirements that are applicable to other public companies that are not emerging growth companies. These exemptions include:

· not being required to comply with the auditor attestation requirements in the assessment of our internal control over financial reporting; and

· not being required to comply with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor’s report providing additional information about the audit and the financial statements.

If some investors find our common shares less attractive as a result of our reliance on these exemptions, trading market for our common shares may be less active and our share price may be more volatile.

We ceased to qualify as a foreign private issuer as of January 1, 2017, and therefore must comply with the Exchange Act, which will result in additional legal, accounting and other expenses.

Beginning in January 2017, we must comply with the Exchange Act reporting and other requirements applicable to U.S. domestic filers, which are more detailed and extensive than the requirements for foreign private issuers to which we were previously subject. In addition, we are now required to report our financial results under U.S. GAAP, including our historical financial results, which have previously been prepared in accordance with International Financial Reporting Standards (“IFRS”). We have made changes in our corporate governance practices in accordance with various SEC and NASDAQ rules. The transition to U.S. GAAP reporting has required additional expenditures, and the related regulatory, compliance and insurance costs to us may be significantly higher than the costs we incurred as a foreign private issuer.

If we fail to implement and maintain an effective system of internal controls, we may be unable to accurately report our results of operations or prevent fraud or fail to meet our reporting obligations, and investor confidence and the market price of our common shares may be materially and adversely affected.

If we fail to achieve and maintain the adequacy of our internal control over financial reporting, we may not be able to conclude on an ongoing basis that we have effective internal control over financial reporting. If we fail to achieve and maintain effective internal control over financial reporting, we could experience material misstatements in our financial statements and fail to meet our reporting obligations, which would likely cause investors to lose confidence in our reported financial information. This could in turn limit our access to capital markets, harm our results of operations, and lead to a decline in the trading price of our common shares. Additionally, ineffective internal control over financial reporting could expose us to increased risk of fraud or misuse of corporate assets and subject us to potential delisting from The NASDAQ Global Select Market, regulatory investigations and civil or criminal sanctions. Our reporting and compliance obligations may place a significant strain on our management, operational and financial resources and systems for the foreseeable future. We have previously identified material weaknesses in our internal controls, and our remediation efforts in this regard may not be effective.

Risks for U.S. Holders

We qualify as a passive foreign investment company as of December 31, 2016, which may result in adverse U.S. federal income tax consequence to U.S. holders.

Based on our average value of our gross assets, our cash and cash equivalents as well as the price of our shares we qualify as a passive foreign investment company (“PFIC”) for U.S. federal income tax for 2016. A corporation organized outside the United States generally will be classified as a PFIC for U.S. federal income tax purposes in any taxable year in which at least 75% of its gross income is passive income or on average at least 50% of the gross value of its assets is attributable to assets that produce passive income or are held for the production of passive income. Passive income for this purpose generally includes dividends, interest, royalties, rents and gains from commodities and securities transactions. Our status in any taxable year will depend on our assets and activities in each year, and because this is a factual determination made annually after the end of each taxable year, there can be no assurance that we will continue to qualify as a PFIC in future taxable years. The market value of our assets may be determined in large part by reference to the market price of our common shares, which is likely to fluctuate, and may fluctuate considerably given that market prices of biotechnology

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companies have been especially volatile. As we are a PFIC for the taxable year 2016, certain adverse U.S. federal income tax consequences, including reporting obligations, could apply to a U.S. holder who held our common shares during 2016.

Any U.S. or other foreign judgments may be difficult to enforce against us in the Netherlands.

Although we now report as a U.S. domestic filer for SEC reporting purposes, we are incorporated under the laws of the Netherlands. Some of the members of our board and senior management reside outside the United States. As a result, it may not be possible for shareholders to effect service of process within the United States upon such persons or to enforce judgments against them or us in U.S. courts, including judgments predicated upon the civil liability provisions of the federal securities laws of the United States. In addition, it is not clear whether a Dutch court would impose civil liability on us or any of our managing directors or supervisory directors in an original action based solely upon the federal securities laws of the United States brought in a court of competent jurisdiction in the Netherlands.

The United States and the Netherlands currently do not have a treaty providing for the reciprocal recognition and enforcement of judgments, other than arbitration awards, in civil and commercial matters. Consequently, a final judgment for payment given by a court in the United States, whether or not predicated solely upon U.S. securities laws, would not automatically be recognized or enforceable in the Netherlands. In order to obtain a judgment which is enforceable in the Netherlands, the party in whose favor a final and conclusive judgment of the U.S. court has been rendered will be required to file its claim with a court of competent jurisdiction in the Netherlands. Such party may submit to the Dutch court the final judgment rendered by the U.S. court. If and to the extent that the Dutch court finds that the jurisdiction of the U.S. court has been based on grounds which are internationally acceptable and that proper legal procedures have been observed, the Dutch court will, in principle, give binding effect to the judgment of the U.S. court, unless such judgment contravenes principles of public policy of the Netherlands. Dutch courts may deny the recognition and enforcement of punitive damages or other awards. Moreover, a Dutch court may reduce the amount of damages granted by a U.S. court and recognize damages only to the extent that they are necessary to compensate actual losses or damages. Enforcement and recognition of judgments of U.S. courts in the Netherlands are solely governed by the provisions of the Dutch Civil Procedure Code.

Therefore U.S. shareholders may not be able to enforce against us or our board members or senior management who are residents of the Netherlands or countries other than the United States any judgments obtained in U.S. courts in civil and commercial matters, including judgments under the U.S. federal securities laws.

The rights and responsibilities of our shareholders and directors are governed by Dutch law and differ in some important respects from the rights and responsibilities of shareholders under U.S. law.

Although we now report as a U.S. domestic filer for SEC purposes, our corporate affairs are governed by our articles of association and by the laws governing companies incorporated in the Netherlands. The rights of our shareholders and the responsibilities of members of our board under Dutch law are different than under the laws of some U.S. jurisdictions. In the performance of their duties, our board members are required by Dutch law to consider the interests of uniQure, its shareholders, its employees and other stakeholders and not only those of our shareholders.

Item 2. Unregistered Sales of Equity Securities and Use of Proceeds

None.

Item 3. Defaults Upon Senior Securities

None.

Item 4. Mine Safety Disclosures

None.

Item 5. Other Information

None.

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Item 6. Exhibits

See the Exhibit Index following the signature page to this Quarterly Report on Form 10-Q for a list of exhibits filed or furnished with this report, which Exhibit Index is incorporated herein by reference.

SIGNATURE

Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.

	UNIQURE, N.V.


	By:	/s/ Matthew Kapusta
	Matthew Kapusta
	Chief Executive Officer and Interim Chief Financial Officer (Principal Executive Officer and Principal Financial Officer)
	Date: May 9, 2017

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EXHIBIT INDEX

3.1 Amended Articles of Association (incorporated by reference to Exhibit 1.1 of the Company’s annual report on Form 10-K for the year ended December 31, 2016 (file no. 0001-36294) filed with the Securities and Exchange Commission).

10.1* Patent License Agreement (L 107 2007), effective as of May 2, 2007, by and between the Company and the National Institutes of Health, as amended on December 31, 2009, May 31, 2013 and November 11, 2013 (a redacted version was previously filed as Exhibit 10.1 of the Company’s registration statement on form F-1 (file no. 333 193158) filed with the SEC).

10.2* Patent License Agreement (L 116 2011), effective as of August 10, 2011, by and between the Company and National Institutes of Health, as amended on May 31, 2013 and November 11, 2013 (a redacted version was previously filed as Exhibit 10.2 of the Company’s registration statement on form F-1 (file no. 333 193158) filed with the SEC).

10.3* Exclusive License Agreement, effective as of July 7, 2008, by and between the Company and St. Jude Children’s Research Hospital, Inc., as amended on July 12, 2012 (a redacted version was previously filed as Exhibit 10.10 of the Company’s registration statement on form F 1 (file no. 333 193158) filed with the SEC).

10.4* Co Development and License Agreement, entered into as of April 29, 2013, by and between the Company and Chiesi Farmaceutici S.p.A. (a redacted version was previously filed as Exhibit 10.11 of the Company’s registration statement on form F 1 (file no. 333 193158) filed with the SEC).

31.1* Rule 13a-14(a)/15d-14(a) Certification of Chief Executive Officer

31.2* Rule 13a-14(a)/15d-14(a) Certification of Chief Executive Officer

32.1* Section 1350 Certification (furnished herewith)

101* The following financial information from our Quarterly Report on Form 10-Q for the period ended March 31, 2017, filed with the Securities and Exchange Commission on May 9, 2017 is formatted in Extensible Business Reporting Language (“XBRL”): (i) Consolidated Balance Sheets; (ii) Consolidated Statements of Operations and Comprehensive Loss; (iii) Consolidated Statements of Shareholders’ Equity; (iv) Consolidated Statements of Cash Flows; and (v) Notes to Consolidated Financial Statements (tagged as blocks of text)

* Filed herewith.

Exhibit 10.1

PUBLIC HEALTH SERVICE

PATENT LICENSE AGREEMENT - NONEXCLUSIVE

COVER PAGE

For PHS internal use only:

License Number:

L - 1 0 7 - 2007 / 0

License Application Number: A-274-2006

Serial Number(s) of Licensed Patent(s) or Patent Application(s):

I. U.S. Patent Application(s) or Patent(s):

(a) U.S. Patent Application Serial No. 09/986,618, filed November 9, 2001, now abandoned, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/0-US-01”];

(b) U.S. Patent No. 6,723,551, issued April 20, 2004, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/1-US-01]; and

(c) U.S. Patent Application Serial No. 10/415,834, filed May 2, 2003, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/2-US-02].

II. PCT or Foreign Patent Application(s) or Patent(s):

(a) PCT Patent Application Serial No. PCT/US02/35829, filed November 8, 2002, now abandoned, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/2-PCT-01];

(b) Canadian Patent Application Serial No. 2,467,959, filed May 6, 2004, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/2-CA-03];

(c) European Patent Application Serial No. 02795604.4, filed June 8, 2004, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/2-EP-04]; and

(d) Australian Patent Application Serial No. 2002360355, filed April 28, 2004, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/2-AU-05].

Licensee: Amsterdam Molecular Therapeutics

Cooperative Research and Development Agreement (CRADA) Number (if a subject invention): N/A

Additional Remarks: None

Public Benefit(s): Commercialization of this technology will benefit the public health by increasing the number of therapeutics available for the public.

This Patent License Agreement, hereinafter referred to as the “ Agreement ”, consists of this Cover Page, an attached Agreement , a Signature Page, Appendix A (List of Patent(s) or Patent Application(s)), Appendix B (Fields of Use and Territory), Appendix C (Royalties), Appendix D ((Benchmarks and Performance), Appendix E (Commercial Development Plan), Appendix F (Example Royalty Report), and Appendix G (Royalty Payment Options) . The Parties to this Agreement are:

1) The National Institutes of Health (“ NIH ”) or the Food and Drug Administration (“ FDA ”), hereinafter singly or collectively referred to as “ PHS ”, agencies of the United States Public Health Service within the Department of Health and Human Services (“ HHS ”); and

2) The person, corporation, or institution identified above and on the Signature Page, having offices at the address indicated on the Signature Page, hereinafter referred to as “ Licensee .”

PHS PATENT LICENSE AGREEMENT- NONEXCLUSIVE

PHS and Licensee agree as follows:

1. BACKGROUND

1.1 In the course of conducting biomedical and behavioral research, PHS investigators made inventions that may have commercial applicability.

1.2 By assignment of rights from PHS employees and other inventors, HHS , on behalf of the Government , owns intellectual property rights claimed in any United States or foreign patent applications or patents corresponding to the assigned inventions . HHS also owns any tangible embodiments of these inventions actually reduced to practice by PHS .

1.3 The Secretary of HHS has delegated to PHS the authority to enter into this Agreement for the licensing of rights to these inventions under 35 U.S.C. §§200-212, the Federal Technology Transfer Act of 1986, 15 U.S.C. §3710(a), and the regulations governing the licensing of Government-owned inventions, 37 CFR Part 404.

1.4 PHS desires to transfer these inventions to the private sector through commercialization licenses to facilitate the commercial development of products and processes for public use and benefit.

1.5 Licensee desires to acquire commercialization rights to certain of these inventions in order to develop processes, methods, or marketable products for public use and benefit.

2. DEFINITIONS

2.1 “ Benchmarks ” mean the performance milestones that are set forth in Appendix D.

2.2 “ Commercial Development Plan ” means the written commercialization plan attached as Appendix E.

2.3 “ First Commercial Sale ” means the initial transfer by or on behalf of Licensee or its sublicensees of Licensed Products or New Products by or on behalf of Licensee or its sublicensees in exchange for cash or some equivalent to which value can be assigned for the purpose of determining Net Sales .

2.4 “ Government ” means the Government of the United States of America.

2.5 “ Licensed Fields of Use ” means the fields of use identified in Appendix B.

2.6 “ Licensed Patent Rights ” shall mean:

(a) Patent applications (including provisional patent applications and PCT patent applications) or patents listed in Appendix A, all divisions and

continuations of these applications, all patents issuing from these applications, divisions, and continuations, and any reissues, reexaminations, and extensions of all these patents;

(b) to the extent that the following contain one or more claims directed to the invention or inventions disclosed in 2.6(a):

(i) continuations-in-part of 2.6(a);

(ii) all divisions and continuations of these continuations-in-part;

(iii) all patents issuing from these continuations-in-part, divisions, and continuations;

(iv) priority patent application(s) of 2.6(a); and

(v) any reissues, reexaminations, and extensions of all these patents;

(c) to the extent that the following contain one or more claims directed to the invention or inventions disclosed in 2.6(a): all counterpart foreign and U.S. patent applications and patents to 2.6(a) and 2.6(b), including those listed in Appendix A; and

(d) Licensed Patent Rights shall not include 2.6(b) or 2.6(c) to the extent that they contain one or more claims directed to new matter which is not the subject matter disclosed in 2.6(a).

2.7 “ Licensed Processes ” means processes, which in the course of being practiced, would be within the scope of one or more claims of the Licensed Patent Rights that have not been held unpatentable, invalid or unenforceable by an unappealed or unappealable judgment of a court of competent jurisdiction.

2.8 “ Licensed Products ” means (a) Supplied Materials and (b) tangible materials, which in the course of manufacture, use, sale, or importation, would be within the scope of one or more claims of the Licensed Patent Rights that have not been held unpatentable, invalid or unenforceable by an unappealed or unappealable judgment of a court of competent jurisdiction.

2.9 “ Licensed Territory ” means the geographical area identified in Appendix B.

2.10 “ Net Sales ” means the total gross receipts for sales of Licensed Products or New Products by or on behalf of Licensee or its sublicensees, and from leasing, renting, or otherwise making Licensed Products or New Products available to others without sale or other dispositions, whether invoiced or not, less returns and allowances, packing costs, insurance costs, freight out, taxes or excise duties imposed on the transaction (if separately invoiced), and wholesaler and cash discounts in amounts customary in the trade to the extent actually granted . No deductions shall be made for commissions paid to individuals, whether they are

with independent sales agencies or regularly employed by Licensee or its sublicensees, and on its payroll, or for the cost of collections.

2.11 “ New Product ” means a product made using a Licensed Process but excluding Licensed Products .

2.12 “ Practical Application ” means to manufacture in the case of a composition or product, to practice in the case of a process or method, or to operate in the case of a machine or system; and in each case, under these conditions as to establish that the invention is being utilized and that its benefits are to the extent permitted by law or Government regulations available to the public on reasonable terms.

2.13 Supplied Materials ” means (a) the plasmid pFBDLSR: a plasmid for the expression of the Rep52 ORF from the baculovirus Polh promoter and the Rep78 ORF from the modified IE-1 promoter . The dual Rep ORF containing plasmid is constructed by separately cloning the Rep78 and Rep52 ORF’s and combining the two ORF’s in a single expression vector/plasmid [see page 22, Paragraphs 79-81 of U.S. Patent Application Serial No. 09/986,618 (HHS Ref. No. E-325-2001/0-US-01)]; (b) the plasmid pFBAAV1pm11: a plasmid for the expression of the products of the AAV1 CAP gene which encodes the VP1, VP2 and VP3 capsid proteins from the baculovirus polh . The VP genes have been modified from the wild type to produce VP1 at a level equal to VP2 without influencing VP3 expression [see pages 22-23, Paragraphs 84-85 of United States Patent Application Serial No. 09/986,618 (HHS Ref No. E-325-2001/0-US-01]; and (c) the plasmid pFBGFPR: a plasmid for the expression of GFP (green fluorescent protein) from a CMV or p10 promoter, where the promoters and GFP sequence are contained between a pair of AAV2 ITR’s . Note that the plasmid has an additional cloning site which facilitates swapping-in/out eGFP with a gene of interest [see Example 1, page 20, paragraph 74 of United States Patent Application Serial No. 09/986,618 (HHS Ref. No. E-325-2001/0-US-01)] . Further, these Supplied Materials were supplied by PHS to Licensee under a Non-Exclusive Patent License Agreement for Internal Commercial Use (L-043-2003/0) which was effective on May 14, 2003.

3. GRANT OF RIGHTS

3.1 PHS hereby grants and Licensee accepts, subject to the terms and conditions of this Agreement, a nonexclusive license under the Licensed Patent Rights in the Licensed Territory to make and have made, to use and have used, to sell and have sold, to offer to sell, and to import any Licensed Products or New Products in the Licensed Fields of Use , to practice and have practiced any Licensed Processes in the Licensed Fields of Use , to make, have made, to use and have used but not to sell any Supplied Materials. As used in this Agreement , “have made” and “have used” means that Licensee shall have the limited right to use a

third party contract manufacturer to make and use only (but not to sell) Supplied Materials , Licensed Products or New Products. Licensee acknowledges and agrees that any such third party contract manufacturer shall be bound to the terms and obligations of this Agreement .

3.2 This Agreement confers no license or rights by implication, estoppel, or otherwise under any patent applications or patents of PHS other than the Licensed Patent Rights regardless of whether these patents are dominant or subordinate to the Licensed Patent Rights .

4. SUBLICENSING

4.1 Upon written approval, which shall include prior review of any sublicense agreement by PHS and which shall not be unreasonably withheld, Licensee may enter into sublicensing agreements under the Licensed Patent Rights , except that Licensee shall not have the right to solely sublicense Licensed Patent Rights. For the avoidance of doubt . Licensee shall only sublicense the Licensed Patent Rights in conjunction with other intellectual property owned by the Licensee or in-licensed by the Licensee .

4.2 Licensee agrees that any sublicenses granted by it shall provide that the obligations to PHS of Paragraphs 5.1, 5.2, 8.1, 10.1, 10.2, 12.5 and 13.6-13.8 of this Agreement shall be binding upon the sublicensee as if it were a party to this Agreement. Licensee further agrees to attach copies of these Paragraphs to all sublicense agreements.

4.3 Any sublicenses granted by Licensee shall provide for the termination of the sublicense, or the conversion to a license directly between the sublicensee and PHS , at the option of the sublicensee, upon termination of this Agreement under Article 13 . This conversion is subject to PHS approval and contingent upon acceptance by the sublicensee of the remaining provisions of this Agreement .

4.4 Licensee agrees to forward PHS a complete copy of each fully executed sublicense agreement postmarked within thirty (30) days of the execution of the agreement . To the extent permitted by law, PHS agrees to maintain each sublicense agreement in confidence.

5. STATUTORY AND PHS REQUIREMENTS AND RESERVED GOVERNMENT RIGHTS

5.1 Prior to the First Commercial Sale , Licensee agrees to provide PHS with reasonable quantities of Licensed Products or New Products made through the Licensed Processes or Supplied Materials solely for PHS research use, if requested in writing.

5.2 Licensee agrees that products used or sold in the United States embodying Licensed Products or New Products or produced through use of Licensed Processes shall be manufactured substantially in the United States, unless a written waiver is obtained in advance from PHS .

6. ROYALTIES AND REIMBURSEMENT

6.1 Licensee agrees to pay PHS a noncreditable, nonrefundable license issue royalty as set forth in Appendix C.

6.2 Licensee agrees to pay PHS a nonrefundable minimum annual royalty as set forth in Appendix C.

6.3 Licensee agrees to pay PHS earned royalties as set forth in Appendix C.

6.4 Licensee agrees to pay PHS sublicensing royalties as set forth in Appendix C.

6.5 A patent or patent application licensed under this Agreement shall cease to fall within the Licensed Patent Rights for the purpose of computing earned royalty payments in any given country on the earliest of the dates that:

(a) the application has been abandoned and not continued;

(b) the patent expires or irrevocably lapses; or

(c) the claim has been held to be invalid or unenforceable by an unappealed or unappealable decision of a court of competent jurisdiction or administrative agency.

6.6 No multiple royalties shall be payable because any Licensed Products or New Products or Licensed Processes are covered by more than one of the Licensed Patent Rights .

6.7 On sales of Licensed Products or New Products by Licensee to sublicensees or on sales made in other than an arms-length transaction, the value of the Net Sales attributed under this Article 6 to this transaction shall be that which would have been received in an arms-length transaction, based on sales of like quantity and quality products on or about the time of this transaction.

7. PATENT FILING, PROSECUTION, AND MAINTENANCE

7.1 PHS agrees to take responsibility for the preparation, filing, prosecution, and maintenance of any and all patent applications or patents included in the Licensed Patent Rights .

8. RECORD KEEPING

8.1 Licensee agrees to keep accurate and correct records of Licensed Products or New Products made, used, sold, or imported and Licensed Processes practiced under this Agreement appropriate to determine the amount of royalties due PHS.

These records shall be retained for at least five (5) years following a given reporting period and shall be available during normal business hours for inspection, at the expense of PHS , by an accountant or other designated auditor selected by PHS for the sole purpose of verifying reports and royalty payments hereunder. The accountant or auditor shall only disclose to PHS information relating to the accuracy of reports and royalty payments made under this Agreement. If an inspection shows an underreporting or underpayment in excess of five percent (5%) for any twelve (12) month period, then Licensee shall reimburse PHS for the cost of the inspection at the time Licensee pays the unreported royalties, including any additional royalties as required by Paragraph 9.8. All royalty payments required under this Paragraph shall be due within thirty (30) days of the date PHS provides Licensee notice of the payment due.

8.2 Licensee agrees to have an audit of sales and royalties conducted by an independent auditor at least every two (2) years if annual sales of the Licensed Products or Licensed Processes or New Products are over two (2) million dollars. The audit shall address, at a minimum, the amount of gross sales by or on behalf of Licensee during the audit period, terms of the license as to percentage or fixed royalty to be remitted to the Government , the amount of royalties owed to the Government under this Agreement , and whether the royalties owed have been paid to the Government and is reflected in the records of the Licensee . The audit shall also indicate the PHS license number, product, and the time period being audited. A report certified by the auditor shall be submitted promptly by the auditor directly to PHS and Licensee on completion.

9. REPORTS ON PROGRESS, BENCHMARKS, SALES, AND PAYMENTS

9.1 Prior to signing this Agreement , Licensee has provided PHS with the Commercial Development Plan in Appendix E, under which Licensee intends to bring the subject matter of the Licensed Patent Rights or New Products to the point of Practical Application. This Commercial Development Plan is hereby incorporated by reference into this Agreement. Based on this plan, performance Benchmarks are determined as specified in Appendix D.

9.2 Licensee shall provide written annual reports on its product development progress or efforts to commercialize under the Commercial Development Plan for the Licensed Fields of Use within sixty (60) days after December 31 of each calendar year. These progress reports shall include, but not be limited to: progress on research and development, status of applications for regulatory approvals, manufacturing, marketing, importing, and sales during the preceding calendar year, as well as, plans for the present calendar year . PHS also encourages these reports to include information on any of Licensee’s public service activities that relate to the Licensed Patent Rights or New Products. If reported progress differs from that projected in the Commercial Development Plan and

Benchmarks , Licensee shall explain the reasons for such differences . In any annual report, Licensee may propose amendments to the Commercial Development Plan , acceptance of which by PHS may not be denied or delayed unreasonably. Licensee agrees to provide any additional information reasonably required by PHS to evaluate Licensee ’s performance under this Agreement. Licensee may amend the Benchmarks at any time upon written approval by PHS. PHS shall not unreasonably withhold approval of any request of Licensee to extend the time periods of this schedule if the request is supported by a reasonable showing by Licensee of diligence in its performance under the Commercial Development Plan and toward bringing the Licensed Products or New Products to the point of Practical Application .

9.3 Licensee shall report to PHS the dates for achieving Benchmarks specified in Appendix D and the First Commercial Sale in each country in the Licensed Territory within thirty (30) days of such occurrences.

9.4 Licensee shall submit to PHS , within sixty (60) days after each calendar half-year ending June 30 and December 31, a royalty report, as described in the example in Appendix F, setting forth for the preceding half-year period the amount of the Licensed Products or New Products sold or Licensed Processes practiced by or on behalf of Licensee in each country within the Licensed Territory , the Net Sales, and the amount of royalty accordingly due . With each royalty report, Licensee shall submit payment of earned royalties due . If no earned royalties are due to PHS for any reporting period, the written report shall so state . The royalty report shall be certified as correct by an authorized officer of Licensee and shall include a detailed listing of all deductions made under Paragraph 2.10 to determine Net Sales made under Article 6 to determine royalties due.

9.5 Licensee agrees to forward semi-annually to PHS a copy of reports received by Licensee from its sublicensees during the preceding half-year period as shall be pertinent to a royalty accounting to PHS by Licensee for activities under the sublicense.

9.6 Royalties due under Article 6 shall be paid in U.S. dollars and payment options are listed in Appendix G. For conversion of foreign currency to U.S. dollars, the conversion rate shall be the New York foreign exchange rate quoted in The Wall Street Journal on the day that the payment is due, and any loss of exchange, value, taxes, or other expenses incurred in the transfer or conversion to U.S. dollars shall be paid entirely by Licensee. The royalty report required by Paragraph 9.4 shall be mailed to PHS at its address for Agreement Notices indicated on the Signature Page.

9.7 Licensee shall be solely responsible for determining if any tax on royalty income is owed outside the United States and shall pay this tax and be responsible for all filings with appropriate agencies of foreign governments.

9.8 Additional royalties may be assessed by PHS on any payment that is more than ninety (90) days overdue at the rate of one percent (1%) per month. This one percent (1%) per month rate may be applied retroactively from the original due date until the date of receipt by PHS of the overdue payment and additional royalties. The payment of any additional royalties shall not prevent PHS from exercising any other rights it may have as a consequence of the lateness of any payment.

