Radius Health, Inc. (Form: 10-Q, Received: 05/06/2015 17:13:24)

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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-Q

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

For the quarterly period ended March 31, 2015.

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 001-35726

Radius Health, Inc.

(Exact name of registrant as specified in its charter)

Delaware		80-0145732
(State or other jurisdiction of		(IRS Employer
Incorporation or organization)		Identification Number)

950 Winter Street
Waltham, Massachusetts		02451
(Address of Principal Executive Offices)		(Zip Code)

(617) 551-4000

(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 Website, if any, every Interactive Data File required to be submitted and posted pursuant to Rule 405 of Regulation S-T 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, or a smaller reporting company. See the definitions of “large accelerated filer”, “accelerated filer” and “smaller reporting company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer o		Accelerated filer x

Non-accelerated filer o		Smaller reporting company 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

Number of shares of the registrant’s Common Stock, $.0001 par value per share, outstanding as of May 1, 2015: 37,890,202 shares

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RADIUS HEALTH, INC.

QUARTERLY REPORT FOR THE QUARTER ENDED MARCH 31, 2015

ON FORM 10-Q

INDEX

PART I FINANCIAL INFORMATION

Item 1.	Financial Statements	2
	Condensed Balance Sheets as of March 31, 2015 and December 31, 2014	2
	Condensed Statements of Operations and Comprehensive Loss for the three months ended March 31, 2015 and 2014	3
	Condensed Statement of Stockholders’ Equity for the three months ended March 31, 2015	4
	Condensed Statements of Cash Flows for the three months ended March 31, 2015 and 2014	5
	Notes to Unaudited Financial Statements	6
Item 2.	Management’s Discussion and Analysis of Financial Condition and Results of Operations	15
Item 3.	Quantitative and Qualitative Disclosures About Market Risk	26
Item 4.	Controls and Procedures	27

PART II OTHER INFORMATION		28

Item 1.	Legal Proceedings	28
Item 1A.	Risk Factors	28
Item 2.	Unregistered Sales of Equity Securities and Use of Proceeds	47
Item 3.	Defaults Upon Senior Securities	47
Item 4.	Mine Safety Disclosures	47
Item 5.	Other Information	47
Item 6.	Exhibits	48

SIGNATURES		49

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CURRENCY AND CONVERSIONS

In this report, references to “dollar” or “$” are to the legal currency of the United States, and references to “euro” or “€” are to the single currency introduced on January 1, 1999 at the start of the third stage of European Economic and Monetary