9.9 All plans and reports required by this Article 9 and marked “confidential” by Licensee shall, to the extent permitted by law, be treated by PHS as commercial and financial information obtained from a person and as privileged and confidential, and any proposed disclosure of these records by the PHS under the Freedom of Information Act (FOIA), 5 U.S.C. §552 shall be subject to the predisclosure notification requirements of 45 CFR §5.65(d).

10. PERFORMANCE

10.1 Licensee shall use its reasonable commercial efforts to bring the Licensed Products or New Products and Licensed Processes to Practical Application. “Reasonable commercial efforts” for the purposes of this provision shall include adherence to the Commercial Development Plan in Appendix E and performance of the Benchmarks in Appendix D . The efforts of a sublicense shall be considered the efforts of Licensee .

10.2 Upon the First Commercial Sale , until the expiration or termination of this Agreement , Licensee shall use its reasonable commercial efforts to make Licensed Products or New Products and Licensed Processes reasonably accessible to the United States public.

10.3 Licensee agrees, after its First Commercial Sale , to make reasonable quantities of Licensed Products or New Products ormaterialsproduced through the use of Licensed Processes available on a compassionate use basis to patients, either through the patient’s physician(s) or the medical center treating the patient.

10.4 Licensee agrees, after its First Commercial Sale and as part of its marketing and product promotion, to develop educational materials (e.g., brochures, website, etc.) directed to patients and physicians detailing the Licensed Products or New Products or medical aspects of the prophylactic and therapeutic uses of the Licensed Products or New Products .

10.5 Licensee agrees to supply, to the Mailing Address for Agreement Notices indicated on the Signature Page, the Office of Technology Transfer, NIH with

inert samples of the Licensed Products or New Products or their packaging for educational and display purposes only.

11. INFRINGEMENT AND PATENT ENFORCEMENT

11.1 PHS and Licensee agree to notify each other promptly of each infringement or possible infringement of the Licensed Patent Rights , as well as, any facts which may affect the validity, scope, or enforceability of the Licensed Patent Rights of which either Party becomes aware.

11.2 In the event that a declaratory judgment action alleging invalidity of any of the Licensed Patent Rights shall be brought against PHS , PHS agrees to notify Licensee that an action alleging invalidity has been brought. PHS does not represent that it shall commence legal action to defend against a declaratory action alleging invalidity. Licensee shall take no action to compel the Government either to initiate or to join in any declaratory judgment action. Should the Government be made a party to any suit by motion or any other action of Licensee , Licensee shall reimburse the Government for any costs, expenses, or fees, which the Government incurs as a result of the motion or other action. Upon Licensee’s payment of all costs incurred by the Government as a result of Licensee’s joinder motion or other action, these actions by Licensee shall not be considered a default in the performance of any material obligation under this Agreement .

12. NEGATION OF WARRANTIES AND INDEMNIFICATION

12.1 PHS offers no warranties other than those specified in Article 1.

12.2 PHS does not warrant the validity of the Licensed Patent Rights and makes no representations whatsoever with regard to the scope of the Licensed Patent Rights , or that the Licensed Patent Rights and Supplied Materials may be exploited without infringing other patents or other intellectual property rights of third parties.

12.3 PHS MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OF ANY SUBJECT MATTER DEFINED BY THE CLAIMS OF THE LICENSED PATENT RIGHTS OR TANGIBLE MATERIALS RELATED THERETO, INCLUDING BUT NOT LIMITED TO SUPPLIED MATERIALS .

12.4 PHS does not represent that it shall commence legal actions against third parties infringing the Licensed Patent Rights or Supplied Materials .

12.5 Licensee shall indemnify and hold PHS , its employees, students, fellows, agents, and consultants harmless from and against all liability, demands, damages,

expenses, and losses, including but not limited to death, personal injury, illness, or property damage in connection with or arising out of:

(a) the use by or on behalf of Licensee , its sublicensees, its directors, employees, or third parties of any Licensed Patent Rights or Supplied Materials ; or

(b) the design, manufacture, distribution, or use of any Licensed Products , Licensed Processes or New Products by Licensee , or other products or processes developed in connection with or arising out of the Licensed Patent Rights. Licensee agrees to maintain a liability insurance program consistent with sound business practice.

12.6 Licensee agrees to maintain a liability insurance program consistent with sound business practice.

13. TERM, TERMINATION, AND MODIFICATION OF RIGHTS

13.1 This Agreement is effective when signed by all parties, unless the provisions of Paragraph 14.15 are not fulfilled, and shall extend to the expiration of the last to expire of the Licensed Patent Rights unless sooner terminated as provided in this Article 13.

13.2 In the event that Licensee is in default in the performance of any material obligations under this Agreement , including but not limited to the obligations listed in Paragraph 13.05, and if the default has not been remedied within ninety (90) days after the date of notice in writing of the default, PHS may terminate this Agreement by written notice and pursue outstanding royalties owed through procedures provided by the Federal Debt Collection Act.

13.3 In the event that Licensee becomes insolvent, files a petition in bankruptcy, has such a petition filed against it, determines to file a petition in bankruptcy, or receives notice of a third party’s intention to file an involuntary petition in bankruptcy, Licensee shall immediately notify PHS in writing . Furthermore, PHS shall have the right to terminate this Agreement immediately upon Licensee’s receipt of written notice.

13.4 Licensee shall have a unilateral right to terminate this Agreement in any country or territory by giving PHS sixty (60) days written notice to that effect.

13.5 PHS shall specifically have the right to terminate or modify, at its option, this Agreement , if PHS determines that the Licensee :

(a) is not executing the Commercial Development Plan submitted with its request for a license and the Licensee cannot otherwise demonstrate to PHS’ satisfaction that the Licensee has taken, or can be expected to take

within a reasonable time, effective steps to achieve Practical Application of the Licensed Products or New Products ;

(b) has not achieved the Benchmarks as may be modified under Paragraph 9.2;

(c) has willfully made a false statement of, or willfully omitted, a material fact in the license application or in any report required by this Agreement ;

(d) has committed a material breach of a covenant or agreement contained in this Agreement ;

(e) is not keeping Licensed Products or New Products reasonably available to the public after commercial use commences;

(f) cannot reasonably satisfy unmet health and safety needs; or

(g) cannot reasonably justify a failure to comply with the domestic production requirement of Paragraph 5.2, unless waived.

13.6 In making the determination referenced in Paragraph 13.5, PHS shall take into account the normal course of such commercial development programs conducted with sound and reasonable business practices and judgment and the annual reports submitted by Licensee under Paragraph 9.2 . Prior to invoking termination or modification of this Agreement under Paragraph 13.5, PHS shall give written notice to Licensee providing Licensee specific notice of, and a ninety (90) day opportunity to respond to, PHS’ concerns as to the items referenced in 13.5(a)-13.5(g) . If Licensee fails to alleviate PHS’ concerns as to the items referenced in 13.5(a)-13.5(g) or fails to initiate corrective action to PHS ’ satisfaction, PHS may terminate this Agreement .

13.7 PHS reserves the right according to 35 U.S.C. §209(d)(3) to terminate or modify this Agreement if it is determined that the action is necessary to meet the requirements for public use specified by federal regulations issued after the date of the license and these requirements are not reasonably satisfied by Licensee .

13.8 Within thirty (30) days of receipt of written notice of PHS’ unilateral decision to modify or terminate this Agreement , Licensee may, consistent with the provisions of 37 CFR §404.11, appeal the decision by written submission to the designated PHS official . The decision of the designated PHS official shall be the final agency decision. Licensee may thereafter exercise any and all administrative or judicial remedies that may be available.

13.9 Within ninety (90) days of expiration or termination of this Agreement under this Article 13, a final report shall be submitted by Licensee. Any royalty payments, including those incurred but not yet paid (such as the full minimum annual royalty), and those related to patent expense, due to PHS shall become

immediately due and payable upon termination or expiration . If terminated under this Article 13, sublicensees may elect to convert their sublicenses to direct licenses with PHS pursuant to Paragraph 4.3. Unless otherwise specifically provided for under this Agreement , upon termination or expiration of this Agreement, Licensee shall return all Licensed Products and New Products or other materials included within the Licensed Patent Rights and under its control to PHS or provide PHS with written certification of the destruction thereof.

14. GENERAL PROVISIONS

14.1 Neither party may waive or release any of its rights or interests in this Agreement except in writing. The failure of the Government to assert a right hereunder or to insist upon compliance with any term or condition of this Agreement shall not constitute a waiver of that right by the Government or excuse a similar subsequent failure to perform any of these terms or conditions by Licensee .

14.2 This Agreement constitutes the entire Agreement between the Parties relating to the subject matter of the Licensed Patent Rights , Licensed Products , New Products , Supplied Materials and Licensed Processes , and all prior negotiations, representations, agreements, and understandings are merged into, extinguished by, and completely expressed by this Agreement .

14.3 The provisions of this Agreement are severable, and in the event that any provision of this Agreement shall be determined to be invalid or unenforceable under any controlling body of law, this determination shall not in any way affect the validity or enforceability of the remaining provisions of this Agreement .

14.4 If either party desires a modification to this Agreement , the parties shall, upon reasonable notice of the proposed modification by the party desiring the change, confer in good faith to determine the desirability of the modification . No modification shall be effective until a written amendment is signed by the signatories to this Agreement or their designees.

14.5 The construction, validity, performance, and effect of this Agreement shall be governed by Federal law as applied by the Federal courts in the District of Columbia.

14.6 All Agreement notices required or permitted by this Agreement shall be given by prepaid, first class, registered or certified mail or by an express/overnight delivery service provided by a commercial carrier, properly addressed to the other party at the address designated on the Signature Page, or to any other address as may be designated in writing by such other party. Agreement notices shall be considered timely if such notices are received on or before the established deadline date or sent on or before the deadline date as verifiable by U.S. Postal Service postmark or dated receipt from a commercial carrier. Parties should

request a legibly dated U.S. Postal Service postmark or obtain a dated receipt from a commercial carrier or the U.S. Postal Service. Private metered postmarks shall not be acceptable as proof of timely mailing.

14.7 This Agreement shall not be assigned by Licensee except:

(a) with the prior written consent of PHS , this consent shall not to be withheld unreasonably; or

(b) as part of a sale or transfer of substantially the entire business of Licensee relating to operations which concern this Agreement ; and

(c) Licensee shall notify PHS within ten (10) days of any assignment of this Agreement by Licensee , and Licensee shall pay PHS , as an additional royalty, one (1) percent of the fair market value of any consideration received for any assignment of this Agreement within thirty (30) days of the assignment.

14.8 Licensee agrees in its use of any Supplied Materials to comply with all applicable statutes, regulations, and guidelines, including PHS and HHS regulations and guidelines . Licensee agrees not to use the Supplied Materials for research involving human subjects or clinical trials in the United States without complying with 21 CFR Part 50 and 45 CFR Part 46. Licensee agrees not to use the Supplied Materials for research involving human subjects or clinical trials outside of the United States without notifying PHS , in writing, of the research or trials and complying with the applicable regulations of the appropriate national control authorities. Written notification to PHS of research involving human subjects or clinical trials outside of the United States shall be given no later than sixty (60) days prior to commencement of the research or trials.

14.9 Licensee acknowledges that it is subject to and agrees to abide by the United States laws and regulations (including the Export Administration Act of 1979 and Arms Export Control Act) controlling the export of technical data, computer software, laboratory prototypes, biological materials, Supplied Materials and other commodities. The transfer of these items may require a license from the appropriate agency of the Government or written assurances by Licensee that it shall not export these items to certain foreign countries without prior approval of the agency. PHS neither represents that a license is or is not required or that, if required, it shall be issued.

14.10 Licensee agrees to mark the Licensed Products or New Products or their packaging sold in the United States with all applicable U.S. patent numbers and similarly to indicate “Patent Pending” status. All Licensed Products or New

Products manufactured in, shipped to, or sold in other countries shall be marked in a manner to preserve PHS patent rights in those countries.

14.11 By entering into this Agreement , PHS does not directly or indirectly endorse any product or service provided, or to be provided, by Licensee whether directly or indirectly related to this Agreement. Licensee shall not state or imply that this Agreement is an endorsement by the Government , PHS , any other Government organizational unit, or any Government employee . Additionally, Licensee shall not use the names of NIH, PHS, FDA or HHS or the Government or their employees in any advertising, promotional, or sales literature without the prior written approval of PHS .

14.12 The Parties agree to attempt to settle amicably any controversy or claim arising under this Agreement or a breach of this Agreement , except for appeals of modifications or termination decisions provided for in Article 13 . Licensee agrees first to appeal any unsettled claims or controversies to the designated PHS official, or designee, whose decision shall be considered the final agency decision. Thereafter, Licensee may exercise any administrative or judicial remedies that may be available.

14.13 Nothing relating to the grant of a license, nor the grant itself, shall be construed to confer upon any person any immunity from or defenses under the antitrust laws or from a charge of patent misuse, and the acquisition and use of rights pursuant to 37 CFR Part 404 shall not be immunized from the operation of state or Federal law by reason of the source of the grant.

14.14 Paragraphs 8.1, 9.7-9.9, 12.1-12.5, 13.8, 13.9, 14.12 and 14.14 of this Agreement shall survive termination of this Agreement .

14.15 The terms and conditions of this Agreement shall, at PHS’ sole option, be considered by PHS to be withdrawn from Licensee’s consideration and the terms and conditions of this Agreement , and the Agreement itself to be null and void, unless this Agreement is executed by the Licensee and a fully executed original is received by PHS within sixty (60) days from the date of PHS signature found at the Signature Page.

SIGNATURES BEGIN ON NEXT PAGE

PHS PATENT LICENSE AGREEMENT — NONEXCLUSIVE

SIGNATURE PAGE

For PHS:

/s/ Steven M. Ferguson		4/25/07
Steven M. Ferguson		Date
Director, Division of Technology Development and Transfer
Office of Technology Transfer
National Institutes of Health

Mailing Address for Agreement notices:

Chief, Monitoring & Enforcement Branch
Office of Technology Transfer
National Institutes of Health
6011 Executive Boulevard, Suite 325
Rockville, Maryland 20852-3804 U.S.A.

For Licensee (Upon, information and belief, the undersigned expressly certifies or affirms that the contents of any statements of Licensee made or referred to in this document are truthful and accurate.):

by:

/s/ Ronald H.W. Lorijn		5/2/07
Signature of Authorized Official		Date

Ronald H.W. Lorijn
Printed Name

C.E.O.
Title

I. Official and Mailing Address for Agreement notices:

Sander van Deventer, M.D.

Chief Scientific Officer

Amsterdam Molecular Therapeutics

Meibergdreef 61

P.O. Box 22506

1100DA Amsterdam, Netherlands

II. Official and Mailing Address for Financial notices ( Licensee’s contact person for royalty payments)

Sander van Deventer, M.D.

Name

Chief Scientific Officer

Title

Mailing Address:

Amsterdam Molecular Therapeutics

Meibergdreef 61

P.O. Box 22506

1100DA Amsterdam, Netherlands

Email Address: s.vandeventer@amtbv.com

Phone: +31-20-5669272

Fax: +31-20-5669272

Any false or misleading statements made, presented, or submitted to the Government , including any relevant omissions, under this Agreement and during the course of negotiation of this Agreement are subject to all applicable civil and criminal statutes including Federal statutes 31 U.S.C. §§3801-3812 (civil liability) and 18 U.S.C. §1001 (criminal liability including fine(s) and/or imprisonment).

APPENDIX A - PATENT(S) OR PATENT APPLICATION(S)

Patent(s) or Patent Application(s):

I. U.S. Patent Application(s) or Patent(s):

(a) U.S. Patent Application Serial No. 09/986,618, filed November 9, 2001, now abandoned, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/0-US-01];

(b) U.S. Patent No. 6,723,551, issued April 20, 2004, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/1-US-01]; and

(c) U.S. Patent Application Serial No. 10/415,834, filed May 2, 2003, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/2-US-02].

II. PCT or Foreign Patent Application(s) or Patent(s):

(a) PCT Patent Application Serial No. PCT/US02/35829, filed November 8, 2002, now abandoned, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/2-PCT-01];

(b) Canadian Patent Application Serial No. 2,467,959, filed May 6, 2004, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/2-CA-03];

(c) European Patent Application Serial No. 02795604.4, filed June 8, 2004, entitled “Production of Adeno-Associated Virus in Insect Cells” [HHS Ref. No. E-325-2001/2-EP-04]; and

(d) Australian Patent Application Serial No. 2002360355, filed April 28, 2004, entitled “Production of Adeno-Associated Virus in Insect Cells” [FIHS Ref. No. E-325-2001/2-AU-05].

APPENDIX B - LICENSED FIELDS OF USE AND TERRITORY

I. Licensed Fields of Use :

Use of the Licensed Patent Rights for the commercial development of AAV related products within the scope of the Agreement .

II. Licensed Territory :

United States, Australia, Canada and Europe.

APPENDIX C - ROYALTIES

Royalties:

I. Licensee agrees to pay to PHS a nonereditable, nonrefundable license issue royalty in the amount of twelve thousand U.S. dollars ($12,000) within thirty (30) days from the effective date of this Agreement .

II. Licensee agrees to pay to PHS a nonrefundable minimum annual royalty in the amount of fifteen thousand U.S. dollars ($15,000) as follows:

(a) The first minimum annual royalty is due within thirty (30) days of the effective date of this Agreement and may be prorated according to the fraction of the calendar year remaining between the effective date of this Agreement and the next subsequent January 1; and

(b) Subsequent minimum annual royalty payments are due and payable on January 1 of each calendar year and may be credited against any earned royalties due for sales made in that year.

III. Licensee agrees to pay PHS earned royalties of one percent (1%) on Net Sales by or on behalf of Licensee for Licensed Products .

IV. Licensee agrees to pay PHS earned royalties of one quarter of one percent (.25%) on Net Sales by or on behalf of Licensee for New Products .

V. Licensee agrees to pay PHS Benchmark royalties within thirty (30) days of achieving each Benchmark :

(a) Thirty thousand U.S. dollars ($30,000) — Initiation of each Phase I clinical trial or foreign equivalent.

(b) Seventy-five thousand U.S. dollars ($75,000) — Initiation of each Phase II clinical trial or foreign equivalent.

(c) One hundred and fifty thousand U.S. dollars ($150,000) — Initiation of each Phase III clinical trial or foreign equivalent.

(d) Initiation of first Marketing Approval or foreign equivalent in the following jurisdictions/countries:

(i) Three hundred thousand U.S. dollars ($300.000) in Europe.

(ii) Three hundred thousand U.S. dollars ($300,000) in the United States.

(iii) Seventy-five thousand U.S. dollars ($75,000) in Australia.

(iv) Seventy-five thousand U.S. dollars ($75,000) in Canada.

IV. Licensee agrees to pay PHS additional sublicensing royalties as follows:

Ten percent (10%) of the fair market value of any consideration received for granting each sublicense.

APPENDIX D - BENCHMARKS AND PERFORMANCE

Licensee agrees to the following Benchmarks for its performance under this Agreement and, within thirty (30) days of achieving a Benchmark , shall notify PHS that the Benchmark has been achieved.

I. Initiation of Preclinical Development phase or foreign equivalent — 4 th quarter 2006.

II. Initiation of first Phase I clinical trial or foreign equivalent — 3 rd quarter 2007.

III. Initiation of first Phase II clinical trial or foreign equivalent — 3 rd quarter 2007.

IV. Initiation of first Phase III clinical trial or foreign equivalent — 4 th quarter 2007.

V. Submission to Regulatory Authority of first Marketing Approval or foreign equivalent — 2 nd quarter 2008.

APPENDIX E - COMMERCIAL DEVELOPMENT PLAN

Introduction

In 2004 the European Regulatory Authority (“EMEA”), assigned the ‘orphan drug’ status to Licensee’s lead product AMT-010. AMT-010 (Adeno-Associated Viral Vector Expressing Human Lipoprotein LipaseS447X), a gene therapy product to treat Lipoprotein Lipase Deficiency Type I and V deficiency, has entered its phase I/II clinical stage. This program is focused on treating the rare, but serious and disabling inherited disease called LPL type 1 deficiency for which no adequate treatment exists today.

Due to a substantial change in the manufacturing process (from DKFZ to Baculo), Licensee does not intend to market AMT-010 but instead the newly produced product AMT-011.

For that reason, Licensee has started preclinical development in 2006, and will initiate a phase II clinical study with AMT-011 in Canada in Q3 2007, as well as a phase II clinical study for type V hyperlipoproteinemia in Q4 2007 . Licensee expects to file the registration dossier for type I hyperlipoproteinemia with the EMEA by Q1 2008.

Early 2007, Licensee will begin discussions with the FDA to prepare the filing of the AMT-011 dossier for registration in the U.S.A. Depending on the feedback from the U.S. authorities, Licensee plans to file its registration dossier with the FDA in 2008.

Technology

Licensee is building gene therapies using adeno-associated viral (AAV)-based vectors . These vectors do not integrate into the host genome and result in long-lasting expression of therapeutic genes. AAV vectors can be specifically targeted to various organs (i.e. muscle, brain, liver, retina) and even to specific cells within a target organ. Improvements in local expression are also achieved by using potent organ specific promoters. Licensee has extensively optimized expression of therapeutic genes in various organs by selection of AAV serotype-promoter combinations and by selection of high expressing transgenes. In relevant preclinical models, this has resulted in lifelong (2 years for mouse and rat) expression of transgenes at therapeutic levels (often 100% of the normal expression) and a complete cure of the disease. Because of this extensive knowledge base, and the availability of all relevant currently available AAV serotypes, Licensee believes it is in the position to rapidly develop genetic therapies for a wide range of diseases caused by single gene defects.

The Disease: Lipoprotein Lipase Deficiency

Genetic lipoprotein lipase (LPL) deficiency results in profound hypertriglyceridemia, which is associated with intense chronic abdominal pain, hepatosplenomegaly, eruptive xanthomas, lipemia retinalis, dyspnea, mono- or polyparesthesias, and memory loss. Prolonged elevations in plasma triglycerides (TG) also induce recurrent episodes of often lethal pancreatitis, chronic pancreatic insufficiency, and diabetes mellitus. Currently, no effective treatment for this disease exists. Patients must follow a strict low-fat diet. However, TG levels often remain above the

critical threshold. Genetic LPL deficiency type I is a rare, autosomal recessive trait. Prevalence varies between 1 in 1,000,000 in the general population to 1 in 5,000 in French Quebec (a ‘founder effect’).

LPL gene therapy will also be investigated to treat type V hyperlipoproteinemia (prevalence of 1.8 in 10,000). LPL gene therapy may improve the quality of life and reduce the risk of morbidity and mortality for a significant number of patients that suffer from this particular lipid disorder.

Currently, no treatment for hyperlipoproteinemia is available, and patients suffer from repeated bouts of pancreatitis. LPL enzyme replacement therapy is not feasible in view of the very short half-life of the enzyme. The only advice a physician can give these patients is to keep a strict fat-free diet, which is extremely difficult to maintain. Further, even with such a diet, the serum triglyceride levels remain far above the critical level of 10 µmol/L.

Business Strategy

Licensee’s core strategy will be to position the new medicine as an orphan drug . This strategy has several important benefits. The Regulatory Authorities in many countries including the EU (EMEA) and the U.S.A. (FDA) have recognized the significance of the development of orphan drugs. Thanks to the regulatory laws and regulations the ‘time-to-market’, IP and marketing rights protection are very favorable for such products.

Marketing exclusivity for orphan drugs after marketing authorization are:

· EU: 10 years

· USA: 7 years

This means that during that period no other sponsor can obtain marketing authorization for a similar product in the designated indication. Licensee received the orphan drug status for the LPL gene therapy from the EMEA last year. Due to these circumstances and the fact that the major pharmaceutical companies have little or no interest in developing products for these niche markets, the opportunities for companies such as Licensee are significant.

In the specific case for the LPL product, there is yet another element that will ensure a quick uptake and fast penetration in the target market. Specifically, there is no treatment today nor in the foreseeable future for patients suffering from LPL Type 1 and V deficiency. In other words, no major competing treatments are available to these patients.

In conclusion, no cure or symptomatic treatment, which would alleviate the disease’s symptoms and its complications exist today. The LPL project is unique because it exploits for the first time the possibility to treat patients suffering from LPL deficiency type I and V.

Marketing and Sales

Market Overview AMT-011

Lipoprotein lipase deficiency Type I

Hypertriglyceridemia Type V

· Orphan indication		· Larger indication
· 3,000-4,000 patients world-wide; very well organized and active patients groups		· 30% of the hypertriglyceridemia patients have underlying LPL deficiency
· Estimated global sales $ 200 M		· Estimated global sales >$500 M
· No competition		· Competition: small molecule approaches

Licensee’s business strategy focuses on market entry for its orphan indications through its own dedicated marketing and sales force in Europe and North America. In the Western world, many patients suffering from serious orphan diseases have formed patient groups. Also their treating physicians, in many instances, are well connected. After marketing approval has been obtained, this situation allows for a very concentrated educational effort to inform patients and physicians about the important benefits of gene therapy. In order to ethically justify and successfully penetrate such markets, Licensee will ensure to build-up a highly educated medical service team to assist physicians in the selection of those patients who will benefit from the treatment. Such a team can be relatively small, which allows management to monitor and guide it closely.

APPENDIX F - EXAMPLE ROYALTY REPORT

Required royalty report information includes :

· OTT license reference number (L-XXX-200X/0)

· Reporting period

· Catalog number and units sold of each Licensed Product (domestic and foreign)

· Gross Sales per catalog number per country

· Total Gross Sales

· Itemized deductions from Gross Sales

· Total Net Sales

· Earned Royalty Rate and associated calculations

· Gross Earned Royalty

· Adjustments for Minimum Annual Royalty (MAR) and other creditable payments made

· Net Earned Royalty due

Example

Catalog Number	Product Name	Country	Units Sold	Gross Sales (US$)
1	A	US	250	62,500
1	A	UK	32	16,500
1	A	France	25	15,625
2	B	US	0	0
3	C	US	57	57,125
4	D	US	12	1,500

			Total Gross Sales	153,250
			Less Deductions:
			Freight	3,000
			Returns	7,000
			Total Net Sales	143,250

			Royalty Rate	8	%
			Royalty Due	11,460
			Less Creditable Payments	10,000
			Net Royalty Due	1,460

APPENDIX G - ROYALTY PAYMENT OPTIONS

NIH/PHS License Agreements

*In order to process payment via Electronic Funds Transfer sender MUST supply the following information:

Procedure for Transfer of Electronic Funds to NIH for Royalty Payments

Bank Name: Federal Reserve Bank

ABA# 021030004
TREAS NYC
BNF=/AC-75080031
OBI=Licensee Name and OTT Reference Number
Dollar Amount Wired=$$

NOTE: Only U.S. banks can wire directly to the Federal Reserve Bank. Foreign banks cannot wire directly to the Federal Reserve Bank, but must go through an intermediary U.S. bank. Foreign banks may send the wire transfer to the U.S. bank of their choice, who, in turn forwards the wire transfer to the Federal Reserve Bank.

Mailing Address for Royalty Payments:

National Institutes of Health
P.O. Box 360120
Pittsburgh, PA 15251-6120 USA

Overnight Mail for Royalty Payments only

National Institutes of Health
360120
Mellon Client Service Center
Room 670
500 Ross Street
Pittsburgh, PA 15262-0001

(412) 234-4381 (Customer Service)

Please make checks payable to: NIH/Patent Licensing

The OTT Reference Number MUST appear on checks, reports and correspondence

PUBLIC HEALTH SERVICE

FIRST AMENDMENT TO L-107-2007/0

This is the first amendment (“ First Amendment ”) of the agreement by and between the National Institutes of Health (“ NIH ”) or the Food and Drug Administration (“ FDA ”), hereinafter singly or collectively referred to as agencies of the United States Public Health Service (“ PHS ”) within the Department of Health and Human Services (“ HHS ”), and Amsterdam Molecular Therapeutics having an effective date of May 2, 2007 and having NIH Reference Number L-107-2007/0 (“ Agreement ”). This First Amendment , having NIH Reference Number L-107-2007/1, is made between the PHS through the Office of Technology Transfer, NIH , having an address at 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804, U.S.A., and Amsterdam Molecular Therapeutics, having an office at Meibergdreef 61, 1005 BA Amsterdam, The Netherlands (“ Licensee ”). This First Amendment includes, in addition to the amendments made below, 1) a Signature Page, 2) Appendix D — Benchmarks and Performance , 3) Appendix E — Commercial Development Plan , 4) Exhibit A — Request to Collaborate with Institute Pasteur, 5) Exhibit B- PHS Consent for Institute Pasteur Exemption, and 6) Attachment 1 (Royalty Payment Information).

WHEREAS, Licensee has requested an amendment to revise the Benchmarks for its lead Licensed Product AMT-011, also known as Glybera™;

WHEREAS, Licensee did not conduct a Phase III clinical trial for Glybera™ and has filed for Marketing Approval for Glybera™ with the European Medicines Agency on January 11, 2010;

WHEREAS, Licensee has requested Benchmark royalty exemption for collaborations with not-for-profit organizations and academic institutions for pre-clinical and clinical development to treat ultra-orphan indications;

WHEREAS, PHS requested that Licensee amend the Appendix E - Commercial Development Plan to state its development plans for Licensed Products other than Glybera™;

WHEREAS, PHS requested that Licensee add Benchmarks for Licensed Products other than Glybera™ to Appendix D - Benchmarks and Performance ;

WHEREAS, PHS and Licensee desire that the Agreement be amended a first time as set forth below in order amend Appendix D - Benchmarks and Performance and Appendix E - Commercial Development Plan .

NOW, THEREFORE, in consideration of the mutual covenants and promises contained herein, PHS and Licensee , intending to be bound, hereby mutually agree to the following:

1) The following modifications shall be made to the Agreement:

a. The following Paragraphs 2.14, 2.15, 2.16, and 6.8 shall be added to the Agreement :

2.14 “ Orphan Indication ” means a disease that affects less than two hundred thousand (200,000) people in the United States as defined by the Food and

Drug Administration or five (5) in ten thousand (10,000) people in the European Union as defined by the European Medicines Agency.

2.15 “ Ultra-Orphan Indication ” means a disease that effects less than one (1) in Fifty Thousand (50,000) people in the United States or the European Union.

2.16 “ Exempt Collaborator ” means a not-for-profit organization or academic institution that has entered a formal collaboration and / or supply agreement with Licensee to conduct pre-clinical development and solely sponsor clinical trials of Licensed Product , excluding Supplied Materials , to treat an Ultra-Orphan Indication ; in which Licensee may acquire clinical development and data for regulatory approval and sale of a Licensed Product .

6.8 Unless otherwise exempted in Article 15, Licensee agrees to pay PHS benchmark royalties as set forth in Appendix C.

b. Paragraph 6.3 shall be deleted from the Agreement and replaced with the following Paragraph 6.3:

6.3 Unless otherwise exempted in Article 15, Licensee agrees to pay PHS earned royalties as set forth in Appendix C.

c. Appendix D - Benchmarks and Performance of the Agreement shall be deleted and replaced with the Appendix D - Benchmarks and Performance attached to this First Amendment .

d. Appendix E - Commercial Development Plan attached to this First Amendment shall be added the Agreement .

e. The following Article 15 shall be added to the Agreement :

15. EXEMPTION FOR ULTRA-ORPHAN INDICATION RESEARCH

15.1 Licensee shall be permitted, upon PHS consent, (not to be unreasonably withheld), to manufacture and supply Licensed Product , excluding Supplied Materials , to an Exempt Collaborator for use solely in pre-clinical and clinical development to treat an Ultra-Orphan Indication . Prior to commencement of manufacturing of Licensed Product for an Exempt Collaborator , Licensee shall request permission in writing and must obtain written consent from PHS . Additional documentation to establish an Exempt Collaborator may be required by PHS .

For avoidance of doubt, Licensee shall retain Supplied Materials and shall not release Supplied Materials to an Exempt Collaborator .

15.2 Upon receipt of written consent from PHS for manufacturing of a Licensed Product for an Exempt Collaborator , Licensee shall not be

obligated to pay Benchmark royalties which would have been payable under Appendix C , Section V for Benchmarks triggered by clinical trials solely sponsored by the Exempt Collaborator until such time as Licensee exercises its option to acquire the clinical development from the Exempt Collaborator .

15.3 Upon acquisition of the clinical development from an Exempt Collaborator , Licensee shall pay PHS royalties which become payable from that point onwards in accordance with Appendix C , Section V. Licensee must inform PHS in writing within thirty (30) days of Licensee’s decision to acquire or not acquire clinical development from the Exempt Collaborator .

For avoidance of doubt, PHS shall consider Licensee’s sponsorship or co-sponsorship of a clinical trial or regulatory submission for a Licensed Product to treat an Ultra-Orphan Indication as an acquisition of clinical development from an Exempt Collaborator .

15.4 Earned royalty payments on Net Sales specified in Appendix C, Section III shall not be applicable to Licensed Product manufactured for research and clinical trials conducted by an Exempt Collaborator approved by PHS per Paragraph 15.1.

In lieu of earned royalty payments, Licensee shall pay PHS a royalty payment of ten thousand dollars ($10,000) for each collaboration with an Exempt Collaborator approved by PHS . Such royalty shall be due within thirty (30) days of the date of PHS written consent per Paragraph 15.1.

In case several PHS licenses apply to the same Licensed Product , only a single payment of $10,000 shall be payable per collaboration.

2) Within sixty (60) days of the execution of this First Amendment , Licensee shall pay PHS an amendment issue royalty in the sum of One Thousand US Dollars ($1,000.00), to be sent to the address specified in Attachment 1.

3) In the event any provision(s) of the Agreement is/are inconsistent with Attachment 1, such provision(s) is/are hereby amended to the extent required to avoid such inconsistency and to give effect to the payment information in such Attachment 1.

4) All terms and conditions of the Agreement not herein amended remain binding and in effect.

5) The terms and conditions of this Amendment shall, at PHS’ sole option, be considered by PHS to be withdrawn from Licensee’s consideration and the terms and conditions of this Amendment , and the Amendment itself to be null and void, unless this Amendment is executed by the Licensee and a fully executed original is received by PHS within sixty (60) days from the date of PHS signature found at the Signature Page.

6) This First Amendment is effective on December 31, 2009 upon execution by all parties.

SIGNATURES BEGIN ON NEXT PAGE

The Netherlands

Email Address: p.morgan@amtbiopharma.com

Phone:	+31(0)20 566 7509

Fax:	+31(0)20 566 9272

II. Official and Mailing Address for Financial notices (Licensee’s contact person for royalty payments):

Piers Morgan
Name

Chief Financial Officer
Title

Mailing Address:

Meibergdreef 61

1105 BA Amsterdam

The Netherlands

Email Address: p.morgan@ amtbiopharma.com

Phone:	+31(0)20 566 7509

Fax:	+31(0)20 566 9272

APPENDIX D - BENCHMARKS AND PERFORMANCE

Licensee agrees to the following Benchmarks for its performance under this Agreement and, within thirty (30) days of achieving a Benchmark, shall notify PHS that the Benchmark has been achieved.

Benchmarks for Lead Licensed Product (AMT-011 also known as Glybera™)

I. Initiation of Preclinical Development phase or foreign equivalent - 4 th quarter 2006.

II. Initiation of first Phase I clinical trial or foreign equivalent - 3 rd quarter 2007.

III. Initiation of first Phase II clinical trial or foreign equivalent - 3 rd quarter 2007.

IV. Submission to Regulatory Authority of first Marketing Approval or foreign equivalent - l stl quarter 2010.

Benchmarks for other Orphan Indication Licensed Product s (AMT-021 or equivalent)

I. Initiation of Preclinical Development phase or foreign equivalent - Q4 2010

II. Initiation of first Phase I clinical trial or foreign equivalent - Q3 2012

III. Initiation of first Phase II clinical trial or foreign equivalent - Q3 2014

IV. Submission to Regulatory Authority of first Marketing Approval or foreign equivalent - Q3 2015

Benchmarks for Licensed Products (AMT-090 or equivalent)

I. Initiation of Preclinical Development phase or foreign equivalent - Q3 2011

II. Initiation of first Phase I clinical trial or foreign equivalent - Q3 2012

III. Initiation of first Phase II clinical trial or foreign equivalent - Q3 2014

IV. Initiation of first Phase III clinical trial or foreign equivalent- Q3 2017

V. Submission to Regulatory Authority of first Marketing Approval or foreign equivalent - Q3 2020

APPENDIX E - COMMERCIAL DEVELOPMENT PLAN

AMT-021 for Acute Intermittent Porphyria

Acute intermittent porphyria (AlP) is an autosomal dominant inherited condition caused by mutations in the porphobilinogen deaminase (PBGD) gene. The PBGD gene is located on chromosome 11 q24.1 -24.2 and spread over fifteen exons. The protein encoded by this gene is a rate-limiting enzyme, the PBGD enzyme, in the haem synthetic pathway.

More than 225 mutations of the PBGD gene have been described, all of them associated with loss of catalytic function. The disease shows incomplete penetrance and only 20-50% of persons with one or more of the described mutations exhibit clinical symptoms of the disease. The genetic disorder results in a 50% reduction of PBGD enzymatic activity. This reduction of hepatic PBGD activity leads to an accumulation of toxic metabolites resulting from the blockade within the haem synthesis pathway. Concentrations of haem precursors porphobilinogen (PGB) and delta-aminolevulinic acid (ALA) increase in blood and urine. Lack of haem and/or accumulation of these metabolites are responsible for the acute attacks characteristic of this disease (Kauppinen et al 2005; Herrick and McColl 2005). Currently, there is no treatment available for the disease.

Over the last couple of years we have explored AMT-021 (replication defective recombinant adeno-associated viral vector, AAV, containing the porphobilinogen deaminase gene) for therapeutic intervention in AlP. AMT-021 is an AAV with pseudotype 5 capsid, which expresses the human PBGD gene under the transcriptional control of a liver specific promoter. The therapeutic expression cassette consists of the human PBGD cDNA (codon optimised for human expression) inserted downstream of the liver specific promoter EalbAAT and upstream of a human PBGD polyadenylation sequence.

AMT-021 acts by delivering the PBGD expression cassette directly into hepatocytes. The increase of PBGD enzymatic activity in the liver of AlP patients will provide sufficient enzyme to prevent the accumulation of toxic metabolites and thus, prevent porphyric attacks.

The aim of the project is to bring AAV5-PBDG therapy to patients. AMT has already secured orphan designation for AAV5-PBDG treatment for AlP in Europe. The table below describes the outline development plans, starting from a research batch production, and moving through to primate proof-of-concept, tox batch, pre-observational study, product development, GMP production, Phase I/II clinical trial, Phase lI/IIl clinical trial, all the way to regulatory filing. Please note that the timelines are preliminary only, and that it is the nature of scientific and clinical development that planned timelines may change.

Preliminary Project Plan (Acute Intermittent Porphyria):

Task		Timelines
Research batch		2010
PoC in non-human primate		2010
Tox batch		2010
Toxicology (12 months)		2011
Pre-observation study		2011-2012

Clinical batch		2011
Interventional Phase I/II clinical trial		2012
2nd Observational study & Phase II/III clinical trial		2014
File with EMA		2015
Market Launch		2017

Project Plan Details:

The aim of this project is to develop a gene therapy product for the treatment of AlP, and to deliver a data package that is suitable for the submission and approval by the European and North American regulatory authorities.

Vector development and manufacturing

To develop a gene therapy for PBGD deficient patients, AAV5-PBDG product was designed to expresses the human PBGD gene under the control of a liver specific promoter. AAV5-PBDG was produced in insect cells using the recombinant baculovirus method; sufficient amount of material was produced for efficacy studies in mice. Methods to determine the quantity and purity of the rAAV batches were developed. A purification process including chromatography and filtration steps was developed, further optimization and characterization of the scale-up procedure will be performed before a final batch for toxicology, for proof of principle and for clinical trials can be produced.

PoC in pre-clinical models

Because total deficiency of PBGD is lethal in mice, a compound heterozygous mouse (PBGD +/- referred to as AlP mice) with ~35% of normal hepatic PBGD activity, has been developed as an established model to study AlP. This murine model of AlP exhibits, after disease induction with phenobarbital (Pb), the typical biochemical characteristics of human AlP, notably, decreased hepatic PBGD activity, massively increased urinary excretion of haem precursors (ALA and PBG) and decreased motor function.

AlP mice were used to test the AAV5-PBDG product. The therapeutic effect was evaluated three month after a single intravenous administration of AAV5-PBDG. Efficacy of the therapy was demonstrated as the treatment was able to prevent disease induction with Pb. ALA and PBG levels in treated animals was reduced, and motor disturbance induced by Pb treatment, as measured in the Rotarod test, was almost completely abolished. In addition, PBGD enzymatic activity increased in the AAV5-PBDG treated group 10 times over that of the control group.

This initial PoC will be repeated with the final version of the therapeutic vector following the completion of the vector development and manufacturing optimisation. The final PoC will include the following:

· PoC in rodent disease model

· PoC in non-human primates, based on agreed protocol

GLP Toxicology

The aim of this section is to deliver toxicology study report suitable for the submission the regulatory authority. The work will entail the following:

· Scientific advice from a regulatory body (AEMPS and/or EMA) for safety and toxicology package

· GLP toxicology study in rodents rats or mice, including any required biodistribution studies

· Supportive data for toxicology study in non-human primates

· GLP germline transmission study

Toxicology study design will take into account:

· Identification of potential target organs of biological activity and of potential target organs of toxicity

· Eventual concomitant medication (e.g. immunosuppressants, standard co-medication)

· Environmental risk/shedding

· Analysis of appropriateness of surrogate markers of efficacy/safety

· Any other relevant issues as may be identified

Clinical observational, pre-intervention study/studies

Before entering the interventional clinical study, an observation clinical study will be conducted to provide baseline information on the course of the disease by recording episodes AlP, abdominal pain, hospitalizations, extent of any possible known or unknown to be related to AlP symptomatology, incidence of (adverse) clinical events per year, etc. Sufficient data will be collected to provide a clinical picture to obtain a baseline data and to determine how efficacy will be shown during the interventional clinical trial.

Phase I/II

The clinical phase I/II should include an estimated minimum 6 patients that are administered the gene therapy drug, and are followed up and clinically assessed for at least 6 months following drug administration. The primary aim of the clinical study will be safety and efficacy of the AAV5-PBDG product. The clinical trial will include all biochemical, imaging, clinical and functional assays to assess the disease state and change therein over time, the phenotypic disease variation, as well as the overall clinical and psychosocial or other health status or change therein over time of the individual trial subjects, both before, during and following drug administration.

Phase II/III & Regulatory submission

After successful completion of Phase I/II study a Phase lI/IIl trial will be conducted with the aim of bringing the AlP therapy to market. We estimate that 20-30 patients in total would be sufficient for regulatory filing of this product, as AlP is an ultra-orphan disease with a very limited patient number world-wide.

AMT-090 for Parkinson’s Disease

of nerve cells in a specific part of the brain known as the substantia nigra. These cells produce dopamine, a substance necessary for communication between nerve cells involved in the coordination of movement.

PD is the second most common neurodegenerative disease. It usually affects people over 65, with an estimated total of 4.5 million patients worldwide. Due to increasing life expectancy of the general population, the number of patients with PD is expected to double to around 9 million patients between now and 2030.

An ideal therapy for PD would decrease disability and slow down or halt disease progression. Unfortunately, such treatments are not available yet and current therapies are limited to symptomatic treatment only. These include levodopa, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors and anticholinergic agents.

Glial cell line-derived neurotrophic factor (GDNF) was shown to promote the survival and differentiation of dopaminergic neurons. The therapy aims to protect and enhance the function of the dopamine-producing nerve cells in the brain. To date a number of clinical trials have been conducted in which recombinant GDNF protein has been directly delivered to the PD brain, using a delivery pump device implanted into patients’ abdomen. Although the results were inconsistent, due to the difficulty of delivering protein continuously into the brain via an implanted pump, some patients have shown a significant clinical response to the treatment. It is therefore not a question whether this approach works, because it definitely did in some patients, but rather how it can be done more consistently. AAV-GDNF gene therapy treatment would result in continues delivery of GDNF protein into brain, and is therefore likely to result in significant clinical benefit for PD patients.

AMT has recently started preclinical development of AAV-GDNF gene therapy that will introduce the gene coding for GDNF using recombinant adeno associated virus vector (AAV). AAV serotype 5 has been shown to be the serotype of choice for gene delivery into the brain. After successful proof of concept (POC) and toxicology studies in rodents and primates, AMT will start an extensive clinical development.

Preliminary timelines for AMT-090

Task		Timelines
POC rats		2010
POC non-human primates		2010
Toxicology study		2011
IND / INPD (approval for phase I)		2011
Start phase I		2012
Start phase II		2014
Start phase III		2017
Filing		2020
Market introduction		2022

Project Plan Details:

The aim of this project is to develop a gene therapy product for the treatment of Parkinson’s disease, and to deliver a data package that is suitable for the submission and approval by the European and North American regulatory authorities.

Vector development and manufacturing

To develop a gene therapy for Parkinson’s disease, AAV-GDNF product was designed to expresses the human GDNF and is produced in insect cells using the recombinant baculovirus method. The AAV5-GDNF is based on AMT’s standard manufacturing process, but in addition incorporates recent new technology of the basic process and makes use of an optimized Rep baculovirus construct in the upstream process and an additional chromatography step in the downstream process. This optimisation delivers enhanced quality and robustness of the AAV5-GDNF product. This process is fully scalable and allows for manufacturing of sufficient GMP-compliant product for PD patients.

Characterization of AAV5-GDNF

The AAV5-GDNF was tested in a functional in vitro assay in cultured E13.5 rat DRG explants. Vigorous neural outgrowth was observed, indicating that the produced AAV5-GDNF is capable of mediating secretion of biologically functional recombinant GDNF.

In vivo characterization

Subsequently, an in-vivo characterisation of the AAV5-GDNF has been conducted. Three different concentrations of AAV5-GDNF were injected unilaterally into the rat striatum. Brains were analyzed for GDNF expression 6 weeks post injection using immunohistochemistry. Resulting data demonstrated that there is a strong, concentration dependent GDNF expression throughout the injected hemisphere.

PoC in pre-clinical models

The produced AAV5-GDNF will be used to show biological activity and efficacy in animal models of Parkinson’s disease. These experiments will be conducted using rat models of Parkinson’s disease (in collaboration with University of Lund, Sweden) as well as non-human primates model of Parkinson’s disease (in collaboration with CEA, Paris, France). In addition to distribution studies, onset and kinetics of GDNF expression, neurochemical measurements (dopamine and dopamine metabolites), immunohistochemistry and behavioural studies will be conducted to test for functional improvement.

GLP Toxicology

The definitive design of the actual studies will be finalized after discussions with relevant agencies. We propose to conduct a six months study in mice and in parallel a 6-12 months study in non-human primates to account for the safety of the drug. The studies will comprise four test groups: 1. Control (vehicle), 2. Low dose (No observed effect level (NOEL) in the proof-of concept studies), 3. Mid-dose (highest dose considered for clinical studies), and 4. High dose (10 times higher than the mid-dose).

The protocol will include the following evaluations:

· Clinical Signs: recorded daily, beginning 7 days prior to surgery

· Food Consumption: recorded daily, beginning 7 days prior to surgery

· Body Weight: Once pre-surgery, day of surgery, then bi-weekly

· Clinical Chemistry: Twice a month presurgery, one week post surgery, then monthly

· Hematology: Twice a month presurgery, one week post surgery, then monthly

· Coagulation: Twice a month presurgery, one week post surgery, then monthly

· Antibodies against GDNF or AAV5 in plasma, twice prior to surgery, monthly thereafter.

· PK - CSF: To determine if there is GDNF in the CSF, twice prior to surgery, monthly thereafter.

· Neurological Examination: Twice prior to surgery, Day 7 post surgery, monthly thereafter

· MRI (T1.T2): Once prior to surgery, within three hours post surgery, and within three days prior to necropsy.

· Pathology

1. Gross pathology at necropsy

2. Selected peripheral tissues collected for histopathological analysis by a Board Certified Pathologist

3. Complete CNS histopathological assessment by a Board Certified Neuropathologist, peer reviewed by another Board Certified Pathologist

· Q-PCR in selected organs in order to assess any biodistribution of the vector DNA to other organs.

Phase I/II

The primary objective of the clinical phase I/II will be to assess the safety and feasibility of intra-putaminal delivery of AAV5-GDNF to patients with PD. Secondary objectives include measuring clinical efficacy and demonstrating improvement in a surrogate marker end point ( 18 F-Dopa PET) as proof of concept.

We are proposing a single centre open label trial of striatally delivered AAV5-GDNF in PD employing a dose escalation design to assess the mentioned primary and secondary outcome measures. We anticipate enrolling 12 patients in this study, with an escalating dose group design with three patients in each dose group. We will start with the lowest dose and progress in an incremental way to higher doses.

Primary outcome assessments will be performed at two weeks, one month, three months, six months, 12 months and 18 months post intra-putaminal infusion of AAV5-GDNF. Clinical secondary outcome assessments will be performed at three months, six months, 12 months and 18 months post intra-putaminal infusion of AAV5-GDNF. 18 F-dopa PET secondary outcome assessments will be performed at six months and 18 months post intra-putaminal infusion of AAV5-GDNF.

If feasibility and safety is confirmed and, serial PET imaging demonstrates increased 18 F-dopa uptake with a trend towards clinical improvement, we will proceed to phase 2/3 clinical trials.

Phase lI/III. Phase III & Regulatory submission

After successful completion of Phase I/II study, two additional clinical trials will be required. The final plans for these trials will be optimised based on the outcome of the Phase I/II study. We estimate 50 patients to be enrolled in the Phase lI/IIl clinical study, and 500 patients to be enrolled in the pivotal trial, the details however will be established, based on the outcome of the Phase I/II trial.

EXHIBIT A - Request for Benchmark Exemption With Institut Pasteur

Walenta, Jeffrey (NIH/OD) [E]

From:	Tamara Tugal [ ttugal@amtbiopharma.com]
Sent:	Tuesday, October 19, 2010 11:36 AM
To:	Walenta, Jeffrey (NIH/OD) [E]
Cc:	Mark Chadwick
Subject:	Manufacture for not-for-profit organisations and academic institutions exemption; L-107-2007 and L-119-207

Dear Jeffrey

It was nice to talk to you the other day and to have the opportunity to discuss with you AMTs plans to participate in the development of products for the treatment of ultra-orphan disorders. We appreciate your openness to help in the development of products for rare disorders that are being developed by not-for-profit organisations. I know that Mark is working with you on a separate amendment to the license, but I would like to take care of this particular point separately.

Sanfilippo Syndrome IIIB (Sanfilippo B) is a lysosomal storage disorder caused by a deficiency of the enzyme a -N-acetylglucosaminidase (NaGlu), resulting in a severe degenerative pathology of central nervous system. Sanfilippo B patients appear normal at birth but develop hyperactivity, sleep disorders, loss of speech, mental retardation and dementia in early childhood. Patients with Sanfilippo B will die at around 10-15 years of age. No treatment or cure is currently available. However, only estimated 20 children are born annually with the disease in Western Europe. These numbers are far too small to justify commercial investment in the therapy. Institut Pasteur has limited charity funding available for the development of treatment for this disease, and would like AMT to manufacture the clinical material for them. AMT would like to clarify our position in relation to NIH while we manufacture to Pasteur, as we discussed on the phone. Please see below the proposed text for such an amendment, I hope that it will be acceptable. Please note that in addition to the L-107-2007 license, the L-119-207 license in also applicable, and we would like to have the same arrangement under both agreements to allow us to work with not-for-profit organisations.

Note that we have been approached by Universities attempting to develop treatments for similar diseases. Hence we would like to be able to extend the mechanism to additional product it the future.

Proposed Amendment: Manufacture for not-for-profit organisations and academic institutions exemption.

AMT will be free to manufacture clinical trial material using the licensed technology for not-for profit organisations and academic institutions without any obligation of payments to NIH. In the first instance, AMT intends to manufacture material for Institut Pasteur for the treatment of Sanfilippo B syndrome. AMT will have an option to license the program from Institut Pasteur and may acquire the program from Institut Pasteur in the future. If AMT acquires the program

from Institut Pasteur, it will, from this point onwards, pay NIH the milestones and royalties as defined in the L-107-2007 (and / or the L-119-207) license. The mechanism will then be applicable to manufacturing of other products for not-for-profit and academic organisations. AMT will notify NIH of any new products that it intends to manufacture under this exemption, prior to the commencement of manufacturing.

Exhibit B - PHS Consent for Benchmark Exemption with Institut Pasteur

(301) 435-5378

March 4, 2011

Tamara Tugal
Business Development Manager
Amsterdam Molecular Therapeutics
Mcibergdreef 61
1105 BA Amsterdam
The Netherlands
Phone Number: +31(0)20 566 7509

Re: Benchmark Exemption for a Proposed Collaboration Between Amsterdam
Molecular Therapeutics (‘AMT’) and Institut Pasteur

Dear Ms. Tugal:

Thank you for your request dated October 19, 2010 for a benchmark royalty exemption for collaboration agreements with not-for-profit organizations or academic institutions to conduct clinical development of potential treatments for ultra-orphan diseases.

Pending execution of the First Amendment to PHS License Reference No. L-107-2007/0 effective May 2, 2007 (the ‘Agreement’), PHS provides consent per Article 15 for AMT to provide material for use in clinical development of a treatment for lysosomal storage disorder Sanfilippo Syndrome IIIB at the Institut Pasteur,

Congratulations on your new collaboration. When AMT makes a decision about acquisition of clinical development from Institut Pasteur, please inform PHS as soon as possible.

We appreciate AMT’s continued interest in PHS technologies. If you have any questions, please do not hesitate to contact our office at any time

	Sincerely,

	/s/ Richard U. Rodriguez
	Richard U. Rodriguez
	Director, Division of Technology Development & Transfer

ATTACHMENT 1 - ROYALTY PAYMENT OPTIONS

The OTT License Number MUST appear on payments, reports and correspondence.

Automated Clearing House (ACH) for payments through U.S. banks only

The NTH encourages our licensees to submit electronic funds transfer payments through the Automated Clearing House (ACH). Submit your ACH payment through the U.S. Treasury web site located at: https://www.pay.gov . Locate the “NIH Agency Form” through the Pay.gov “Agency List”.

Electronic Funds Wire Transfers

The following account information is provided for wire payments. In order to process payment via Electronic Funds Wire Transfer sender MUST supply the following information within the transmission:

Drawn on a U.S. bank account via FEDWIRE should be sent directly to the following account;

Beneficiary Account:	Federal Reserve Bank of New York or TREAS NYC
Bank:	Federal Reserve Bank of New York
ABA#	021030004
Account Number:	75080031
Bank Address:	33 Liberty Street, New York, NY 10045
Payment Details:	License Number (L-XXX-XXXX) Name of Licensee

Drawn on a foreign bank account should be sent directly to the following account. Payment must be sent in U.S. Dollars (USD) using the following instructions:

Beneficiary Account:	Federal Reserve Bank of New York/ITS or FRBNY/ITS
Bank:	Citibank N.A. (New York)
SWIFT Code#	CITIUS33
Account Number:	36838868
Bank Address:	388 Greenwich Street, New York, NY 10013
Payment Details: (Line 70):	NIH 75080031 License Number (L-XXX-XXXX) Name of Licensee
Detail of Charges (line 71a):	Charge Our

Checks

All checks should be made payable to “NIH Patent Licensing”

Checks drawn on a U.S. bank account and sent by US Postal Service should be sent directly to the following address:

National Institutes of Health (NIH)
P.O. Box 979071
St. Louis, MO 63197-9000

Checks drawn on a U.S. bank account and sent by overnight or courier should be sent to the following address:

US Bank
Government Lockbox SL-MO-C2GL
1005 Convention Plaza
St. Louis, MO 63101
Phone: 314-418-4087

Checks drawn on a foreign bank account should be sent directly to the following address:

National Institutes of Health (NIH)
Office of Technology Transfer
Royalties Administration Unit
6011 Executive Boulevard
Suite 325, MSC 7660
Rockville, Maryland 20852

NATIONAL INSTITUTES OF HEALTH

SECOND AMENDMENT TO L-l 07-2007/0

This is the second amendment (“ Second Amendment ”) of the agreement by and between the National Institutes of Health (“ NIH ”) within the Department of Health and Human Services (“ HHS ”), and UniQure biopharma B.V. (formerly Amsterdam Molecular Therapeutics N.V. (AMT)) having an effective date of May 2, 2007 and NIH Reference Number L-107-2007/0, and having been amended for the first time on December 31, 2009 ( NIH Reference L-107-2007/1) (“ Agreement ”). This Second Amendment , having NIH Reference Number L-107-2007/2, is made between the NIH through the Office of Technology Transfer, NIH , having an address at (6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804, U.S.A., and UniQure biopharma B.V. (formerly Amsterdam Molecular Therapeutics N.V. (AMT)), having an office at Meibergdreef 61, 1105 BA Amsterdam, The Netherlands (“ Licensee ”). This Second Amendment includes, in addition to the amendments made below, 1) a Signature Page, and 2) Attachment 1 (Royalty Payment Information).

WHEREAS, NIH and Licensee desire that the Agreement be amended a second time as set forth below in order to

a) Change the name of Licensee from Amsterdam Molecular Therapeutics N.V. (AMT) to UniQure biopharma B.V. (UniQure). This name change is the result of a transaction that took place on 30 March 2012, whereby AMT, a public company, was liquidated and all its operations and stocks were transferred to UniQure, a privately held company.

b) Modify language related to financial terms associated with sublicensing, so as to cause a reduction in financial obligations due to NIH from sublicensing of the Agreement by Licensee in order to expedite the development of therapeutics for rare diseases.

NOW, THEREFORE, in consideration of the mutual covenants and promises contained herein, NIH and Licensee , intending to be bound, hereby mutually agree to the following:

1) a) In Cover page following the list of “licensed patent and patent application”, the name of Licensee has been changed to UniQure biopharma B.V.

b) In the signature page under “signature of authorized official”, under “Official and Mailing Address for Agreement notices”, and under “Official and Mailing Address for Financial notices” “Amsterdam Molecular Therapeutics” has been changed to UniQure biopharma B.V.

c) In the caption of the Agreement AMT is changed to UniQure.

2) a) Paragraph 6.6 is deleted in its entirety and replaced with the following:

6.6 No multiple royalties shall be payable if any Licensed Products or Licensed Processes are covered by more than one of the Licensed Patent Rights . In the event that this Agreement and NIH license L-116-2011/0 as amended from time to time apply to the same product sold by the Licensee or its sublicensees, then the Licensee shall only pay earned

royalties, benchmark royalties, and sublicensing royalties under NIH license L-l16-2011/0.

b) In Appendix C, the second occurrence of Roman numeral “IV” at the bottom of the page is replaced with Roman numeral “VI”. Section VI has been deleted in its entirety and replaced with the following:

Licensee agrees to pay NIH additional sublicensing royalties on the fair market value of any consideration received for granting each sublicense within sixty (60) days of the execution of each sublicense as follows:

(i) For any sublicense executed by the Licensee before the completion of any phase I clinical trial or foreign equivalent for any disease indication, Licensee agrees to pay a sublicensing royalty of ten percent (10%); and

(ii) For any sublicense executed by the Licensee after the completion of any phase I clinical trial or foreign equivalent but before the completion of any phase II clinical trial or foreign equivalent for any disease indications, Licensee agrees to pay a sublicensing royalty of six percent (6%); and

(iii) For any sublicense executed by the Licensee either after the completion of any phase III clinical trial or foreign equivalent for any disease of Orphan Indication or Ultra-Orphan Indication (as defined in L-l16-2011/0), or after the completion of any phase III clinical trial or foreign equivalent for any other disease indications, Licensee agrees to pay a sublicensing royalty of three percent (3%).

Contractual payments made by a sublicensee to the Licensee or an Affiliate received after the effective date of this Agreement for costs, services and expenses for the Licensee or Affiliate to perform research and development activities, or to conduct, supervise or participate in one or more clinical trial(s) for the development of the Licensed Products , or to manufacture clinical and commercial batches of Licensed Products , shall not be accounted for in the calculation of sublicensing royalties.

3) Licensee shall pay NIH an amendment issue royalty in the sum of two hundred and fifty thousand US Dollars ($250,000.00) as follows:

i) One hundred and fifty thousand Dollars ($150,000) shall be paid by Licensee within sixty (60) days of the effective date of this Second Amendment .

ii) The remaining amount of one hundred thousand Dollars ($100,000) shall be paid to NIH upon execution by Licensee of any new sublicensing or partnership agreement, or on the first anniversary of this Second Amendment , whichever occurs first.

4) In the event any provision(s) of the Agreement is/are inconsistent with Attachment 1, such provision(s) is/are hereby amended to the extent required to avoid such inconsistency and to give effect to payment information in such Attachment 1.

5) All terms and conditions of the Agreement not herein amended remain binding and in effect.

6) The terms and conditions of this Second Amendment shall, at NIH ’ sole option, be considered by NIH to be withdrawn from Licensee’s consideration and the terms and conditions of this Second Amendment , and the Second Amendment itself, to be null and void, unless this Second Amendment is executed by Licensee and a fully executed original is received by NIH within sixty (60) days from the date of NIH signature found at the Signature Page.

7) This Second Amendment is effective on May 31, 2013 upon execution by all parties.

SECOND AMENDMENT TO L-107-2007/0

SIGNATURE PAGE

In Witness Whereof, the parties have executed this Second Amendment on the dates set forth below. Any communication or notice to be given shall be forwarded to the respective addresses listed below.

For NIH :

/s/ Richard U. Rodriguez		5-23-13
Richard U. Rodriguez		Date
Director, Division of Technology Development and Transfer
Office of Technology Transfer
National Institutes of Health

Mailing Address or E-mail Address for Agreement notices and reports:

Chief, Monitoring & Enforcement Branch, DTDT
Office of Technology Transfer
National Institutes of Health
6011 Executive Boulevard, Suite 325
Rockville, Maryland 20852-3804 U.S.A.

E-mail: LicenseNotices_Reports@mail.nih.gov

For Licensee (Upon information and belief, the undersigned expressly certifies or affirms that the contents of any statements of Licensee made or referred to in this document are truthful and accurate.):

/s/ Jorn Alday			5-31-13
Jorn Alday, CEO, uniQure biopharma B.V.			Date

I.	Official and Mailing Address for Agreement notices:
	Chief Executive Officer;
	Legal@uniqure.com

II.	For invoices, payments, and Financial notices (including royalty payments):
	Finance Dept
	Finance@uniqure.com

uniQure biopharma B.V.
Meibergdreef 61
1105BA Amsterdam
The Netherlands

Phone:		0031 205667394

Fax:		0031 20 566 9272

ATTACHMENT 1 - ROYALTY PAYMENT OPTIONS

The OTT License Number MUST appear on payments, reports and correspondence.

Automated Clearing House (ACH) for payments through U.S. banks only

The NIH encourages our licensees to submit electronic funds transfer payments through the Automated Clearing House (ACH). Submit your ACH payment through the U.S. Treasury web site located at : https://www.pay.gov . Locate the “NIH Agency Form” through the Pay.gov “Agency List”.

Electronic Funds Wire Transfers

The following account information is provided for wire payments. In order to process payment via Electronic Funds Wire Transfer sender MUST supply the following information within the transmission:

Drawn on a U.S. bank account via FEDW1RE should be sent directly to the following account:

Beneficiary Account:	Federal Reserve Bank of New York or TREAS NYC

Bank:	Federal Reserve Bank of New York

ABA#	021030004

Account Number:	75080031

Bank Address:	33 Liberty Street, New York, NY 10045

Payment Details:	License Number (L-XXX-XXXX) Name of Licensee

Drawn on a foreign bank account should be sent directly to the following account. Payment must be sent in U.S. Dollars (USD) using the following instructions:

Beneficiary Account:	Federal Reserve Bank of New York/ITS or FRBNY/ITS

Bank:	Citibank N.A. (New York)

SWIFT Code:	CITIUS33

Account Number:	36838868

Bank Address:	388 Greenwich Street, New York, NY 10013

Payment Details (Line 70):	NIH 75080031

	License Number (L-XXX-XXXX)

	Name of Licensee

Detail of Charges (line 71 a):	Charge Our

Checks

All checks should be made payable to “NIH Patent Licensing”

Checks drawn on a U.S. bank account and sent by US Postal Service should be sent directly to the following address:

National Institutes of Health (NIH)
P.O. Box 979071
St. Louis, MO 63197-9000

Checks drawn on a U.S. bank account and sent by overnight or courier should be sent to the following address:

US Bank
Government Lockbox SL-MO-C2GL
1005 Convention Plaza
St. Louis, MO 63101
Phone: 314-418-4087

Checks drawn on a foreign bank account should be sent directly to the following address:

National Institutes of Health (NIH)
Office of Technology Transfer
Royalties Administration Unit
6011 Executive Boulevard
Suite 325, MSC 7660
Rockville, Maryland 20852

NATIONAL INSTITUTES OF HEALTH

THIRD AMENDMENT TO L-107-2007/0

This is the third amendment (“ Third Amendment ”) of the agreement by and between the National Institutes of Health (“ NIH ”) within the Department of Health and Human Services (“ HHS ”), and UniQure biopharma B.V. (formerly Amsterdam Molecular Therapeutics (AMT) B.V.) having an effective date of May 2, 2007 as amended for the first time on December 31, 2009, and amended for the second time on May 31, 2013, and having NIH Reference Number L-107-2007/0, L-107-2007/1, and L-107-2007/2 respectively (“ Agreement ”). This Third Amendment , having NIH Reference Number L-107-2007/3, is made between the NIH through the Office of Technology Transfer, NIH , having an address at 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804, U.S.A., and UniQure biopharma B.V. (formerly Amsterdam Molecular Therapeutics (AMT) B.V.), having an office at Meibergdreef 61, 1105 BA Amsterdam, The Netherlands (“ Licensee ”). This Third Amendment includes, in addition to the amendments made below, a Signature Page.

WHEREAS, NIH and Licensee desire that the Agreement be amended a third time as set forth below in order to a) clarify the Field of Use , and b) to update appendices D and E of the Agreement to capture all of Licensee’s past, current and future Commercial Development Plan ,

NOW, THEREFORE, in consideration of the mutual covenants and promises contained herein, NIH and Licensee , intending to be bound, hereby mutually agree to the following:

1) In Appendix B Paragraph I, replace the Licensed Field of Use with the following:

Use of Licensed Patent Rights for development and sale of AAV related products

2) Replace Appendix D with Appendix D attached to this Second Amendment as EXHIBIT 1.

3) Replace Appendix E with Appendix E attached to this Second Amendment as EXHIBIT 2.

4) All terms and conditions of the Agreement not herein amended remain binding and in effect.

5) The terms and conditions of this Third Amendment shall, at NIH sole option, be considered by NIH to be withdrawn from Licensee ’s consideration and the terms and conditions of this Third Amendment , and the Third Amendment itself, to be null and void, unless this Third Amendment is executed by Licensee and a fully executed original is received by NIH within sixty (60) days from the date of NIH signature found at the Signature Page.

6) This Third Amendment is effective on the date of execution by the last party to execute this Third Amendment .

THIRD AMENDMENT TO L-107-2007/0

SIGNATURE PAGE

In Witness Whereof, the parties have executed this Third Amendment on the dates set forth below. Any communication or notice to be given shall be forwarded to the respective addresses listed below.

For NIH :

/s/ Ricahrd U. Rodriguez		11-6-13
Richard U. Rodriguez		Date
Director, Division of Technology Development and Transfer
Office of Technology Transfer
National Institutes of Health

Mailing Address or E-mail Address for Agreement notices and reports:

Chief, Monitoring & Enforcement Branch, DTDT
Office of Technology Transfer
National Institutes of Health
6011 Executive Boulevard, Suite 325
Rockville, Maryland 20852-3804 U.S.A.

E-mail: LicenseNotices_Reports@mail.nih.gov

/s/ Piers J. Morgan — PJ Morgan CFO			November 11, 2013
Piers J Morgan, CFO, uniQure biopharma B.V.			Date

I	Official and Mailing Address for Agreement notices:
	Chief Executive Officer;
	Legal@uniqure.com

II	For invoices, payments, and Financial notices (including royalty payments):
	Finance Dept
	Finance@uniqure.com

uniQure biopharma B.V.
Meibergdreef 61
1105BA Amseterdam
The Netherlands

Phone:		0031 205667394
Fax:		0031 20 566 9272

EXHIBIT 1

APPENDIX D — BENCHMARKS AND PERFORMANCE (L-107/2007)

Licensee agrees to the following Benchmarks for its performance under this Agreement and, within thirty (30) days after achieving a Benchmark , shall notify PHS that the Benchmark has been achieved.

Note: No formal Phase III clinical trial is required for Marketing Approval for any Orphan Indication

Benchmarks for lead Licensed Product (AMT-011 also known as Glybera™)

I. Initiation of Preclinical Development phase or foreign equivalent — 4 th quarter 2006

II. Initiation of first Phase I clinical trial or foreign equivalent — 3 rd quarter 2007

III. Initiation of first Phase II clinical trial or foreign equivalent — 3 rd quarter 2007

IV. Submission to Regulatory Authority of first Marketing Approval or foreign equivalent — 1 st quarter 2010

Benchmarks for another Orphan Indication Licensed Product (AMT-021 or equivalent)

I. Initiation of Preclinical Development phase or foreign equivalent — 4 th quarter 2010

II. Initiation of first Phase I clinical trial or foreign equivalent — 4 th quarter 2012

III. Initiation of first Phase II clinical trial or foreign equivalent — 4 th quarter 2016

IV. Submission to Regulatory Authority of first Marketing Approval or foreign equivalent — 2 nd quarter 2018

Benchmarks for a non- Orphan Indication Licensed Product (AMT-090 or equivalent)

I. Initiation of Preclinical Development phase or foreign equivalent — 3 rd quarter 2011

II. Initiation of first Phase I clinical trial or foreign equivalent — 2 nd quarter 2013

III. Initiation of first Phase II clinical trial or foreign equivalent — 2 nd quarter 2017

IV. Initiation of first Phase III clinical trial or foreign equivalent — 4 th quarter 2020

V. Submission to Regulatory Authority of first Marketing Approval or foreign equivalent — 2024

EXHIBIT 2

APPENDIX E — COMMERCIAL DEVELOPMENT PLAN (L-107-2007)

The table below (table 1) presents a comprehensive list of all uniQure research and development projects utilizing the Licensed Patent Rights, according to main disease site and divided into projects that are, a) commercial projects, b) already in development stages, c) active research (there is already internal research activity ongoing and d) exploratory research projects (currently being considered as potential projects worth further investigation in the near future).

Table 1: uniQure R&D projects

		Brain & CNS (AAV5 based unless otherwise indicated)
Commercial Projects	· Lipoprotein Lipase Deficiency (Glybera) (AAV1 based)	—
	Liver (AAV5 based unless otherwise indicated)
Development Projects	· Acute Intermittent Porphyria (AMT-021) · Hemophilia B (AMT-060)	· Sanfilippo B (MPS IIIB) (AMT-110) · Parkinson’s Disease (AMT-090) (AAV2 based)
Active Research Projects	· Hemophilia A (HA) · Cirrhosis · Hyperoxaluria (HP1)	· Huntington’s Disease · Multiple System Atrophy (MSA) · Hearing loss
Exploratory Research Projects	· Phenylketonuria (PH1) · Ornithine transcarbamylase deficiency (OTCD) · Glycogen storage disease type II (Pompe) · Maroteaux-Lamy syndrome (MPS VI) · Fabry disease	· Amyotrophic lateral sclerosis (ALS - motor neurone disease or Lou Gehrig’s disease) · Spinal muscular atrophy (SMA) · Batten’s disease · Tay Sacks · Krabbe disease (globoid cell leukodystrophy or galactosylceramide lipidosis)

Detailed information on the commercial, development and active research projects is provided below.

NOTE: All dates contained in this Commercial Development Plan are projected estimates only.

A) Commercial Projects

Glybera

Glybera, an AAV1 based product for lipoprotein lipase deficiency, was approved under exceptional circumstances by the EMA in October 2012. Currently uniQure is in the phase of preparation of product launch, for which it has

found a partner in Chiesi. It is our aim together with Chiesi to launch in Europe in the first half of 2014. The commercialization agreement with Chiesi has been shared with NIH.

uniQure is actively working on post-approval commitments which came with the approval under exceptional circumstances. Besides some CMC related commitment, there is a commitment for a Phase IV study to collect more biomarker data on the chylomicron handling before and after treatment with Glybera as well as setting up a registry for LPLD patients. Both studies are in progress and in accordance with timelines of the commitments to the EMA.

Furthermore, uniQure has initiated the first campaign for the product of commercial product. This campaign is ongoing and will result in release of the first batch in quarter 1, meeting the planning of the launch of Glybera.

In the context of the European pricing and reimbursement (P&MA) preparations for Glybera, these have been initiated and efforts are ongoing to prepare a pricing strategy as well as a European Core value Dossier (CVD). The agency selected to support the development of the pricing strategy as well as the European CVD has been nominated following a thorough screening and selection process, - the mutual CDA does not allow a disclosure of the agency, which has been agreed with our partner Chiesi. Please be aware that the continued management of the P&MA preparations is now led by Chiesi, who have the commercialization rights for Glybera in the EU.

The P&MA dossier is the crystallization of a multifactorial approach to P&MA and will focus on the Clinical and Epidemiology Data & Publications, Economic Tools & Data, P&MA Strategy and Goals as well as P&MA Implementation & Tactics.

The Initial evaluation and assessment of the current available market information is sparse due to the new concept of introducing the first gene therapy, a market which today has basically no treatment for LPLD patients and the first time introduction of a one-time administration treatment for an ultra-rare disease.

Key clinical data will be incorporated into the CVD and translated into value statements and economic benefits that will provide rationale and evidence for the positioning of Glybera® with key stakeholders, especially physicians and payers.

The Core Value Dossier is, therefore, a crucial vehicle to deliver the P&MA strategy for Glybera® and support tactical execution. Based on the initial preparations, a stepwise approach to the design and development of the Core Value Dossier for Glybera® has been planned.

In the event that serious gaps exist in the data and/or major problems are identified in this initial review, with regard to the usability and credibility of the data with payers and customers, these issues will be discussed between Chiesi and uniQure.

The Glybera® Core Value Dossier will be the internal reference document summarizing the available evidence and documentation and developing these into value statements and approaches to the various relevant stakeholders.

The CVD structure is designed to bring consistency to the messages delivered in each country and, at the same time, provide the depth of information on each point to allow for the essential local market tailoring.

As per 30th September 2013, Chiesi has reported having one informal meeting with a European Health authority to discuss the process and management of the P&MA dossier. As the meeting was informal there was no agenda and no official minutes have been taken. As per 30th September, no reimbursement reports are available. The on-going development of the CVD and the pricing strategy are managed by the same agency.

Discussions with the FDA were started in August of 2013, which will be followed by filing of an IND in Q1 of 2014.

uniQure is currently developing a geographical expansion strategy to find partners and product approval in other

territories, such as Israel, Canada and South Korea.

Liver Programs

B) Development Programs

1. AMT-021 for Acute Intermittent Porphyria

Disease Background

Acute Intermittent Porphyria, or AIP, is a rare liver metabolic disorder resulting from mutations in the PBGD gene. This gene encodes for the enzyme porphobilinogen deaminase (also known as hydroxymethylbilane synthase — HMBS), a liver protein necessary for the production of heme, a component of hemoglobin and other blood proteins. Insufficient activity of this protein leads to an accumulation of toxic metabolites (ALA and PBG), resulting in a wide variety of serious clinical problems, including acute, severe abdominal pain, muscular weakness and an array of neurologic manifestations, including psychiatric episodes, seizures and coma. In the majority of cases, attacks are triggered by precipitating factors such as hormonal fluctuations, infections, drugs and dietary changes. Long-term consequences may include irreversible nerve damage, liver cancer and kidney failure. Patients with AIP experience regular hospitalizations and extremely poor quality of life, and may in some cases require liver transplants. Acute attacks can be life-threatening. Current therapies only target the disease symptoms and do not prevent attacks or fully minimize or control their consequences.

A recent epidemiological study reported that, in Europe (excluding Sweden), the incidence of AIP is 0.13 per million population per year and based on that they estimated a prevalence of 5.9 per million population (Elder et al., 2012). In Sweden the incidence and prevalence of AIP are about four times higher than in the rest of Europe due to a founder effect originating in Lappland (Floderus et al., 2002). The frequency in the United States is estimated to be 1-5 cases per 100,000 population ( www.emedicine.medscape.com/article/205220-overview#a0199 ).

Overview of AMT-021 Program

The goal of our AMT-021 program is to provide long-term normalization of the PBGD protein in order to prevent acute AIP attacks and their complications.

The program has been developed through a collaborative agreement with the Foundation for Applied Medical Research (FIMA), its Center for Applied Medical Research (CIMA) and its commercialization arm, DIGNA Biotech, of the University of Navarra (Pamplona, Spain). Part of the funding to support for the Phase I trial (including GLP safety & toxicology studies and the observational trial) was secured through the European Commission Framework Programme 7 award (€3.3 million, grant agreement 261506) made to the AIPGENE consortium ( www.aipgene.org/ ), of which uniQure is a partner.

UniQure holds an exclusive license to the gene cassette being used in the Phase I clinical trial. Under our agreement with DIGNA Biotech and the other consortium members, Licensee has an exclusive right to all data related to the program.

Preclinical Development

· Product Profile

AMT-021 is designed to be delivered systemically through a peripheral vein in a single administration.

AMT-021 or rAAV5-hPBGD, is a recombinant adeno-associated vector of serotype 5, consisting of:

· Inverted terminal regions or ITRs of the adeno-associated serotype 2

· A human codon optimized porphobilinogen deaminase gene or hPBGDco as the therapeutic gene

· A liver specific promoter constituted by the albumin enhancer (Ealb) and the alfa-1-antitrypsin promoter (hAAT)

· Pre-clinical Proof of Concept

Pre-clinical proof of concept (PoC) studies have been performed using the AIP murine model developed by Lindberg et al. (1999). In these studies, long term therapeutic efficacy was achieved. More specifically, at 5x10 13 gc/kg, metabolic correction of the hepatic PBGD enzyme activity, normalization of the PBG and ALA precursor’s accumulation in urine and improvement of the motor coordination were observed. Additionally, a complete neurological study indicated the correction of neurotoxic porphyrin precursors was able to restore nerve conduction and the impaired peripheral neuropathy.

In non-human primates (NHP) treated with AMT-021 at a dose of 5x10 13 gc/kg endogenous PBGD enzymatic activity increased by a factor of two in male and between three and five times in female animals.

· Non-clinical safety & toxicology studies

The following table presents a summary of the AMT-021 non-clinical safety and toxicology studies that have been conducted to support the clinical development program.

Parameter to be
assessed

Study performed

Results

Pharmacokinetics

1) GLP biodistribution in C57Bl/6 mice (180 days) with validated QPCR method.

2) Biodistribution data in Rhesus macaques (supportive)

In both species,

· Clear correlation between the dose of vector administered and the genome copies of the vector as well as vector RNA (expression) quantified in the liver.

· Tissue biodistribution was mainly limited to liver although some significant transduction was detected in spleen, lymph nodes, heart and adrenal glands.

Toxicity	1) GLP toxicity study in Rhesus macaques, 30 days 2) GLP toxicity study in C57Bl/6 mice (180 days)	In Rhesus macaques: · No specific macroscopic or microscopic findings, no severe immune/inflammatory reactions (NOAEL 5x10 13 gc/kg) In C57Bl/6 mice: · No severe adverse toxicologically significant findings · At highest dose limited hepatocyte vacuolation due to metabolic adaptation to high PBGD activity in liver (NOAEL 5x10 14 gc/kg)
Off-target expression	Included in the GLP toxicity study in monkey and mouse	Vector RNA analysis for all tissues other than liver showed that there is no PBGD transcription and translation elsewhere.
Shedding pattern	Included in the Rhesus macaques study	Shedding in semen and saliva is transient (cleared by day 30)
Persistence in semen and risk of germline transmission	Mouse Germline transmission study in C57Bl/6 mice	No transmission to offspring
Carcinogenicity	Analyze tissues from the Rhesus studies using LAM-PCR	· Low frequency of integration sites, with random distribution · No preferences for CpG islands · No preference for palindromic regions · No hotspots (low clustering level)

1.1.1 Summary of AMT-021 Preclinical Development Program

Single intravenous administration of AMT-021 into wild type mice and Rhesus macaques results in:

· Efficient liver transduction resulting in dose dependent increase in viral RNA copy numbers and in turn producing increased PBGD activity

· No morbidity, no changes in body weight or food intake

· No changes in biochemistry, hematology, coagulation and urinalysis associated with AAV5-hPBGD

· Negative vector shedding 30 days after viral administration in serum, saliva, nasal secretions, urine, faeces and semen

· Tissue biodistribution that is mainly limited to liver although some significant transduction was detected in spleen, lymph nodes, heart and adrenal glands

· Specific hepatic PBGD expression

Clinical Development Program

The key regulatory and clinical development best estimate milestones for AMT-021 include the following,

· EMA Orphan Drug Designation (EU/3/09/632)	Apr 2009

· FIMA/ CITA/ UTE/ DIGNA - AMT Collaborative Agreement	May 2010

· EU-FP7 AIPGene Consortium	Jan 2011

· Observational Study AEMPS approval	May 2011

· Observational Study start	Jul 2011

· Phase I Study AEMPS approval	Oct 2012

· Phase I Study: first patient treated	Dec 2012

· Phase I Study: last patient treated	Aug 2013

Expected milestones

· Phase II/III start:	4Q2016

· MAA/ NDA submission:	2Q2018

· Observational trial

A prospective non-interventional (pre-treatment) observational study started at the end of 2011 that aims to assess the evolution of disease-related clinical and laboratory parameters in time, as well as characterize aspects of disease management such as AIP-related hospitalization. This baseline assessment is intended to study possible relationships

between biochemical parameters and clinical endpoints that will in turn be valuable in evaluating any signs of efficacy in the Phase I trial as well as in subsequent trials. Eight patients are expected to be enrolled who after completion of this observational phase would then enter the interventional stage of the program, i.e., first-in-human clinical study (Phase I). The observational study is to last for at least six months for each participant.

To date all 8 AIP-patients have been recruited into the observational study and all but one have completed a minimum of 6 months pre-treatment assessments. The last patient completed the observational study in August 2013.

· Phase I trial

The Investigational Medicinal Product Dossier (IMPD) was submitted to the AEMPS (Spanish Agency for Medicines and Medical Devices) in June 2012 and was approved by the Agency in October 2012.

The Phase I study is a multicenter, open label, prospective, interventional, single dose, dose-escalation clinical trial to investigate the safety and tolerability of AAV5-hPBGDco (AMT-021) in patients with severe Acute Intermitted Prophyria (Eudra CT no. 2011-005590-23).

The primary objective is to assess the safety of systemic administration and determine the maximum tolerated doses (MTD). Secondary objectives include urinary levels of toxic metabolites (ALA and PBG), disease symptoms evaluation, quality of life evaluation and assessment of pharmacokinetics. Exploratory objectives include, neurological involvement, identification of novel biomarkers and pharmacokinetic modeling.

The Phase I study was initiated in December 2012 in the Department of Medicine (Liver Unit) at the University Clinic of the University of Navarra (Pamplona, Spain). There are two patients per cohort and four cohorts in the trial (each cohort receiving 5x10 11 , 2x10 12 , 6x10 12 or 1.8x10 13 gc/kg) and all patients will be followed- up for one year as part of the Phase I study.

All 8 patients who completed the observational trial have also been treated as part of the Phase I study. In the 8 treated patients, no Serious Adverse Events, Treatment Emergent Adverse Events or Liver Events (Dose Limiting Toxicities - DLT’s) related to the study medication have been observed to date.

· Future Clinical Development

It is envisaged that the Phase II/III will be a confirmatory trial where the study population and the outcomes to be assessed (efficacy endpoints — clinical and biochemical) will be based on those as for Phase I. Licensee also intends to carry out the study in both Europe and the USA .

Summary of AMT-021 Clinical Development Program

· The first time an AAV5 gene therapy product has been tested in humans

· The first time an AAV gene therapy product has been tested in humans at such high dose, i.e., 1.8x10 13 gc/kg

· No Serious Adverse Events, Treatment Emergent Adverse Events or Liver Events (DLT’s) related to the study medication have been observed in the Phase I study to date

· The Phase I is expected to be completed in 3Q14 and Phase II/III is expected to start by the end of 2014

· The Phase II/III program will run in parallel in Europe and US where MAA and NDA, respectively, are expected in 4Q2016

2. AMT-060 for Hemophilia B

Disease Background

Hemophilia B is a serious inherited orphan disease in males characterized by insufficient blood clotting. The condition can lead to repeated and sometimes life-threatening episodes of external and internal bleeding following accidental trauma or medical interventions. The episodes may cause long-term damage, for example to the joints, and may be fatal if they occur in the brain. The deficient blood clotting is caused by the lack of functional human Factor IX, or hFIX, a blood clotting factor, as a result of mutations in the gene responsible for encoding this essential protein. The presence of hFIX at greater than 1% of normal levels has a therapeutic effect in promoting clotting. The current standard treatment is prophylactic protein replacement therapy, in which frequent intravenous administrations of recombinant Factor IX (often 2-3 times per week) are required to stop or prevent bleeding. Protein replacement therapy is costly ($150,000-200,000 per patient per year) and burdensome, and does not completely prevent bleeding.

The total Hemophilia B patient population in the European Union and the United States is estimated at approximately 25,000, according to the World Federation of Hemophilia 2010 Report on the Annual Global Survey. About 40% of individuals with the disease have a severe disorder, characterized by functional factor IX levels that are less than 1% of normal, whereas moderately severe Hemophiliacs (about 30% of the Hemophiliac population) have 1%-5% of normal and those with the mild phenotype (the remaining 30%) have between 5% and 40% of normal factor IX levels ( www.orpha.net ). Based on these estimates Licensee believes that approximately 70-85% of the worldwide patient population would be eligible for treatment with gene therapy. Licensee believes that the treatment would not be appropriate for those patients with very mild disease phenotype.

Overview of AMT-060 Program

The goal of our AMT-060 program is to restore blood clotting on a long-term basis through the introduction of the functional gene for hFIX into the patient’s liver cells. Licensee is currently in the process of finalizing pivotal (GLP) safety and toxicology studies and preparing to conduct a Phase I trial.

Preclinical Development

· Product Profile

AMT-060 is designed to be delivered systemically through a peripheral vein in a single administration .

The use of recombinant adeno-associate vectors (rAAV) of serotype 5 (rAAV5) for targeted gene delivery to the liver was pioneered by St. Jude Children’s Research Hospital (SJCRH) where for pre-clinical experiments the hFIX expression cassette was packaged into AAV5 capsids in HEK-293T mammalian cells. HEK-293 produced AAV5-hFIX is not suitable for further development because as a production system it is not amenable to large-scale production. To allow up scaling, the expression cassette has now been transferred into uniQure’s proprietary baculovirus expression vector system (BEVS) that can be adapted to a GMP setting. The resulting vector produced

using the baculovirus expression system is termed AAV5-hFIXco or AMT-060. Licensee also holds a license from SJCRH to the gene cassette used in the currently ongoing Phase I/II AAV 2/8-LP1-hFIXco trial.

AMT-060, rAAV5-hFIXco, is a recombinant adeno-associated vector of serotype 5, consisting of:

· Inverted terminal regions (or ITRs) of the adeno-associated serotype 2

· A human codon optimized FIX gene (or hFIXco) as the therapeutic gene

· The liver specific promoter, LP1, derived from the human apolipoprotein hepatic control region and the human alpha-1-antitrypsin (or hAAT) promoter

· Virus serotype selection

The hFIXco expression cassette and rAAV5 or AAV8 vectors have been extensively studied in mice and non-human primate. Both vectors have been shown to have similar tropism to (preference to transduce) the liver (Nathwani et al., 2007) and AAV5-hFIXco was shown to mediate expression of significant levels of human factor IX in non-human primates (NHP) during a monitoring period of more than 5 years (Nathwani et al., 2011). In this study none of the animals presented elevated liver enzymes levels or other signs of toxicity during the whole observation period. Liver examination by MRI scanning did not reveal any abnormalities in any of the animals.

These pre-clinical data suggest that i.v. administration of the AAV5-hFIXco vector is able to mediate a similar level of human factor IX as presented for AAV8-hFIXco, and such administration is not associated with safety concerns or immunogenicity against the human factor IX.

· Pre-clinical Proof of Concept

Pre-clinical PoC studies have been carried out in wild type mice, non-human primates (NHP) and are currently being completed in transgenic Hemophilia B mice. In wild type mice (C57Bl/6) intravenous administration of AMT-060 mice resulted in dose-dependent levels of (human) factor IX levels in murine plasma as determined by ELISA. Human factor IX levels amounted up to 11% of those in normal human plasma 4 weeks after infusion of 5x10 12 gc/kg, demonstrating that AAV5-hFIXco produced in the BEVS is biologically active.

In Rhesus monkeys dosed with AMT-060 (5x10 12 gc/kg) by intravenous infusion, human FIX levels peaked to 7%-16% of normal human levels one week after infusion, and stabilized to 5-10% of normal human levels 4 weeks after infusion until sacrifice (12 weeks after dosing). These kinetics are in accordance with those observed in previous studies (Nathwani et al., 2007; Jiang et al., 2006), indicating that i.v. administration of AAV5-hFIXco produced in BEVS results in a level of factor IX in plasma that is similar to that produced using AAV5-hFIXco produced in HEK293 cells. Post mortem, (RT)-QPCR demonstrated homogeneous vector DNA delivery and transgene expression in the liver. No signs of adverse reactions were observed. Infusion was associated with slight and transient effects in plasma chemistry shortly after dosing, such as a brief increase of liver enzyme activity levels, consistent with infusion of a viral protein. Necropsy revealed no significant macroscopic or microscopic abnormalities.

Preliminary data in Hemophilia B mice indicate that treatment with AMT-060 induces normalization of FIX levels as well as clotting time.

· Non-clinical safety & toxicology studies

The following table presents a summary of the AMT-060 non-clinical safety and toxicology studies that are being conducted to support the clinical development program.

Parameter to be assessed	Study performed	Status
Pharmacokinetics	1) GLP biodistribution in C57Bl/6 mice (180 days) with validated QPCR method. 2) Biodistribution data in Rhesus macaques (supportive)	Ongoing
Toxicity	1) GLP toxicity study in Cynomolgus monkeys (180 days) 2) GLP toxicity study in C57Bl/6 mice (180 days) 3) Liver pathology in Rhesus macaques (supportive)	Ongoing
Off-target expression	Included in the GLP toxicity study in monkey and mouse	Ongoing
Shedding pattern	Partly included in the mouse GLP toxicity study. Partly included in the Rhesus macaques study.	Ongoing
Persistence in semen and risk of germline transmission	1) Mouse Germline transmission study in C57Bl/6 mice 2) QPCR of the testis in the Rhesus macaques at 90 days (non-GLP).	Ongoing
Carcinogenicity	Analyze tissues from the Rhesus studies using LAM-PCR	Ongoing
Juvenile toxicity	Ethical approval obtained and study is being planned (to support PIP plans)	Ongoing

Summary of AMT-060 Preclinical Development Program

· AAV5-hFIXco shows similar liver tropism to AAV8-hFIXco and results in significant and long lasting increase in FIX expression.

· Single intravenous administration of AMT-060 into wild type mice and Rhesus macaques results in significant and long lasting hFIX levels with no noticeable adverse events and no macroscopic or microscopic findings.

· GLP safety and toxicology studies are expected to be completed in December 2013 .

Clinical Development Program

The key regulatory and clinical development milestones for AMT-060 include the following,

· EMA Orphan Drug Designation:	Nov 2011

· FDA Orphan Drug Designation:	Jan 2012

· EMA Scientific Advice:	Feb 2012

· EMA Phase I Protocol Advice:	Aug 2012

· GLP Safety & Tox Studies:	2Q2012 to 4Q2013

Expected milestones

· IMPD submission:	2Q2014

· Phase I start:	3Q2014

· Phase II/III start:	3Q2016

· MAA/ NDA submission:	2Q2018

· Phase I trial

The Phase I study will be a multicenter, open label, prospective, interventional, single dose, dose-escalation clinical trial to investigate the safety and tolerability of AAV5-hFIXco (AMT-060) in patients with severe Hemophilia B.

The primary objective is to assess the safety of systemic administration and determine the maximum tolerated doses (MTD). Secondary objectives include:

· To estimate the appropriate dose required to achieve stable expression of hFIX at or above 3% of normal

· To evaluate kinetics (dose-related duration and magnitude) of expression

· To assess the immune response to hFIX transgene product

· To assess the immune response to the AAV5 capsid proteins

· To assess viral shedding in various body fluids (including semen)

· To assess the occurrence of FIX inhibitors

· To evaluate coagulation parameters

· To assess need for FIX concomitant treatment

Twelve male adults patients ( > 18 year old to < 35 year old) with genetically confirmed Hemophilia B and phenotypically defined as having severe disease ( < 1% of normal plasma FIX levels) are expected to be enrolled. Initial patient follow-up will last for 12 months as part of the Phase I trial.

· Future Clinical Development

It is envisaged that the Phase II/III will be a confirmatory trial where the study population and the outcomes (efficacy endpoints — clinical and biochemical) will be based on those for the Phase I. Licensee will also consider expanding the patient population to moderately severe patients and intend to carry out the study in both Europe and USA.

Summary of AMT-060 Clinical Development Program

· The IMPD is planned to be submitted in 2Q2014

· Phase I is planned in patients with severe Hemophilia B and is expected to start in 3Q2014

· It is the intention that in Phase II/III the patient population will expand to moderately severe Hemophilia B patients

· The Phase II/III program will run in parallel in Europe and USA where MAA and NDA, respectively, are expected in 2Q2017

The Hemophilia B program has been partnered with Chiesi. The co-development agreement has been shared with NIH.

C) Active Research Projects

1. Hemophilia A

Disease Background : Hemophilia A (HA) is a genetic, X-linked, recessive disorder caused by production of dysfunctional or by production of insufficient amount of factor VIII (FVIII) protein, a key protein involved in the blood coagulation cascade. Hemophilia A patients suffer from spontaneous bleeding in the large joints and soft tissue, and are at risk for intracranial hemorrhage. Recurrent episodes of joint bleeding can lead to crippling arthropathy, particularly in severely affected patients. HA comprises the majority of hemophilia patients (80%), with incidence of ~1:10,000 to 1:50,000 males affecting 400,000 people worldwide.

Numerous mutations in the FVIII gene have been described giving rise to different disease phenotypes. Similarly to Hemophilia B (HB), individuals with less than 1% active factor are classified as having severe hemophilia, those with 1—5% active factor have moderate hemophilia, and those with mild hemophilia have between 5—40% of normal levels of active clotting factor.

rFVIII protein for bleeding episodes. Although, prophylactic infusion of FVIII concentrates is generally effective in alleviating bleeding episodes and subsequent joint disease, the short half-life of FVIII (~12 hours) and the high cost of purified FVIII products make life-long prophylactic treatment demanding for patients and costly.

Feasibility

Gene : The gene of factor VIII is located on the long arm of the X chromosome. It spans over 180 kb, and as such is one of the largest genes known. It comprises of 26 exons, which encode a polypeptide chain of 2351 amino acids including a signal peptide of 19 and a mature protein of 2332 amino acids. It is a secreted protein. Its primary structure, deduced from the cloned factor VIII cDNA, includes discrete domain structure: A1-a1-A2-a2-B-a3-A3-C1-C26-8. The B domain is unique in that it exhibits no significant homology with any other known protein and can be deleted with the resulting recombinant protein displaying essentially normal survival in circulation and able to correct the bleeding tendency in HA patients.

Vector optimization : A rAAV5 containing HLP-hFVIIIco (promoter HLP; codon optimized hFVIII with partial B-domain deletion) has been generated in-house where the preserved B-domain consists of 225 N-terminal amino acids containing 6N-glycosilation sites. This variant has been previously shown to increase secretion of FVIII as compared to wild type or to FVIII with complete B-domain deletion and in-house work with HLP-hFVIII has shown that it produces active FVIII protein in vitro and in vivo .

This FVIII expression cassette size is however ~5.6 kbp, which exceeds the AAV packaging limit (4,7-4,9 kbp). In-house molecular analysis studies of the encapsidation products showed that the 5.6kbp FVIII expression cassette is not entirely encapsidated in the AAV particle. Instead + and – DNA strands of the encapsidated molecules revealed missing 5’ ends. This is consistent with previously reported unidirectional (starting at 3’ end) packaging mechanism operating according to “head-full principia” with 4.7-4,9 kbp limit. Licensee hypothesizes that the correct template for production of FVIII was assembled in the target cell based on complementation of + and – DNA strains each of which delivering the 5’ missing end. This is to be expected since + and – strain complementation is responsible for normal rAAV episome formation. Licensee proposes therefore to develop a product that consist of incomplete + and – DNA strains, which are assembled into complete expression cassette upon episome formation.

A proof of concept study has been initiated involving a number of FVIII construct and including full FVIII codon optimized gene. The study aims to characterize the viral DNA, formation of episomes upon delivery of the expression cassette to the nucleus, resulting mRNA and FVIII protein. The potency of the vector is currently being investigated in a number of animal models.

It is our aim to develop this product to clinical stage Phase I by the end of 2015. Duration of clinical development and further timelines have not been defined.

Development overview to IMPD:

Completion of vector optimization work will provide the first milestone (Go/No Go) for the project.

Safety Assessment : The disease and gene therapy approach are similar (or equivalent) to Hemophilia B where no major safety concerns have been described.

2. Cirrhosis

Disease Background : Liver cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules (resulting from regeneration of damaged tissue), leading to loss of liver function. The four leading causes of cirrhosis and primary liver cancer in Europe include harmful alcohol consumption, viral hepatitis B, viral hepatitis C and metabolic syndromes related to overweight and obesity. The European Association for the Study of the Liver in its 2013 report reported that approximately 29 million people in the European Union suffer from a chronic liver condition and that the incidence and prevalence of two conditions, cirrhosis and primary liver cancer, are key to understanding the burden of liver disease. Both conditions represent the end-stage of liver pathology and thus are indicative of the associated mortality.

The hypothesis behind this project is that liver cirrhosis is a state of IGF-I insufficiency and low expression of IGF-I locally in the liver will revert and/ or prevent further exacerbation of cirrhosis. A confidentiality agreement concerning this project was signed between DIGNA/ CIMA and uniQure in October 2012.

Pre-clinical evidence to support this hypothesis includes the following:

· Proof of Mechanism: SV40-IGF-I administration in rat cirrhotic liver models resulted in increased mRNA and protein levels of IGF and IGF-BP3 compared to control animals in the hepatocytes and levels remained constant for up to 6 months (Sobrevals et al., 2010).

· Proof of Principle: SV40-IGF-I mediated expression in rat cirrhotic liver models, induced fibrolysis through upreguation of MMPs and downregulation of TIMP-1/-2, reduced expression of pro-fiborgenic factors (TGFb, amphilregulin, PDGF, CTGF, VEGF), induced antifibrogenic and cytoprotective factors (HGF), promoted hepatocyte differentiation through upregulation of HNF4a and downeregulation of WT-1 (Sobrevals et al., 2010).

Treatment with recombinant IGF-I protein resulted in improved hepatic function, decreased oxidative stress/ damage, improved mitochondrial function and decreased fibrosis (Castillo-Cortazar et al., 2000; García-Fernández et al., 2005; Lorenzo-Zuniga et al., 2006).

· Proof of Concept: SV40-IGF-I-mediated expression in rat cirrhotic liver reversed fibrosis by decreasing expression of collagen I & IV and deactivation of HSC, and improved liver function through normalisation of AST, ALT, ALP, bilirubin and albumin (Sobrevals et al., 2010).

Clinical evidence to support disease linkage includes the following:

· In patients suffering from liver cirrhosis circulating IGF-I levels (or IGF-BP3) correlate with disease severity scores; Child-Pugh and MELD (Kratzsch et al., 2005; Khoshnood et al., 2013).

· A short course (for 4 months) of IGF-I recombinant therapy treatment increased the levels of albumin and tended to improve energy metabolism (surrogates for liver function) & the levels of serum albumin positively correlated with IGF-I/IGF-I BP3 ratio (Conchillo et al., 2005).

Clinical need : Transplantation is the only curative option for the disease and contraindications to transplantation include, a) co-morbidities (e.g., TB), b) over 65 years of age, c) coronary artery disease and d) tumours in previous 5

years.

The initial target population for IGF-I gene therapy for liver cirrhosis could/ would be those cirrhotic patients with IGF-I insufficiency (i.e., 50% of all cirrhotic patients), possibly patients with Child-Pugh A and/ or B score and with IGF-I levels below normal values. An ODD application for this specific population may be considered. The table below indicates the Child-Pugh scoring scheme for liver disease prognosis.

Points	Class	One year survival		Two year survival
5-6	A	100	%	85	%
7-9	B	81	%	57	%
10-15	C	45	%	35	%

Feasibility :

Gene: The IGF1 gene is located on chromosome 12 and spans 7.3 kb encoding a 70 amino acid residue protein. It contains 6 exons, 4 of which are alternatively spliced depending on tissue type and hormonal environment. The IGF1 coding region is flanked by sequences encoding an amino-terminal peptide of at least 25 residues and a carboxyl-terminal peptide of 35 amino acids which indicates that IGF1 is synthesized as a precursor protein that undergoes proteolytic processing at both ends before being secreted.

Vector optimization: The IGF-1 rat version is available with CIMA and was used for proof of concept studies. Human IGF-I vectors are being developed in-house as part of work done by the Emerging Technologies Research Group on regulated gene expression systems.

Animal models: A rat model is available with CIMA and has been used for proof of concept studies. A number of other small animal models have been described (Liu et al., 2013).

Biomarkers: Circulating IGF-I (and other related proteins) can be monitored using commercially available methodology. However the relevance of this to liver (local) levels of IGF-I and whether GT can deliver sufficient amounts of IGF-I that that can be readily detectable in the circulation need to be established.

Liver function and signs of cirrhosis can be monitored following well established standard procedures (e.g., liver enzymes, markers of fibrosis etc.).

The PoC obtained at CIMA will have to be repeated with uniQure’s AAV5-IGF1 vector. Licensee is at the initial stages of research aiming to initiate a Phase I clinical trial by the end of 2016.

Development overview to IMPD:

The GLP safety and toxicology studies will provide the first milestone (Go/No Go) for the project.

Safety Assessment : Safety studies in rat disease models (8 months) and wild type rats (8 weeks) showed no signs of toxicity due to treatment with SV40-IGF-I (Sobrevals et al., 2010).

Potential toxicity concerns include tumor formation and interference with insulin/ glucose metabolism albeit both issues are unlikely as the aim of this approach would be to upregulate levels of IGF-I where they are already below normal rather than to achieve supra-physiological levels. In addition, gene therapy vectors are likely to induce lower level of localized expression without substantial increase in serum IGF-I levels. Regarding potential for tumorigenesis, IGF-I therapy is thought to favor hepatocellular differentiation, i.e., opposes carcinogenesis, and studies have shown that sharp decrease in IGF-I in cirrhotic liver may contribute to hepatocellular carcinoma (HCC). In addition it is believed that it is IGF-II that is the key player in HCC. Furthermore, patients with existing tumor nodules in their liver could/ should be excluded from trials.

[NOTE: Hepatocellular carcinoma occurs at a rate of 1% to 4% per year after cirrhosis is established and cirrhosis underlies HCC in approximately 80%-90% of cases worldwide (Giovanna Fattovich et al., 2004), i.e., the vast majority of cirrhotic patients do not develop HCC or at least they do not live live long enough to develop it]

3. Hyperoxaluria

Disease Background : Primary hyperoxaluria type I (PH1) is a rare, autosomal recessive inherited metabolic disorder characterized by a deficiency of the hepatic enzyme alanine-glyoxylate aminotransferase (AGXT), which produces a marked increase in endogenous oxalate synthesis by the liver. Oxalate is a metabolic end product in humans and excess oxalate provokes hyperoxaluria, causing progressive urolithiasis, nephrocalcinosis and chronic renal failure, ultimately leading to end-stage renal failure (ESRF) and death if untreated.

It is the most common and severe variant among a spectrum of metabolic disorders resulting in hyperoxaluria. The disease has an estimated prevalence ranging from 1 to 3 per 1 million individuals and an estimated incidence of 1-9:100,000 live births per year in Europe. However, higher rates are reported in historically isolated populations, like the Canary Islands. PH1 accounts for <1% of pediatric ESRF in developed countries.

A pre-clinical proof of concept study has already been conducted in collaboration with Eduardo Salido (University Hospital of Canary Islands) using AGXT knockout mice demonstrating that in the GT treated animals oxalurea reduced to normal levels with restoration of liver enzyme levels in the absence of any hepatotoxicity or immune reactions.

Clinical need: Currently, most of the therapeutic options are diet-mediated to reduce the amount of glyoxylate intake and maximize the intake of vitamin B6. The most effective treatment for PH1 is pre-emptive liver transplantation, alone or liver combined with kidney transplantation in ESRF. There is therefore a clear need for alternative or new treatments options.

Feasibility :

Gene : the AGXT gene maps onto chromosome 2q36-q37, has a 10 kb coding sequence and contains 11 exons generating a 392-residue protein.

Vector optimization: Eight constructs different containing codon optimized AGXT genes have already been generated in-house and are currently being characterized.

Animal models: Small animal models already exist and have been used for pre-clinical proof of concept studies.

Biomarkers: Measurements of oxalate are part of routine clinical practice for the disease setting and

monitoring of kidney changes can also be done using standard techniques.

After a phase of further vector optimization it is our aim to develop this product for a first Phase I clinical study by mid 2016. Further development timelines have not been defined.

Development overview to IMPD:

The GLP safety and toxicology studies will provide the first milestone (Go/No Go) for the project.

Safety Assessment: At this stage is not possible to make any inferences in relation to potential safety concerns.

Central Nervous System Programs

A) Development Programs

1. AMT-110 for Sanfilippo B

Disease Background

Sanfilippo syndrome, or Mucopolysaccharidosis type III (MPSIII), is a rare lysosomal storage disorder (LSD) that occurs when enzymes needed to break down the heparan sulfate sugar chain are missing or are defective. Sanfilippo B is one of the four types of MPSIII that results in serious brain degeneration in children, and is generally lethal. The deficient enzyme responsible for the disease is alpha-N-acetylglucosaminidase (NaGlu). The clinical manifestations are mainly neurological, with early symptoms observed during the first five years of age, leading to a progressive deterioration of cognitive abilities. Affected children require specific care after age seven and progressively develop profound mental retardation with reduced somatic manifestations. Death frequently occurs at the median age of 15. No treatment is currently available.

Birth prevalences of 0.28—4.1 per 100, 000 have been reported (Valstar et al., 2008). More recently, He´ron et al. (2010) estimated the mean annual incidence for Sanfilippo B in France at 0.15 per 100,000 births.

Overview of AMT-110

The goal of our AMT-110 program is to provide a gene therapy for Sanfilippo B syndrome through the introduction of a functional NaGlu gene into the patients’ brain cells.

This project is being pursued together with the Pasteur Institute (Paris) whereby uniQure is responsible for developing the manufacturing process and producing clinical grade material and the Pasteur Institute for conducting the clinical trials.

Preclinical Development

· Product Profile

AMT-110 is designed to be delivered via intracranial administration.

AMT-110 or rAAV5-hNaGlu, is a recombinant adeno-associated vector of serotype 5, consisting of:

· Inverted terminal regions or ITRs of the adeno-associated serotype 2

· A human α-N-acetylglucosaminidase, or hNaGlu, gene the therapeutic gene

· The mouse phosphoglycerate kinase-1 promoter (muPGK)

· Pre-clinical Proof of Concept

Preclinical PoC studies were conducted in mouse and dog disease models at the Pasteur Institute. These studies showed that mice with MSPIIIB a single AAV5-NaGlu intracranial injection resulted in reversion of storage lesions throughout the brain and prevented loss of Purkinje cells. Furthermore, it improved animal behavior and corrected pathological featured of the disease including, neuro-inflammation, axonal transport, synaptic vesicle content and the autophagy defect.

In MSPIIIB dogs treatment (four simultaneous injections) with AAV5-hNaGlu was well tolerated, vector particles were broadly distributed and the therapeutic enzyme was delivered to the entire brain leading to improvement in MPSIIIB-induced histological lesions and normalization of glycosaminoglycan and ganglioside levels. These studies also confirmed that the combination of gene therapy with efficient immunosuppression was required for treatment efficacy.

· Non-clinical safety & toxicology studies

The following table presents a summary of the AMT-10 non-clinical safety and toxicology studies that have been conducted to support the clinical development program.

Parameter to be
assessed

Study performed

Results

Pharmacokinetics

1) GLP biodistribution in Sprague-Dawley rats with or without immunosuppression (180 days)

2) GLP biodistribution in Dogs

In in Sprague-Dawley rats:

· Constant high number of genome copies present in the brain with no vector in the blood at 3 months.

· No difference between immunosuppressed and non-

with immunosuppression (90 days)

immuno-suppressed animals. In dogs

· Organs negative for vector DNA (< LOQ) were heart, lung, kidney and testis whereas positive organs (> LOQ) included spleen, liver and cervical spinal cord.

Toxicity

GLP toxicity study in Sprague-Dawley rats (180 days)

(French Authorities endorsed the use of a single species for safety and toxicology studies)

· No specific toxicity

· Only injection traces in the brain at some injection sites

· No effect on body weight, growth, food consumption, behaviour

· No decedents, no inflammation

· No histopathological findings

· NOAEL: 3.4 x 10 11 /animal

Persistence in semen and risk of germline transmission

Based on pilot dog preliminary data where no vector DNA was found in the gonads, French Authorities endorsed the proposal that no germline transmission studies were necessary.

Summary of AMT-110 Preclinical Development Program

· In animal models of Sanfilippo B, treatment with AAV5-hNaGlu ameliorated pathophysiological signs and symptoms of the disease.

· AMT-110 administered into the striatum of non-immunosuppressed rats and immunosuppressed rats and dogs produced long lasting presence of vector DNA in the brain and caused no mortality and no signs of toxicity.

Clinical Development Program

The key regulatory and clinical development milestones for AMT-110 include the following ,

·	1 st Scientific Advice with French Regulatory Authorities	March 2012

·	2 nd Scientific Advice with French Regulatory Authorities	March 2012

·	IMPD Submission	April 2013

·	IMPD Approval	3Q13

·	Phase I start	October 2013

Expected Milestones

·	Phase II/III start	2016

·	Registration	2018

The Phase I/II study is a single center, open label, prospective, interventional, single dose of AAV5-hFIXco (AMT-060) trial in children with Sanfilippo type B syndrome. Administration will be performed into the brain parenchyma and cerebellum at 8 image-guided tracks, with 2 deposits per tracks, in a single neurosurgical session. Each patient will receive 960 μL of vector suspension as 16 simultaneous vector deposit each containing 2.4 10 11 gc (4 10 12 gc in total). Patients will receive immunosuppression starting 10 days prior to treatment.

The primary objective of the study is to evaluate the clinical, radiological and biological safety of the treatment. The secondary objective is to collect samples and data to define exploratory tests that could become evaluation criteria for further clinical efficacy studies (Brain MRI; neurological tests and biological markers).

The study will be conducted at the Bicêtre Hospital which is part of the University Hospitals of South Paris and is expected to enroll a total of 4 children during an 8 to 12 months inclusion period. The duration of follow-up for each patient is one year. The first patient was dosed in October 2013.

· Future Clinical Development

Licensee plans to complete the Phase I and start a Phase II/III trial in multiple sites worldwide. Following initiation of this trial one of the options on how to proceed would be applying for approval for compassionate use to treat on a named patient basis. This can be well justified based on the size of the indication and lethality of the condition.

Summary of AMT-110 Clinical Development Program

· The IMPD was submitted in April 2013

· Phase I was started in October 2013

1.2

2. AMT-090 for Parkinson’s Disease

Disease Background

Parkinson’s Disease (PD) is a progressive neurodegenerative disorder that affects motor skills, speech, and other neurological functions. As the condition progresses, every action becomes increasingly difficult, and eventually impossible. The symptoms are caused by degeneration and death of nerve cells in the substantia nigra, a part of the brain that produces dopamine needed to specifically control body movements. Dopamine is a chemical that sends messages in the brain to coordinate and control muscular action and movements. There is currently no cure for Parkinson’s Disease, but medications or surgery can provide symptomatic relief, the efficacy of which declines over time and which create significant side effects and co-morbidities, such as depression and dyskinesias. The most widely used treatment is L-dopa in various forms, which is converted to dopamine in the central nervous system. Current symptomatic treatments for Parkinson’s Disease represent a multi-billion dollar market.

While medications can temporarily alleviate the symptoms of PD, they do not influence the degenerative process. Progressive loss of nigral dopaminergic (DA) neurons (the pathological hallmark of PD) results in progressive neurologic dysfunction and death. Glial cell line-derived neurotrophic factor (GDNF) was first identified based on its ability to promote the survival of embryonic DA neurons in vitro, and research has demonstrated beneficial effects of GDNF in animal models of PD. Recent evidence indicates that gene transfer via direct delivery of viral vectors may represent a superior approach for the treatment of PD with GDNF.

Based on the overwhelming preclinical data of GDNF protective effects on DA neurons, a series of preclinical and clinical studies conducted by third parties have consistently indicated that the infusion of GDNF protein into the brain is effective in Parkinson’s Disease. Three clinical trials were performed with direct infusion into the putamen. Two of the studies (Bristol, UK and University of Kentucky) reported favorable clinical response (Gill et al., 2003, Patel et al., 2005, Slevin et al., 2005), and one sponsored by Amgen in the US was abandoned due to apparent lack of efficacy and the appearance of neutralizing antibodies to GDNF in some patients (Lang et al., 2006a). The outcome of these GDNF protein trials still remains controversial (Barker, 2006, Chebrolu et al., 2006, Lang et al., 2006a, Lang et al., 2006b, Penn et al., 2006, Slevin et al., 2006), but the consensus in the scientific community seems to be that the cannula used in the Amgen trial was not optimal, leading to a leakage of the protein into cerebrospinal fluid (CSF). Results from these early clinical trials with GDNF protein underscore the need for a clinical approach in which appropriate levels of GDNF are delivered accurately to the intended sites in the brain where the DA neurons and their terminals reside. Stereotactic parenchymal convection-enhanced delivery of viral vectors carrying the GDNF gene is more likely to achieve precise delivery.

PD is a progressive neurodegenerative disease that advances inexorably over a period of 10 to 30 years to disability and death. Medications, generally those aimed at ameliorating the known striatal dopamine deficiency, can provide substantial benefits for the cardinal symptoms of PD, namely resting tremor, rigidity, bradykinesia and postural instability. Unfortunately, the clinical response wanes over time and a variety of medication-related complications emerge including motor fluctuations, dyskinesias, short duration responses, and psychosis. Disease progression continues since dopamine replacement and other medical therapies have no impact on the underlying neurodegenerative process. Stereotactic deep brain stimulation has emerged as a rational treatment option, but this surgical approach is also symptomatic only and may be associated with serious adverse effects like stroke, hemorrhage, or infection, and hardware-related complications.

Overview of AMT-090 Program

Licensee’s AMT-090 program seeks to introduce the gene encoding the GDNF protein to provide a consistent supply of GDNF to the relevant areas of the brain. Our goal is to inject our AAV2 vector carrying the gene for GDNF into the brain to stop the progression of the disease and possibly measurable clinical and neuroimaging improvement. One of the key elements here is the MRI-guided convection enhanced delivery, which ensures for proper targeting of the vector.

Preclinical Development

Initial preclinical research was conducted in partnership with the University of Lund, Sweden, which established proof of concept in rodents. Moreover, the University of California San Francisco (UCSF) has conducted many studies consistently demonstrating a therapeutic effect of GDNF in rodents and primates. Key findings include:

· successful gene transfer with AAV2 in the Putamen of rats

· MRI-guided CED delivery of the AAV2 vector to the putamen in non-human primates resulted in GDNF expression in the putamen but also in the substantia nigra

· in a rat lesion model, AAV-GDNF delivery was able to protect neurons from degeneration

· in a primate lesion model, AAV-GDNF delivery was able to protect neurons from degeneration

· no toxicity was observed at any dose levels

· AAV-GDNF was therapeutic in rodent and primate models

Development Program

· Phase I Clinical Trial

uniQure has entered into an agreement with UCSF and the National Institute of Neurological Diseases and Stroke. Under this agreement, UCSF commenced a Phase I trial of an AAV2 glial cell line-derived neurotrophic factor (GDNF) treatment for Parkinson’s Disease in May 2013. This trial is being funded by the National Institutes of Health. Licensee has an exclusive right from UCSF to obtain all data related to the program.

The trial includes 24 patients afflicted with advanced Parkinson’s Disease (Hoehn and Yahr Stage III or IV off medication) with a Unified PD Rating Scale (UPDRS) (Fahn et al., 1987) total motor score > 30 in the defined off state and a serum anti-AAV2 total antibody titer <1000.

The study will entail a Phase 1 single-center, open-label, dose escalation, safety and tolerability study of adeno-associated virus, serotype 2 vector (AAV2) containing human GDNF complementary DNA bilaterally delivered by MRI-guided convection-enhanced delivery (CED) to the putamen (450 µl per hemisphere) of the. Four escalating dose levels will be evaluated in the following dose cohorts (6 patients per cohort): Cohort 1 = 9 x 10 10 vg, Cohort 2 = 3 x 10 11 vg, Cohort 3 = 9 x 10 11 vg and Cohort 4 = 3 x 10 12 vg.

The trial’s primary objectives are to assess the safety and tolerability of 4 different dose levels of AAV2-GDNF. The secondary objectives of the trial are to obtain preliminary data regarding the potential for clinical responses of the 4 dose levels tested by assessing the magnitude and variability of any treatment effects (via clinical, laboratory and neuroimaging studies).

· Future Clinical Development

Licensee intends to transition this program to our vector and manufacturing platforms and continue the clinical development program. Bridging of the vectors shall include at least testing in Parkinsonian primates and is anticipated to start one year after the first injections in patients are performed. This will then be followed by a multicenter randomized (delayed) start, blinded, sham-controlled Phase 2 efficacy study of this experimental therapy with our vector. However, prior to finalizing the design of such a trial, Licensee propose sto conduct a preliminary clinical study that should provide critical information for translating the laboratory research to investigations

involving human subjects and critical data for finalizing the ultimate efficacy trial protocol. The preliminary study will also allow us to develop the organizational and logistical processes that will be needed for the anticipated multicenter efficacy trial.

Summary of AMT-090 Clinical Development Program

· uniQure has licensed the GDNF gene from Amgen

· Pre-clinical PoC studies have been conducted in rodents and non-human primates in partnership with the University of Lund (Sweden) and UCF

· A Phase I human trial in Parkinson’s disease with AAV2 delivering GDNF has been initiated through a partnership with UCSF

· Initiation of first Phase I clinical trial or foreign equivalent — May 2013

Expected milestones

· Initiation of first Phase I clinical trial or foreign equivalent — 2nd quarter 2013

· Initiation of first Phase II clinical trial or foreign equivalent — 2nd quarter 2017

· Initiation of first Phase III clinical trial or foreign equivalent — 4th quarter 2020

· Submission to Regulatory Authority of First Marketing Approval or foreign equivalent — 2024

B) Active Research Projects

1. Huntington’s Disease

Disease background : Huntington’s Disease (HD) is a neurodegenerative genetic disorder that affects motor control and leads to cognitive decline and dementia. It typically becomes noticeable in middle age, but can begin at any age from infancy to old age. HD has a prevalence of around 1 affected individual in 100,000.

The mutated form of the protein huntingtin causes cellular dysfunction and death in a number of CNS sites but is most noticeable in the striatum and cortex. The mutation is caused by CAG repeats in the DNA of patients. The earliest features of HD are involuntary movements and irritability and a loss of executive function. This progresses over time and in the more advanced stages, the patient is demented and bed-bound. The disease is currently incurable with patients dying about 20-25 years after it begins.

Clinical need : The clinical need for these patients is high as there is no cure for the disease.

Feasibility

As the CAG repeats in the Huntingtin gene are the cause of the disease, downregulation of the expression of the CAG repeats is an option. Also rescuing the neurons from degeneration using GDNF is an option. Both options are currently under investigation. Replacing the gene is not an option as this is far too large to fit into an AAV vector.

Several transgenic mice models exist. Severity and time of onset are based on the number of CAG repeats in the model. Mostly used are the R6/1 and R6/2 transgenic models.

Preclinical work: Proof of concept using GDNF has been established in one laboratory. Licensee iscurrently trying to establish this with our own vector in the laboratory of Roger Barker.

Proof of concept with siRNA has been established in mice models and Licensee is in the process of implementing this into our studies.

Development overview to IMPD:

The proof of concept studies ( in vivo/ in vitro work) will provide the first milestone (Go/No Go) for the project.

With regards to the siRNA approach to HD, vector generation & optimization will require an additional 9 months prior to any other activity. Then a similar development path to what is shown above will need to be followed.

It is Licensee’s aim upon a successful PoC to develop this product further to a Phase I clinical investigation which should start mid 2016.

Deglon (Lausanne University), Anna Skorupska (Lublin University) and Sebastian Kuegler (Gottingen University) in a Eurostars grant setting. Competition comes from siRNA companies.

Safety concerns: Potential safety concerns could be the complete downregulation of the Huntingtin gene, even though not fully supported by the Eurostars team. The use of GDNF could lead to side effects, such as weight loss.

IP: For GDNF, Licensee has a license from Amgen. For the siRNA work Licensee has a non-exclusive license from Benitec.

2. Multiple System Atrophy

Disease Background: Multiple System Atrophy (MSA) is a sporadic neurodegenerative disease that is characterized by the presence of glial inclusion bodies, which stain positive for a synuclein. The clinical picture is that of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal signs in differing combinations. Approximately 80% of patients present with predominantly parkinsonian features (MSA-P) manifesting in rapidly deteriorating akinesia, rigidity, postural instability and high pitched dysarthria. Most such patients do not exhibit the classic resting tremor of Parkinson’s disease and virtually all develop frank dysautonomia in the course of the illness. The cause of the disease is not known.

Clinical need: Although a minority of patients may achieve modest benefit from dopaminergic therapy, there is no satisfactory treatment for the parkinsonian disabilities of MSA-P. Additionally, deep brain stimulation of the subthalamic nucleus has been of little or no value. Within 5 years of disease onset patients die so the clinical need is high for these patients.

Feasibility:

MSA is not a single monogenic disease, but may be treated with a single neuroprotective protein. In this case, this could be GDNF. Some transgenic animal models exist, all overexpressing the alpha-synuclein protein. The rationale to use GDNF (besides its general neuroprotective effect on neurons) is that both in patients and the transgenic mouse model, GDNF expression is downregulated. Introduction of an elevated level of GDNF may serve as the treatment. Read out parameters for the disease progression are all related to those of Parkinson’s Disease. PoC has not yet been established, but is under investigation in the mouse model.

Development overview to IMPD:

The proof of concept studies ( in vivo/ in vitro work) will provide the first milestone (Go/No Go) for the project.

It is our aim upon a successful PoC to develop this product further to a Phase I clinical investigation which should start mid 2016.

Collaborators: Licensee is working together with Erwan Bezard (University of Bordeaux) and Olivier Rascol (University of Toulouse) who are together running the French reference center for MSA.

Safety Assessment: The use of GDNF could lead to side effects, such as weight loss. The exact mechanism through

which the treatments would have its effect is not clear yet.

3. Hearing loss

Disease background : Hearing loss is a serious clinical problem. Underlying mechanisms for the loss of neurons in the cochlea can vary from ischemia, mechanical stress to toxic insults. The actual numbers of patients is not easy to define, but it could be rather large. When age-related hearing loss is also taken into account, this is no longer an orphan indication.

Clinical need : Patients with hearing loss could be helped with cochlear implants. However, progressive neurodegeneration is not stopped by that. There is high clinical need as there is no cure for the disease.

Feasibility:

Neuron function and survival is dependent on a delicate balance of neurotrophins. Following trauma or toxic insult to neurons, they may slowly die. To reverse this state of degeneration, it could be beneficial to supply the neurons with a neurotrophin such as GDNF. This neurotrophin has been shown to be able to rescue neurons from degeneration in several models, including those of the substantia nigra and for instance motorneurons in the spinal cord after trauma.

Animal models are available and include for instance use of Kanamycin in cats, mice or guinea pigs. Also chemotherapeutic agents from the class of statins are used.

Preclinical work: Proof of concept using recombinant brain-derived neurotrophic factor (BDNF) and/or GDNF has been established. Licensee is currently trying to establish this with our own vector in the laboratory of Patricia Leake.

Cochlea of mice can be transduced to express a recombinant transgene.

Development overview to IMPD:

The proof of concept studies ( in vivo/ in vitro work) will provide the first milestone (Go/No Go) for the project.

This new project has just been initiated upon a successful PoC it is our aim to develop this product further to a Phase I clinical trial, which should start by the end 2016.

Collaborators: Licensee is working together with Patricia Leake (University College of San Francisco) on the use of GDNF to rescue neurons in mouse and cat models. She is the investigator who developed the cochlear implant. This could also be included in the experimental plan.

Safety concerns: The use of GDNF could lead to side effects. Weight loss is not expected, but as the GDNF also has a neurotrophic effect, nerve fibers could sprout in an aberrant way possibly leading to incorrect connections.

IP: For GDNF, Licensee has a license from Amgen; the program as a whole is under investigation.

Exploratory Research Projects

The projects listed under this category in Table 1 above are not in active research yet, but are likely targets for our platform technology and are being assessed on feasibility before starting active bench work.

Exhibit 10.2

PUBLIC HEALTH SERVICE

PATENT LICENSE AGREEMENT - EXCLUSIVE and NON-EXCLUSIVE

COVER PAGE

For PHS internal use only:

License Number:
L-116-2011/0

License Application Number: A-063-2009

Serial Number(s) of Licensed Patent(s) or Patent Application(s):

1. U.S. Patent 6,984,517, issued January 10, 2006, entitled “AAV5 Vector and Uses Thereof; U.S. Patent 7,479,554, issued January 20, 2009, entitled “AAV5 Nucleic Acids” as well as all issued and pending foreign counterparts [ HHS Ref. No. E-127-1998/0];

2. U. S. Patent 6,855,314, issued February 15, 2005, entitled “AAV5 Vector for Transducing Brain Cells and Lung Cells” [ HHS Ref. No. E-072-2000/0]

Licensee: Amsterdam Molecular Therapeutics (AMT) B.V.

Cooperative Research and Development Agreement (CRADA) Number (if a subject invention): N/A

Additional Remarks: This Patent License Agreement will replace PHS license L-119-2007/0 and any amendments thereto.

Public Benefit(s): Commercialization of this technology will benefit the public health by providing AAV5 based gene therapies to treat diseases originated from the brain and liver.

This Patent License Agreement, hereinafter referred to as the “ Agreement ”, consists of this Cover Page, an attached Agreement , a Signature Page, Appendix A (List of Patent(s) or Patent Application(s)), Appendix B (Fields of Use and Territory), Appendix C (Royalties), Appendix D (Benchmarks and Performance), Appendix E (Commercial Development Plan), Appendix F (Example Royalty Report), and Appendix G (Royalty Payment Options). The Parties to this Agreement are:

2) The person, corporation, or institution identified above or on the Signature Page, having offices at the address indicated on the Signature Page, hereinafter referred to as “ Licensee ”.

PHS PATENT LICENSE AGREEMENT - EXCLUSIVE and NON-EXCLUSIVE

PHS and Licensee agree as follows:

1. BACKGROUND

1.1 In the course of conducting biomedical and behavioral research, PHS investigators made inventions that may have commercial applicability.

1.2 By assignment of rights from PHS employees and other inventors, HHS , on behalf of the Government , owns intellectual property rights claimed in any United States or foreign patent applications or patents corresponding to the assigned inventions. HHS also owns any tangible embodiments of these inventions actually reduced to practice by PHS .

1.3 The Secretary of HHS has delegated to PHS the authority to enter into this Agreement for the licensing of rights to these inventions.

1.5 Licensee desires to acquire commercialization rights to certain of these inventions in order to develop processes, methods, or marketable products for public use and benefit.

2. DEFINITIONS

2.1 “ Affiliate(s) ” means a corporation or other business entity, which directly or indirectly is controlled by or controls, or is under common control with Licensee . For this purpose, the term “control” shall mean ownership of more than fifty percent (50%) of the voting stock or other ownership interest of the corporation or other business entity, or the power to elect or appoint more than fifty percent (50%) of the members of the governing body of the corporation or other business entity.

2.2 “ Benchmarks ” mean the performance milestones that are set forth in Appendix D.

2.3 “ Commercial Development Plan ” means the written commercialization plan attached as Appendix E.

2.4 “ Exempt Collaborator ” means a not-for-profit organization or academic institution that has entered into a formal collaboration and / or supply agreement with Licensee to conduct pre-clinical development and solely sponsor clinical trials of Licensed Product , excluding Supplied Materials , to treat an Ultra-Orphan Indication ; in which Licensee may acquire clinical development and data for regulatory approval and sale of a Licensed Product .

2.5 “ First Commercial Sale ” means the initial transfer by or on behalf of Licensee or its sublicensees of Licensed Products or the initial practice of a Licensed Process by or on behalf of Licensee or its sublicensees in exchange for cash or some equivalent to which value can be assigned for the purpose of determining Net Sales .

2.6 “ Government ” means the Government of the United States of America.

2.7 “ Licensed Fields of Use ” means the fields of use a) and b) as identified in Appendix B.

2.8 “ Licensed Patent Rights ” shall mean:

(a) Patent applications (including provisional patent applications and PCT patent applications) or patents listed in Appendix A, all divisions and continuations of these applications, all patents issuing from these applications, divisions, and continuations, and any reissues, reexaminations, and extensions of these patents;

(b) to the extent that the following contain one or more claims directed to the invention or inventions disclosed in 2.8(a):

(i) continuations-in-part of 2.8(a);

(ii) all divisions and continuations of these continuations-in-part;

(iii) all patents issuing from these continuations-in-part, divisions, and continuations;

(iv) priority patent application(s) of 2.8(a); and

(v) any reissues, reexaminations, and extensions of these patents;

(c) to the extent that the following contain one or more claims directed to the invention or inventions disclosed in 2.8(a): all counterpart foreign and U.S. patent applications and patents to 2.8(a) and 2.8(b), including those listed in Appendix A; and

(d) Licensed Patent Rights shall not include 2.8(b) or 2.8(c) to the extent that they contain one or more claims directed to new matter which is not the subject matter disclosed in 2.8(a).

2.9 “ Licensed Processes ” means processes which, in the course of being practiced, would be within the scope of one or more claims of the Licensed Patent Rights that have not been held unpatentable, invalid or unenforceable by an unappealed or unappealable judgment of a court of competent jurisdiction.

2.10 “ Licensed Products ” means tangible materials which, in the course of manufacture, use, sale, or importation, would be within the scope of one or more claims of the Licensed Patent Rights that have not been held unpatentable, invalid or unenforceable by an unappealed or unappealable judgment of a court of competent jurisdiction.

2.11 “ Licensed Territory ” means the geographical area identified in Appendix B.

2.12 “ Marketing Approval ” means any and all approvals (including price and reimbursement approvals, if required), licenses, registrations, or authorizations of regulatory authorities in any country that are necessary for the manufacture, use, storage, import, transport and/or sale of a Licensed Product in the Licensed Fields of Use in such country.

2.13 “ Net Sales ” means the total gross receipts for sales of Licensed Products or practice of Licensed Processes by or on behalf of Licensee or its sublicensees, and from leasing, renting, or otherwise making Licensed Products available to others without sale or other dispositions, whether invoiced or not, less returns and allowances, packing costs, insurance costs, freight out, taxes or excise duties imposed on the transaction (if separately invoiced), and wholesaler and cash discounts in amounts customary in the trade to the extent actually granted. No deductions shall be made for commissions paid to individuals, whether they are with independent sales agencies or regularly employed by Licensee , or sublicensees, and on its payroll, or for the cost of collections.

2.14 “ Orphan Indication ” means a disease that affects less than two hundred thousand (200,000) people in the United States as defined by the Food and Drug Administration or five (5) in ten thousand (10,000) people in the European Union as defined by the European Medicines Agency.

2.15 “ Practical Application ” means to manufacture in the case of a composition or product, to practice in the case of a process or method, or to operate in the case of a machine or system; and in each case, under these conditions as to establish that the invention is being utilized and that its benefits are to the extent permitted by law or Government regulations available to the public on reasonable terms.

2.16 “ Research License ” means a nontransferable, nonexclusive license to make and to use Licensed Products or Licensed Processes as defined by the Licensed Patent Rights for purposes of research and not for purposes of commercial manufacture or distribution or in lieu of purchase.

2.17 “ Supplied Materials ” means (a) A helper plasmid for AAV5 5RepCap 5RepCapB containing the p5 promoter, the AAV5 Rep and AAV5 Cap genes and an SV40ori adjacent to the polyadenylation signal at the 3’ end or equivalent; (b) A vector plasmid for AAV5, pAAV5LacZ/pAAV5RnLacZ expressing nucleus localized beta-galactosidase contains the LacZ gene under control of Rous Sarcoma Virus (RSV) promoter between the AAV5 ITRs or equivalent both of which are described in Chiorini et at Virol;. 73(2):1309-19 (Feb. 1999), including any progeny, subclones, or unmodified derivatives thereof where “unmodified derivatives” is defined as set forth in the Uniform Biological Material Transfer Agreement as published in the Federal Register at 60(45): 12771-75 (March 8, 1995); and (c) Plasmid maps corresponding to items (a) and (b) as set forth in the Paragraph. Further, these Supplied Materials were supplied by PHS to Licensee under a Material Transfer Agreement.

2.18 “ Third Party Applicant ” shall mean any non- Licensee applicant from whom PHS receives a license application for Licensed Patent Rights in an indication for which proposed commercial development is not addressed in Licensee ’s then current Commercial Development Plan outlined in Appendix E of this Agreement .

2.19 “ Ultra-Orphan Indication ” means a disease that affects less than one (1) in Fifty Thousand (50,000) people in the United States or the European Union.

3. GRANT OF RIGHTS

3.1 PHS hereby grants and Licensee accepts, subject to the terms and conditions of this Agreement , an exclusive license and non-exclusive license, as specified in Appendix B, under the Licensed Patent Rights in the Licensed Territory to make and have made, to use and have used, to sell and have sold, to offer to sell, and to import any Licensed Products in the Licensed Fields of Use and to practice and have practiced any Licensed Processes in the Licensed Fields of Use .

4. SUBLICENSING

4.2 Licensee agrees that any sublicenses granted by it shall provide that the obligations to PHS of Paragraphs 5.1-5.4, 8.1, 10.1, 10.2, 12.5, and 13.8-13.10 of this Agreement shall be binding upon

the sublicensee as if it were a party to this Agreement . Licensee further agrees to attach copies of these Paragraphs to all sublicense agreements.

4.3 Any sublicenses granted by Licensee shall provide for the termination of the sublicense, or the conversion to a license directly between the sublicensees and PHS , at the option of the sublicensee, upon termination of this Agreement under Article 13. This conversion is subject to PHS approval (not to be unreasonably withheld) and contingent upon acceptance by the sublicensee of the remaining provisions of this Agreement .

4.4 Licensee agrees to forward to PHS a complete copy of each fully executed sublicense agreement postmarked within thirty (30) days of the execution of the agreement. To the extent permitted by law, PHS agrees to maintain each sublicense agreement in confidence.

5. STATUTORY AND PHS REQUIREMENTS AND RESERVED GOVERNMENT RIGHTS

5.1 (a) PHS reserves on behalf of the Government an irrevocable, nonexclusive, nontransferable, royalty-free license for the practice of all inventions licensed under the Licensed Patent Rights throughout the world by or on behalf of the Government and on behalf of any foreign government or international organization pursuant to any existing or future treaty or agreement to which the Government is a signatory. Prior to the First Commercial Sale , Licensee agrees to provide PHS with reasonable quantities of Licensed Products or materials made through the Licensed Processes for PHS research use; and

(b) In the event that the Licensed Patent Rights are Subject Inventions made under a Cooperative Research and Development Agreement (“ CRADA ”), Licensee grants to the Government , pursuant to 15 U.S.C. §3710a(b)(l)(A), a nonexclusive, nontransferable, irrevocable, paid-up license to practice Licensed Patent Rights or have Licensed Patent Rights practiced throughout the world by or on behalf of the Government . In the exercise of this license, the Government shall not publicly disclose trade secrets or commercial or financial information that is privileged or confidential within the meaning of 5 U.S.C. §552(b)(4) or which would be considered as such if it had been obtained from a non-Federal party. Prior to the First Commercial Sale , Licensee agrees to provide PHS reasonable quantities of Licensed Products or materials made through the Licensed Processes for PHS research use.

5.2 Licensee agrees that products used or sold in the United States embodying Licensed Products or produced through use of Licensed Processes shall be manufactured substantially in the United States, unless a written waiver is obtained in advance from PHS .

5.3 Licensee acknowledges that PHS may enter into future CRADAs under the Federal Technology Transfer Act of 1986 that relate to the subject matter of this Agreement . Licensee agrees not to unreasonably deny requests for a Research License from future collaborators with PHS when acquiring these rights is necessary in order to make a CRADA project feasible. Licensee may request an opportunity to join as a party to the proposed CRADA .

5.4 (a) In addition to the reserved license of Paragraph 5.1, PHS reserves the right to grant Research License s directly or to require Licensee to grant Research License s on reasonable terms. The purpose of these Research License s is to encourage basic research, whether conducted at an academic or corporate facility. In order to safeguard the Licensed Patent Rights , however, PHS shall consult with Licensee before granting to commercial entities a Research License or providing to them research samples of materials made through the Licensed Processes ; and

(b) In exceptional circumstances, and in the event that Licensed Patent Rights are Subject Inventions made under a CRADA , the Government , pursuant to 15 U.S.C. §3710a(b)(l)(B), retains the right to require the Licensee to grant to a responsible applicant a nonexclusive, partially exclusive, or exclusive sublicense to use the Licensed Patent Rights in the Licensed Field of Use on terms that are reasonable under the circumstances, or if Licensee fails to grant this license, the Government retains the right to grant the license itself. The exercise of these rights by the Government shall only be in exceptional circumstances and only if the Government determines:

(i) the action is necessary to meet health or safety needs that are not reasonably satisfied by Licensee ;

(ii) the action is necessary to meet requirements for public use specified by Federal regulations, and these requirements are not reasonably satisfied by the Licensee ; or

(iii) the Licensee has failed to comply with an agreement containing provisions described in 15 U.S.C. §3710a(c)(4)(B); and

(c) The determination made by the Government under this Paragraph 5.4 is subject to administrative appeal and judicial review under 35 U.S.C. §203(b).

6. ROYALTIES AND REIMBURSEMENT

6.1 Licensee agrees to pay PHS a noncreditable, nonrefundable license issue royalty as set forth in Appendix C.

6.2 Licensee agrees to pay PHS a nonrefundable minimum annual royalty as set forth in Appendix C.

6.3 Unless otherwise exempted in Paragraphs 6.13-6.19, Licensee agrees to pay PHS earned royalties as set forth in Appendix C.

6.4 Unless otherwise exempted in Paragraphs 6.13-6.19, Licensee agrees to pay PHS benchmark royalties as set forth in Appendix C.

6.5 Licensee agrees to pay PHS sublicensing royalties as set forth in Appendix C.

6.6 A patent or patent application licensed under this Agreement shall cease to fall within the Licensed Patent Rights for the purpose of computing earned royalty payments in any given country on the earliest of the dates that:

(a) the application has been abandoned and not continued;

(b) the patent expires or irrevocably lapses, or

(c) the patent has been held to be invalid or unenforceable by an unappealed or unappealable decision of a court of competent jurisdiction or administrative agency.

6.7 No multiple royalties shall be payable because any Licensed Products or Licensed Processes are covered by more than one of the Licensed Patent Rights . In the event that this Agreement and PHS license L-107-2007/0 as amended from time to time apply to the same product sold by the

Licensee or its sublicensees then the Licensee shall only pay earned royalties and benchmark royalties under this Agreement .

6.8 On sales of Licensed Products by Licensee to sublicensees or on sales made in other than an arms-length transaction, the value of the Net Sales attributed under this Article 6 to this transaction shall be that which would have been received in an arms-length transaction, based on sales of like quantity and quality products on or about the time of this transaction.

6.9 With regard to unreimbursed expenses associated with the preparation, filing, prosecution, and maintenance of all patent applications and patents included within the Licensed Patent Rights and paid by PHS prior to the effective date of this Agreement . Licensee shall pay PHS , as an additional royalty, on or before March 1, 2012, and upon PHS ’ submission of a statement and request for payment to Licensee , an amount equivalent to these unreimbursed expenses previously paid by PHS , the total amount should not exceed two hundred and fifty thousand U.S. dollars ($250,000). If this Agreement is terminated by Licensee on or before March 1, 2012, Licensee agrees to pay the amount in full within sixty (60) days before termination.

6.10 With regard to unreimbursed expenses associated with the preparation, filing, prosecution, and maintenance of all patent applications and patents included within the Licensed Patent Rights and paid by PHS on or after the effective date of this Agreement . PHS , at its sole option, may require Licensee :

(a) to pay PHS on an annual basis, within sixty (60) days of PHS ’ submission of a statement and request for payment, a royalty amount equivalent to these unreimbursed expenses paid during the previous calendar year;

(b) to pay these unreimbursed expenses directly to the law firm employed by PHS to handle these functions. However, in this event, PHS and not Licensee shall be the client of the law firm; or

(c) in limited circumstances, Licensee may be given the right to assume responsibility for the preparation, filing, prosecution, or maintenance of any patent application or patent included with the Licensed Patent Rights . In that event, Licensee shall directly pay the attorneys or agents engaged to prepare, file, prosecute, or maintain these patent applications or patents and shall provide PHS with copies of each invoice associated with these services as well as documentation that these invoices have been paid.

6.11 PHS agrees, upon written request, to provide Licensee with summaries of patent prosecution invoices for which PHS has requested payment from the Licensee under Paragraphs 6.9 and 6.10. Licensee agrees that all information provided by PHS related to patent prosecution costs shall be treated as confidential commercial information and shall not be released to a third party except as required by law or a court of competent jurisdiction.

6.12 Licensee may elect to surrender its rights in any country of the Licensed Territory under any of the Licensed Patent Rights upon sixty (60) days written notice to PHS and owe no payment obligation under Paragraph 6.10 for patent-related expenses paid in that country after ninety (90) days of the effective date of the written notice.

6.13 Exemption for Ultra-Orphan Indication Research

(a) Licensee shall be permitted, upon PHS consent, (not to be unreasonably withheld), to manufacture and supply Licensed Product , excluding Supplied Materials , to an Exempt Collaborator for use solely in pre-clinical and clinical development to treat an

Ultra-Orphan Indication . Prior to commencement of manufacturing of Licensed Product for an Exempt Collaborator, Licensee shall request permission in writing and must obtain written consent from PHS . Additional documentation to establish an Exempt Collaborator may be required by PHS .

(b) For avoidance of doubt, Licensee shall retain Supplied Materials and shall not release Supplied Materials alone to an Exempt Collaborator .

(c) Upon receipt of written consent from PHS for manufacturing of a Licensed Product for an Exempt Collaborator . Licensee shall not be obligated to pay Benchmark royalties which would have been payable under Appendix C , Section IV for Benchmarks triggered by clinical trials solely sponsored by the Exempt Collaborator until such time as Licensee exercises its option to acquire the clinical development from the Exempt Collaborator .

(d) Upon acquisition of the clinical development from an Exempt Collaborator . Licensee shall pay PHS royalties which become payable from that point onwards in accordance with Appendix C , Section IV. Licensee must inform PHS in writing within thirty (30) days of Licensee ’s decision to acquire or not acquire clinical development from the Exempt Collaborator.

(e) For avoidance of doubt, PHS shall consider Licensee ’s sponsorship or co-sponsorship of a clinical trial or regulatory submission for a Licensed Product to treat an Ultra-Orphan Indication as an acquisition of clinical development from an Exempt Collaborator .

(f) Earned royalty payments on Net Sales specified in Appendix C , Section III shall not be applicable to Licensed Product manufactured for research and clinical trials conducted by an Exempt Collaborator approved by PHS per Paragraph 6.13.

(g) In lieu of earned royalty payments, Licensee shall pay PHS a royalty payment of ten thousand U.S. dollars ($10,000) for each collaboration approved by PHS with an Exempt Collaborator . Such royalty shall be due within thirty (30) days of the date of PHS written consent per Paragraph 6.13. In the event that several licenses granted by PHS to the Licensee apply to the same product, only a single payment of $10,000 will be payable per collaboration.

7. PATENT FILING, PROSECUTION, AND MAINTENANCE

7.1 Except as otherwise provided in this Article 7, PHS agrees to take responsibility for, but to consult with, the Licensee in the preparation, filing, prosecution, and maintenance of any and all patent applications or patents included in the Licensed Patent Rights and shall furnish copies of relevant patent-related documents to Licensee .

7.2 Upon PHS ’ written request, Licensee shall assume the responsibility for the preparation, filing, prosecution, and maintenance of any and all patent applications or patents included in the Licensed Patent Rights and shall, on an ongoing basis, promptly furnish copies of all patent-related documents to PHS . In this event, Licensee shall, subject to the prior approval of PHS , select registered patent attorneys or patent agents to provide these services on behalf of Licensee and PHS . PHS shall provide appropriate powers of attorney and other documents necessary to undertake this action to the patent attorneys or patent agents providing these services. Licensee and its attorneys or agents shall consult with PHS in all material aspects of the preparation, filing, prosecution and maintenance of patent applications and patents included within the Licensed

Patent Rights and shall provide PHS sufficient opportunity to comment on any document that Licensee intends to file or to cause to be filed with the relevant intellectual property or patent office.

7.3 At any time, PHS may provide Licensee with written notice that PHS wishes to assume control of the preparation, filing, prosecution, and maintenance of any and all patent applications or patents included in the Licensed Patent Rights such that the terms of Paragraph 7.1 shall then apply. If PHS elects to reassume these responsibilities, Licensee agrees to cooperate fully with PHS , its attorneys, and agents in the preparation, filing, prosecution, and maintenance of any and all patent applications or patents included in the Licensed Patent Rights and to provide PHS with complete copies of any and all documents or other materials that PHS deems necessary to undertake such responsibilities. Licensee shall be responsible for all costs associated with transferring patent prosecution responsibilities to an attorney or agent of PHS ’ choice.

7.4 Each party shall promptly inform the other as to all matters that come to its attention that may materially affect the preparation, filing, prosecution, or maintenance of the Licensed Patent Rights and permit each other to provide comments and suggestions with respect to the preparation, filing, prosecution, and maintenance of Licensed Patent Rights , which comments and suggestions shall be considered by the other party .

8. RECORD KEEPING

8.1 Licensee agrees to keep accurate and correct records of Licensed Products made, used, sold, or imported and Licensed Processes practiced under this Agreement appropriate to determine the amount of royalties due PHS . These records shall be retained for at least five (5) years following a given reporting period and shall be available during normal business hours for inspection, at the expense of PHS , by an accountant selected by PHS for the sole purpose of verifying reports and royalty payments hereunder. The accountant shall only disclose to PHS information relating to the accuracy of reports and royalty payments made under this Agreement . Such inspections may be made no more than once each calendar year, with reasonable efforts to minimize disruption of Licensee ’s normal business activities. Such records for any particular calendar quarter shall be subject to no more than one (1) inspection. If an inspection shows an underreporting or underpayment in excess of five percent (5%) for any twelve (12) month period, then Licensee shall reimburse PHS for the cost of the inspection at the time Licensee pays the unreported royalties, including any additional royalties as required by Paragraph 9.8. All royalty payments required under this Paragraph shall be due within sixty (60) days of the date PHS provides Licensee notice of the payment due.

9. REPORTS ON PROGRESS, BENCHMARKS, SALES, AND PAYMENTS

9.1 Prior to signing this Agreement , Licensee has provided PHS with the Commercial Development Plan in Appendix E, under which Licensee intends to bring the subject matter of the Licensed Patent Rights to the point of Practical Application . This Commercial Development Plan is hereby incorporated by reference into this Agreement . Based on this plan, performance Benchmarks are determined as specified in Appendix D.

9.2 Licensee shall provide written annual reports on its product development progress or efforts to commercialize under the Commercial Development Plan for each of the Licensed Fields of Use within sixty (60) days after December 31 of each calendar year. These progress reports shall include, but not be limited to: progress on research and development, status of applications for regulatory approvals, manufacturing, sublicensing, marketing, importing, and sales during the preceding calendar year, as well as, plans for the present calendar year. PHS also encourages these reports to include information on any of Licensee ’s public service activities that relate to the Licensed Patent Rights . If reported progress differs from that projected in the Commercial

Development Plan and Benchmarks , Licensee shall explain the reasons for these differences. In the annual report, Licensee may propose amendments to the Commercial Development Plan , acceptance of which by PHS may not be denied unreasonably. Licensee agrees to provide any additional information reasonably required by PHS to evaluate Licensee ’s performance under this Agreement . Licensee may amend the Benchmarks at any time upon written approval by PHS . PHS shall not unreasonably withhold approval of any request of Licensee to extend the time periods of this schedule if the request is supported by a reasonable showing by Licensee of diligence in its performance under the Commercial Development Plan and toward bringing the Licensed Products to the point of Practical Application as defined in 37 C.F.R. §404.3(d). Licensee shall amend the Commercial Development Plan and Benchmarks at the request of PHS to address any Licensed Fields of Use not specifically addressed in the plan originally submitted.

9.4 Licensee shall submit to PHS , within sixty (60) days after each calendar half-year ending June 30 and December 31, a royalty report, as described in the example in Appendix F, setting forth for the preceding half-year period the amount of the Licensed Products sold or Licensed Processes practiced by or on behalf of Licensee in each country within the Licensed Territory , the Net Sales , and the amount of royalty accordingly due. With each royalty report, Licensee shall submit payment of earned royalties due. If no earned royalties are due to PHS for any reporting period, the written report shall so state. The royalty report shall be certified as correct by an authorized officer of Licensee and shall include a detailed listing of all deductions made under Paragraph 2.13 to determine Net Sales made under Article 6 to determine royalties due.

9.5 Licensee agrees to forward semi-annually to PHS a copy of these reports received by Licensee from its sublicensees during the preceding half-year period as shall be pertinent to a royalty accounting to PHS by Licensee for activities under the sublicense.

9.6 Royalties due under Article 6 shall be paid in U.S. dollars and payment options are listed in Appendix G. For conversion of foreign currency to U.S. dollars, the conversion rate shall be the New York foreign exchange rate quoted in The Wall Street Journal on the day that the payment is due. Any loss of exchange, value, taxes, or other expenses incurred in the transfer or conversion to U.S. dollars shall be paid entirely by Licensee . The royalty report required by Paragraph 9.4 shall be mailed to PHS at its address for Agreement Notices indicated on the Signature Page.

9.7 Licensee shall be solely responsible for determining if any tax on royalty income is owed outside the United States and shall pay the tax and be responsible for all filings with appropriate agencies of foreign governments.

9.10 In the event PHS receives a license application from a Third Party Applicant for commercial development of one or more Licensed Products or Licensed Processes in the exclusive Licensed Fields of Use , as they pertain to Licensed Patent Rights for which the proposed commercial development is not specifically addressed in Licensee ’s then-current Commercial Development Plan (“ Third Party Applications ”), PHS shall notify Licensee , in writing, of the existence of the Third Party Applicant ’s license application. Upon receipt of the written notice, Licensee shall respond in writing by either: (a) amending its Commercial Development Plan within one hundred and twenty (120) days in a manner acceptable to PHS to include a clinical research and development program for the proposed commercial development of the Third Party Applications including revised Benchmarks to be incorporated into Appendix E, and acceptance of the amendment to the Commercial Development Plan by PHS shall take into account if Licensee has already carried out work in respect of such Third Party Applications prior to notification by PHS ; or (b) amending its Commercial Development Plan within one-hundred eighty (180) days (or such longer period agreed by Licensee and such Third Party Applicant ) in a manner acceptable to PHS to include a joint pre-clinical research and development program with the Third Party Applicant for the proposed commercial development of the Third Party Applications ; or (c) granting an exclusive or non-exclusive sublicense under commercially reasonable terms to the Third Party Applicant under Licensed Patent Rights in respect of the Third Party Applications within one-hundred eighty (180) days (or such longer period agreed by Licensee and such Third Party Applicant ); or both (b) and (c). If Licensee does not respond to the written notice as described in this Paragraph 9.10, and after thirty (30) days of final notice being sent to Licensee , PHS may remove the Licensed Products or Licensed Processes in respect of the Third Party Applications from the exclusive Licensed Field of Use in this Agreement , and PHS shall be free to grant a license to the Third Party Applicant under the Licensed Patent Rights in respect of the Third Party Applications .

10. PERFORMANCE

10.1 Licensee shall use its reasonable commercial efforts to bring the Licensed Products and Licensed Processes to Practical Application . “Reasonable commercial efforts” for the purposes of this provision shall include adherence to the Commercial Development Plan in Appendix E and performance of the Benchmarks in Appendix D. The efforts of a sublicensee shall be considered the efforts of Licensee .

10.2 Upon the First Commercial Sale , until the expiration or termination of this Agreement , Licensee shall use its reasonable commercial efforts to make Licensed Products and Licensed Processes reasonably accessible to the United States public.

10.3 Licensee agrees, after its First Commercial Sale , to make reasonable quantities of Licensed Products or materials produced through the use of Licensed Processes available to patient assistance programs at cost. Patient assistance programs are programs run by pharmaceutical companies to provide free medications to people who cannot afford to buy their medicine. For each indication in each calendar year, the quantity of Licensed Products to be made available under this provision available to patient assistance programs at cost shall be defined as the higher of: (i) the maximum quantity of Licensed Products for such indication that was available in the previous calendar year (whether or not such Licensed Products were actually supplied); and (ii) five (5) percent of the total number of Licensed Products for such indication prescribed within the United States and its dependant territories in the previous calendar year.

10.4 Licensee agrees, after its First Commercial Sale in a country in the Licensed Territory and as part of its marketing and product promotion in such country, to develop educational materials (e.g., brochures, website, etc.) directed to patients and physicians in that country detailing the Licensed

Products or medical aspects of the prophylactic and therapeutic uses of the Licensed Products to the extent permitted by law in such country.

10.5 Licensee agrees to supply, upon request, to the Mailing Address for Agreement Notices indicated on the Signature Page, the Office of Technology Transfer, NIH with inert samples of the Licensed Products or Licensed Processes or their packaging for educational and display purposes only

11. INFRINGEMENT AND PATENT ENFORCEMENT

11.1 PHS and Licensee agree to notify each other promptly of each infringement or possible infringement of the Licensed Patent Rights , as well as, any facts which may materially affect the validity, scope, or enforceability of the Licensed Patent Rights of which either party becomes aware.

11.2 Pursuant to this Agreement and the provisions of 35 U.S.C. Part 29. Licensee may in accordance with the provisions of Paragraph 11.3:

(a) bring suit in its own name, at its own expense, and on its own behalf for infringement of presumably valid claims in the Licensed Patent Rights ;

(b) in any suit, enjoin infringement and collect for its use, damages, profits, and awards of whatever nature recoverable for the infringement; or

(c) settle any claim or suit for infringement of the Licensed Patent Rights .provided, however, that PHS and appropriate Government authorities shall have the first right to take such actions.

11.3 If Licensee desires to initiate a suit for patent infringement, Licensee shall notify PHS in writing. If PHS does not notify Licensee of its intent to pursue legal action within ninety (90) days, Licensee shall be free to initiate suit. PHS shall have a continuing right to intervene in the suit. Licensee shall take no action to compel the Government either to initiate or to join in any suit for patent infringement. Licensee may request the Government to initiate or join in any suit if necessary to avoid dismissal of the suit Should the Government be made a party to any suit by motion or any other action of Licensee , Licensee shall reimburse the Government for any costs, expenses, or fees which the Government incurs as a result of the motion or other action. In all cases, Licensee agrees to keep PHS reasonably apprised of the status and progress of any litigation. Before Licensee commences an infringement action, Licensee shall notify PHS and give careful consideration to the views of PHS and to any potential effects of the litigation on the public health in deciding whether to bring suit.

11.4 In the event that a declaratory judgment action alleging invalidity or non-infringement of any of the Licensed Patent Rights shall be brought against Licensee or raised by way of counterclaim or affirmative defense in an infringement suit brought by Licensee under Paragraph 11.3, pursuant to this Agreement and the provisions of 35 U.S.C. Part 29 or other statutes, Licensee may:

(a) defend the suit in its own name, at its own expense, and on its own behalf for presumably valid claims in the Licensed Patent Rights ;

(b) in any suit, ultimately to enjoin infringement and to collect for its use, damages, profits, and awards of whatever nature recoverable for the infringement; and

(c) settle any claim or suit for declaratory judgment involving the Licensed Patent Rights -provided, however, that PHS and appropriate Government authorities shall have the first right to take these actions and shall have a continuing right to intervene in the suit; and

(d) If PHS does not notify Licensee of its intent to respond to the legal action within a reasonable time, Licensee shall be free to do so. Licensee shall take no action to compel the Government either to initiate or to join in any declaratory judgment action. Licensee may request the Government to initiate or to join any suit if necessary to avoid dismissal of the suit. Should the Government be made a party to any suit by motion or any other action of Licensee , Licensee shall reimburse the Government for any costs, expenses, or fees, which the Government incurs as a result of the motion or other action. If Licensee elects not to defend against the declaratory judgment action, PHS , at its option, may do so at its own expense. In all cases, Licensee agrees to keep PHS reasonably apprised of the status and progress of any litigation. Before Licensee commences an infringement action, Licensee shall notify PHS and give careful consideration to the views of PHS and to any potential effects of the litigation on the public health in deciding whether to bring suit.

11.5 In any action under Paragraphs 11.2, 11.3 or 11.4 the expenses including costs, fees, attorney fees, and disbursements, shall be paid by Licensee . The value of any recovery made by Licensee through court judgment or settlement shall be treated as Net Sales and subject to earned royalties.

11.6 PHS shall cooperate fully with Licensee in connection with any action under Paragraphs 11.2, 11.3 or 11.4. PHS agrees promptly to provide access to all necessary documents and to render reasonable assistance in response to a request by Licensee .

12. NEGATION OF WARRANTIES AND INDEMNIFICATION

12.1 PHS offers no warranties other than those specified in Article 1.

12.2 PHS does not warrant the validity of the Licensed Patent Rights and makes no representations whatsoever with regard to the scope of the Licensed Patent Rights , or that the Licensed Patent Rights may be exploited without infringing other patents or other intellectual property rights of third parties.

12.3 PHS MAKES NO WARRANTIES, EXPRESS OR IMPLIED, OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OF ANY SUBJECT MATTER DEFINED BY THE CLAIMS OF THE LICENSED PATENT RIGHTS OR TANGIBLE MATERIALS RELATED THERETO.

12.4 PHS does not represent that it shall commence legal actions against third parties infringing the Licensed Patent Rights .

12.5 Licensee shall indemnify and hold PHS , its employees, students, fellows, agents, and consultants harmless from and against all liability, demands, damages, expenses, and losses, including but not limited to death, personal injury, illness, or property damage in connection with or arising out of:

(a) the use by or on behalf of Licensee , its sublicensees, directors, employees, or third parties of any Licensed Patent Rights ; or

(b) the design, manufacture, distribution, or use of any Licensed Products , Licensed Processes or materials by Licensee , or other products or processes developed in connection with or arising out of the Licensed Patent Rights .

12.6 Licensee agrees to maintain a liability insurance program consistent with sound business practice.

13. TERM, TERMINATION, AND MODIFICATION OF RIGHTS

13.1 This Agreement is effective when signed by all parties, unless the provisions of Paragraph 14.16 are not fulfilled, and shall extend to the expiration of the last to expire of the Licensed Patent Rights unless sooner terminated as provided in this Article 13.

13.2 In the event that Licensee is in default in the performance of any material obligations under this Agreement , including but not limited to the obligations listed in Paragraph 13.5, and if the default has not been remedied within ninety (90) days after the date of notice in writing of the default, PHS may terminate this Agreement by written notice and pursue outstanding royalties owed through procedures provided by the Federal Debt Collection Act.

13.3 In the event that Licensee becomes insolvent, files a petition in bankruptcy, has such a petition filed against it that is not discharged within ninety (90) days, determines to file a petition in bankruptcy, Licensee shall immediately notify PHS in writing. Furthermore, PHS shall have the right to terminate this Agreement immediately upon Licensee ’s receipt of written notice.

13.4 Licensee shall have a unilateral right to terminate this Agreement or any licenses in any country or territory by giving PHS sixty (60) days written notice to that effect.

13.5 PHS shall specifically have the right to terminate or modify, at its option, this Agreement , if PHS determines that the Licensee :

(a) is not executing the Commercial Development Plan submitted with its request for a license and the Licensee cannot otherwise demonstrate to PHS ’ satisfaction that the Licensee has taken, or can be expected to take within a reasonable time, effective steps to achieve Practical Application of the Licensed Products or Licensed Processes ;

(b) has not achieved the Benchmarks as may be modified under Paragraph 9.2;

(c) has willfully made a false statement of, or willfully omitted a material fact in the license application or in any report required by this Agreement ;

(d) has committed a material breach of a covenant or agreement contained in this Agreement ;

(e) is not keeping Licensed Products in a commercially reasonable manner available to the public after commercial use commences;

(f) cannot reasonably satisfy unmet health and safety needs; or

(g) cannot reasonably justify a failure to comply with the domestic production requirement of Paragraph 5.2 unless waived.

13.6 In making the determination referenced in Paragraph 13.5, PHS shall take into account (a) the normal course of such commercial development programs relating to gene therapy conducted with sound and reasonable business practices and judgment, (b) regulatory considerations, and the annual reports submitted by Licensee under Paragraph 9.2. Prior to invoking termination or modification of this Agreement under Paragraph 13.5, PHS shall give written notice to Licensee providing Licensee specific notice of, and a ninety (90) day opportunity to respond to, PHS ’ concerns as to the items referenced in 13.5(a)-13.5(g). If Licensee fails to alleviate PHS ’ concerns as to the items

referenced in 13.5(a)-13.5(g) or fails to initiate corrective action to PHS ’ reasonable satisfaction, PHS may terminate this Agreement .

13.7 When the public health and safety so require, and after written notice to Licensee providing Licensee a sixty (60) day opportunity to respond, PHS shall have the right to require Licensee to grant sublicenses to responsible applicants, on reasonable terms, in any Licensed Fields of Use under the Licensed Patent Rights , unless Licensee can reasonably demonstrate that the granting of the sublicense would not materially increase the availability to the public of the subject matter of the Licensed Patent Rights . PHS shall not require the granting of a sublicense unless the responsible applicant has first negotiated in good faith with Licensee .

13.8 PHS reserves the right according to 35 U.S.C. 5209(d)(3) to terminate or modify this Agreement if it is determined that this action is necessary to meet the requirements for public use specified by federal regulations issued after the date of the license and these requirements are not reasonably satisfied by Licensee .

13.9 Within thirty (30) days of receipt of written notice of PHS ’ unilateral decision to modify or terminate this Agreement , Licensee may, consistent with the provisions of 37 C.F.R. §404.11, appeal the decision by written submission to the designated PHS official. The decision of the designated PHS official shall be the final agency decision. Licensee may thereafter exercise any and all administrative or judicial remedies that may be available.

13.10 Within ninety (90) days of expiration or termination of this Agreement under this Article 13, a final report shall be submitted by Licensee . Any royalty payments, including those incurred but not yet paid (such as the full minimum annual royalty), and those related to patent expense, due to PHS shall become immediately due and payable upon termination or expiration. If terminated under this Article 13, sublicensees may elect to convert their sublicenses to direct licenses with PHS pursuant to Paragraph 4.3. Unless otherwise specifically provided for under this Agreement , upon termination or expiration of this Agreement , Licensee shall return all Licensed Products or other materials included within the Licensed Patent Rights to PHS or provide PHS with certification of the destruction thereof. Licensee may not be granted additional PHS licenses if the final reporting requirement is not fulfilled.

14. GENERAL PROVISIONS

14.1 Neither party may waive or release any of its rights or interests in this Agreement except in writing. The failure of a party to assert a right hereunder or to insist upon compliance with any term or condition of this Agreement shall not constitute a waiver of that right by that party or excuse a similar subsequent failure to perform any of these terms or conditions by the other party.

14.2 This Agreement constitutes the entire agreement between the parties relating to the subject matter of the Licensed Patent Rights , Licensed Products and Licensed Processes , and all prior negotiations, representations, agreements, and understandings are merged into, extinguished by, and completely expressed by this Agreement .

desirability of the modification. No modification shall be effective until a written amendment is signed by the signatories to this Agreement or their designees.

14.5 The construction, validity, performance, and effect of this Agreement shall be governed by Federal law as applied by the Federal courts in the District of Columbia.

14.6 All Agreement notices required or permitted by this Agreement shall be given by prepaid, first class, registered or certified mail or by an express/overnight delivery service provided by a commercial carrier, properly addressed to the other party at the address designated on the following Signature Page, or to another address as may be designated in writing by the other party. Agreement notices shall be considered timely if the notices are received on or before the established deadline date or sent on or before the deadline date as verifiable by Postal Service postmark or dated receipt from a commercial carrier. Parties should request a legibly dated Postal Service postmark or obtain a dated receipt from a commercial carrier or the Postal Service. Private metered postmarks shall not be acceptable as proof of timely mailing. Notices can also be sent by an email, or a fax.

14.7 This Agreement shall not be assigned or otherwise transferred (including any transfer by legal process or by operation of law, and any transfer in bankruptcy or insolvency, or in any other compulsory procedure or order of court) except to Licensee’s Affiliate(s) without the prior written consent of PHS . The parties agree that the identity of the parties is material to the formation of this Agreement and that the obligations under this Agreement are nondelegable. In the event that PHS approves a proposed assignment, Licensee shall pay PHS , as an additional royalty, one percent (1%) of the fair market value of any consideration received for any assignment of this Agreement within sixty (60) days of the assignment.

14.8 Licensee agrees in its use of any PHS -supplied materials to comply with all applicable statutes, regulations, and guidelines, including PHS and HHS regulations and guidelines. Licensee agrees not to use the materials for research involving human subjects or clinical trials in the United States without complying with 21 C.F.R. Part 50 and 45 C.F.R. Part 46. Licensee agrees not to use the materials for research involving human subjects or clinical trials outside of the United States without notifying PHS , in writing, of the research or trials and complying with the applicable regulations of the appropriate national control authorities. Written notification to PHS of research involving human subjects or clinical trials outside of the United States shall be given no later than sixty (60) days prior to commencement of the research or trials.

14.9 Licensee acknowledges that it is subject to and agrees to abide by the United States laws and regulations (including the Export Administration Act of 1979 and Arms Export Control Act) controlling the export of technical data, computer software, laboratory prototypes, biological material, and other commodities. The transfer of these items may require a license from the appropriate agency of the U.S. Government or written assurances by Licensee that it shall not export these items to certain foreign countries without prior approval of this agency. PHS neither represents that a license is or is not required or that, if required, it shall be issued.

14.10 To the extent practicable and allowed by law and regulation, Licensee agrees to mark the Licensed Products or their packaging sold in the United States with all applicable U.S. patent numbers and similarly to indicate “Patent Pending” status. All Licensed Products manufactured in, shipped to, or sold in other countries shall be, to the extent practicable and allowed by law and regulation in such countries, marked in a manner to preserve PHS patent rights in those countries.

any other Government organizational unit, or any Government employee. Additionally, Licensee shall not use the names of NIH , FDA , PHS , or HHS or the Government or their employees in any advertising, promotional, or sales literature without the prior written approval of PHS .

14.12 The parties agree to attempt to settle amicably any controversy or claim arising under this Agreement or a breach of this Agreement , except for appeals of modifications or termination decisions provided for in Article 13. Licensee agrees first to appeal any unsettled claims or controversies to the designated PHS official, or designee, whose decision shall be considered the final agency decision. Thereafter, Licensee may exercise any administrative or judicial remedies that may be available.

14.13 Nothing relating to the grant of a license, nor the grant itself, shall be construed to confer upon any person any immunity from or defenses under the antitrust laws or from a charge of patent misuse, and the acquisition and use of rights pursuant to 37 C.F.R. Part 404 shall not be immunized from the operation of state or Federal law by reason of the source of the grant.

14.14 Any formal recordation of this Agreement required by the laws of any Licensed Territory as a prerequisite to enforceability of the Agreement in the courts of any foreign jurisdiction or for other reasons shall be carried out by Licensee at its expense, and appropriately verified proof of recordation shall be promptly furnished to PHS .

14.15 Paragraphs 4.3, 8.1, 9.5-9.7 (in respects of sales carried out prior to termination), 12.1-12.4, 12.5 (in respects of acts carried out prior to termination), 13.9, 13.10, 14.12 and 14.15 of this Agreement shall survive termination of this Agreement .

14.16 The terms and conditions of this Agreement shall, at PHS ’ sole option, be considered by PHS to be withdrawn from Licensee ’s consideration and the terms and conditions of this Agreement , and the Agreement itself to be null and void, unless this Agreement is executed by the Licensee and a fully executed original is received by PHS within sixty (60) days from the date of PHS signature found at the Signature Page.

SIGNATURES BEGIN ON NEXT PAGE

PHS PATENT LICENSE AGREEMENT - EXCLUS1VE

SIGNATURE PAGE

For PHS :

/s/ Richard U. Rodriquez		8-5-11
Richard U. Rodriguez		Date
Director, Division of Technology Development and Transfer
Office of Technology Transfer
National Institutes of Health

Mailing Address or E-mail Address for Agreement notices and reports:

Chief, Monitoring & Enforcement Branch
Office of Technology Transfer
National Institutes of Health
6011 Executive Boulevard, Suite 325
Rockville, Maryland 20852-3804 U.S.A.

E-mail: LicenseNotices_ Reports@mail.nih.gov

By:


/s/ Piers Morgan		10 August 2011

Signature of Authorized Official		Date

Piers Morgan

Chief Financial Officer

Amsterdam Molecular Therapeutics

Mailing Address for Agreement notices:

Chief Executive Officer

Amsterdam Molecular Therapeutics

P.O. Box 22506

1100 DA Amsterdam

The Netherlands

Tel. +31(0)20 566 7394

I. Official and Mailing Address for Financial notices ( Licensee’s contact person for royalty payments)

Piers Morgan

Chief Financial Officer

Amsterdam Molecular Therapeutics

P.O. Box 22506

1100 DA Amsterdam

The Netherlands

Tel.+31(0)20 566 7394

E-mail: p.morgan@amtbiopharma.com

APPENDIX A - PATENT(S) OR PATENT APPLICATION(S)

Patent(s) or Patent Application(s):

1. U. S. Patent 6,984,517, issued January 10, 2006, entitled “AAV5 Vector and Uses Thereof; U.S. Patent 7,479,554, issued January 20, 2009, entitled “AA V5 Nucleic Acids”as well as all issued and pending foreign counterparts [ HHS Ref. No. E-127-1998/0];

2. U. S. Patent 6,855,314, issued February 15, 2005, entitled “AAV5 Vector for Transducing Brain Cells and Lung Cells” [HHS Ref. No. E-072-2000/0].

APPENDIX B - LICENSED FIELDS OF USE AND TERRITORY

I. Licensed Fields of Use :

(a) Exclusive Licensed Field of Use : (i) Use of the Licensed Patent Rights for the development and sale of AAV5 based therapeutic products to be delivered to the brain or liver for treatment of human diseases originating in the brain or liver; (ii) Note that arthritis related diseases are expressly excluded.

(b) Non-Exclusive Licensed Field of Use : Use of the Licensed Patent Rights for the development and sale of AAV5 based therapeutic products to treat human diseases other than the ones covered under (a)(i).

II. Licensed Territory :

(a) Worldwide.

APPENDIX C - ROYALTIES

Royalties:

I. Licensee agrees to pay to PHS a noncreditable, nonrefundable license issue royalty in the amount of one hundred forty thousand dollars ($140,000). Payment will be made in two tranches, the first payment of one hundred thousand dollars ($100,000) being payable within sixty (60) days from the effective date of this Agreement ; the second payment of forty thousand dollars ($40,000) being payable on March 1, 2012. If this Agreement is terminated by Licensee on or before March 1, 2012, Licensee agrees to pay the remaining tranch of license issue royalty in full within sixty (60) days before termination

II. Licensee agrees to pay to PHS a nonrefundable minimum annual royalty in the amount of fifteen thousand dollars ($15,000) as follows:

(a) The first minimum annual royalty is due within sixty (60) days of the effective date of this Agreement and may be prorated according to the fraction of the calendar year remaining between the effective date of this Agreement and the next subsequent January 1; and

(b) Subsequent minimum annual royalty payments are due and payable on January 1 of each calendar year and may be credited against any earned royalties due for sales made in that year.

III. Licensee agrees to pay PHS earned royalties of one and two-tenth percent (1.2%) on Net Sales by or on behalf of Licensee and its sublicensees.

IV. Licensee agrees to pay PHS Benchmark royalties within sixty (60) days of achieving each Benchmark :

(a) Thirty-one thousand and five hundred U.S. dollars ($31,500) - Initiation of each Phase 1 clinical trial or foreign equivalent.

(b) Seventy-eight thousand five hundred U.S. dollars ($78,500) - Initiation of each Phase II clinical trial or foreign equivalent.

(c) One hundred and fifty-seven thousand and five hundred U.S. dollars ($157,500) - Initiation of each Phase III clinical trial or foreign equivalent.

(d) Initiation of first Marketing Approval or foreign equivalent for any indications in the liver in the following jurisdictions/countries:

(i) Three hundred fifteen thousand U.S. dollars ($315,000) in Europe.

(ii) Three hundred fifteen thousand U.S. dollars ($315,000) in the United States.

(iii) Seventy-eight thousand five hundred U.S. dollars ($78,500) in Australia.

(iv) Seventy-eight thousand five hundred U.S. dollars ($78,500) in Canada.

(v) Seventy-eight thousand five hundred U.S. dollars ($78,500) in Japan.

(e) Initiation of first Marketing Approval or foreign equivalent for any indications in the brain in the following jurisdictions/countries:

(i) Three hundred fifteen thousand U.S. dollars (S315,000) in Europe.

(ii) Three hundred fifteen thousand U.S. dollars ($315,000) in the United States.

(iii) Seventy-eight thousand five hundred U.S. dollars ($78,500) in Australia.

(iv) Seventy-eight thousand five hundred U.S. dollars ($78,500) in Canada.

(v) Seventy-eight thousand five hundred U.S. dollars ($78,500) in Japan.

V. Licensee agrees to pay PHS additional sublicensing royalties, as following, on the fair market value of any consideration received for granting each sublicense within sixty (60) days of the execution of each sublicense:

(a) For any sublicense executed by the Licensee before the completion of any phase I clinical trial or foreign equivalent for any disease indications, Licensee agrees to pay a sublicensing royalty of ten percent (10%); and

(b) For any sublicense executed by the Licensee after the completion of any phase I clinical trial or foreign equivalent but before the completion of any phase II clinical trial or foreign equivalent for any disease indications, Licensee agrees to pay a sublicensing royalty of six percent (6%); and

(c) For any sublicense executed by the Licensee either after the completion of any phase II clinical trial or foreign equivalent for any disease of Orphan Indication , or after the completion of any phase III clinical trial or foreign equivalent for any other disease indications, whichever comes first. Licensee agrees to pay a sublicensing royalty of three percent (3%).

Contractual payments made by a sublicensee to the Licensee or an Affiliate received after the effective date of this Agreement for costs, services and expenses for the Licensee or Affiliate to conduct, supervise or participate in one or more clinical trial(s) for the development of the Licensed Products shall not be accounted for as sublicensing royalties.

APPENDIX D - BENCHMARKS AND PERFORMANCE

Benchmarks for Licensed Products of Orphan Indication (there is no formal Phase III clinical trial required for Marketing Approval) - liver

I. Initiation of first Phase I clinical trial or foreign equivalent - 2012

II. Initiation of first Phase II clinical trial or foreign equivalent - 2014

III. Submission to Regulatory Authority of first Marketing Approval or foreign equivalent - 2015

Benchmarks for Licensed Products - brain

I. Initiation of Preclinical Development phase or foreign equivalent - 2011

II. Initiation of first Phase I clinical trial or foreign equivalent - 2012

III. Initiation of first Phase II clinical trial or foreign equivalent - 2014

IV. Initiation of first Phase III clinical trial or foreign equivalent - 2017

V. Submission to Regulatory Authority of first Marketing Approval or foreign equivalent - 2020

APPENDIX E - COMMERCIAL DEVELOPMENT PLAN

Project Plan Details - Liver:

Acute intermittent porphyria (AIP) is an autosomal dominant inherited condition caused by mutations in the porphobilinogen deaminase (PBGD) gene. The PBGD gene is located on chromosome 11q24.1-24.2 and spread over fifteen exons. The protein encoded by this gene is a rate-limiting enzyme, the PBGD enzyme, in the haem synthetic pathway.

Over the last couple of years Licensee has explored AMT-021 (replication defective recombinant adeno-associated viral vector, AAV, containing the porphobilinogen deaminase gene) for therapeutic intervention in AIP. AMT-021 is an AAV with pseudotype 5 capsid, which expresses the human PBGD gene under the transcriptional control of a liver specific promoter. The therapeutic expression cassette consists of the human PBGD cDNA (codon optimised for human expression) inserted downstream of the liver specific promoter EalbAAT and upstream of a human PBGD polyadenylation sequence.

AMT-021 acts by delivering the PBGD expression cassette directly into hepatocytes. The increase of PBGD enzymatic activity in the liver of AIP patients will provide sufficient enzyme to prevent the accumulation of toxic metabolites and thus, prevent porphyric attacks.

The aim of the project is to bring AAV5-PBDG therapy to patients. Licensee has already secured orphan designation for AAV5-PBDG treatment for AIP in Europe. The table below describes the outline development plans, starting from a research batch production, and moving through to primate proof-of-concept, tox batch, pre-observational study, product development, GMP production, Phase I/II clinical trial, Phase Il/III clinical trial, all the way to regulatory filing. Please note that the timelines are preliminary only, and that it is the nature of scientific and clinical development that planned timelines may change.

The aim of this project is to develop a gene therapy product for the treatment of AIP, and to deliver a data package that is suitable for the submission and approval by the European and North American regulatory authorities.

Vector development and manufacturing

PoC in pre-clinical models

Because total deficiency of PBGD is lethal in mice, a compound heterozygous mouse (PBGD+/- referred to as AIP mice) with ~35% of normal hepatic PBGD activity, has been developed as an established model to study AIP. This murine model of AIP exhibits, after disease induction with phenobarbital (Pb), the typical biochemical characteristics

of human AIP, notably, decreased hepatic PBGD activity, massively increased urinary excretion of haem precursors (ALA and PBG) and decreased motor function.

AIP mice were used to test the AAV5-PBDG product. The therapeutic effect was evaluated three month after a single intravenous administration of AAV5-PBDG. Efficacy of the therapy was demonstrated as the treatment was able to prevent disease induction with Pb. ALA and PBG levels in treated animals was reduced, and motor disturbance induced by Pb treatment, as measured in the Rotarod test, was almost completely abolished. In addition, PBGD enzymatic activity increased in the AAV5-PBDG treated group 10 times over that of the control group.

This initial PoC will be repeated with the final version of the therapeutic vector following the completion of the vector development and manufacturing optimization. The final PoC will include the following:

PoC in rodent disease model

· PoC in non-human primates, based on agreed protocol

GLP Toxicology

The aim of this section is to deliver toxicology study report suitable for the submission the regulatory authority. The work will entail the following:

· Scientific advice from a regulatory body (AEMPS and/or EMA) for safety and toxicology package

· GLP toxicology study in rodents rats or mice, including any required biodistribution studies

· Supportive data for toxicology study in non-human primates

· GLP germline transmission study

Toxicology study design will take into account:

· Identification of potential target organs of biological activity and of potential target organs of toxicity

· Eventual concomitant medication (e.g. immunosuppressants, standard co-medication)

· Environmental risk/shedding

· Analysis of appropriateness of surrogate markers of efficacy/safety

· Any other relevant issues as may be identified

Clinical observational, pre-intervention study/studies

Before entering the interventional clinical study, an observation clinical study will be conducted to provide baseline information on the course of the disease by recording episodes AIP, abdominal pain, hospitalizations, extent of any possible known or unknown to be related to AIP symptomatology, incidence of (adverse) clinical events per year, etc. Sufficient data will be collected to provide a clinical picture to obtain a baseline data and to determine how efficacy will be shown during the interventional clinical trial.

Phase I/II

Phase II/III & Regulatory submission

After successful completion of Phase I/Il study a Phase II/III trial will be conducted with the aim of bringing the AIP therapy to market. Licensee estimates that 20-30 patients in total would be sufficient for regulatory filing of this product, as AIP is an ultra-orphan disease with a very limited patient number world-wide.

Project Plan Details-Brain (Parkinson’s Disease)

Parkinson’s disease (PD) is a progressive neurodegenerative disease, resulting in tremors, stiffness, slowness of movement, and lack of coordination. Patients are faced with a severely debilitating disease and a serious loss in quality of life. PD is caused by degeneration and death of nerve cells in a specific part of the brain known as the substantia nigra. These cells produce dopamine, a substance necessary for communication between nerve cells involved in the coordination of movement.

Licensee has recently started preclinical development of AAV-GDNF gene therapy that will introduce the gene coding for GDNF using recombinant adeno associated virus vector (AAV). AAV serotype 5 has been shown to be the serotype of choice for gene delivery into the brain. After successful proof of concept (POC) and toxicology studies in rodents and primates, AMT will start an extensive clinical development.

Vector development and manufacturing

To develop a gene therapy for Parkinson’s disease, AAV-GDNF product was designed to expresses the human GDNF and is produced in insect cells using the recombinant baculovirus method. The AAV5-GDNF is based on Licensee ’s standard manufacturing process, but in addition incorporates recent new technology of the basic process and makes use of an optimized Rep baculovirus construct in the upstream process and an additional chromatography step in the downstream process. This optimisation delivers enhanced quality and robustness of the AAV5-GDNF product. This process is fully scalable and allows for manufacturing of sufficient GMP-compliant product for PD patients.

Characterization of AAV5-GDNF

The AAV5-GDNF was tested in a functional in vitro assay in cultured E13.5 rat DRG explants. Vigorous neural outgrowth was observed, indicating that the produced AAV5-GDNF is capable of mediating secretion of biologically functional recombinant GDNF.

In vivo characterization

Subsequently, an in-vivo characterisation of the AAV5-GDNF has been conducted. Three different concentrations of AAV5-GDNF were injected unilaterally into the rat striatum. Brains were analyzed for GDNF expression 6 weeks post injection using immunohistochemistry. Resulting data demonstrated that there is a strong, concentration dependent GDNF expression throughout the injected hemisphere.

PoC in pre-clinical models

The produced AAV5-GDNF will be used to show biological activity and efficacy in animal models of Parkinson’s disease. These experiments will be conducted using rat models of Parkinson’s disease (in collaboration with University of Lund, Sweden) as well as non-human primates’ model of Parkinson’s disease (in collaboration with CEA, Paris, France). In addition to distribution studies, onset and kinetics of GDNF expression, neurochemical measurements (dopamine and dopamine metabolites), immunohistochemistry and behavioral studies will be conducted to test for functional improvement.

GLP Toxicology

The definitive design of the actual studies will be finalized after discussions with relevant agencies. Licensee proposes to conduct a six months study in mice and in parallel a 6-12 months study in non-human primates to account for the safety of the drug. The studies will comprise four test groups: 1. Control (vehicle), 2. Low dose (No observed effect level (NOEL) in the proof-of concept studies), 3. Mid-dose (highest dose considered for clinical studies), and 4. High dose (10 times higher than the mid-dose).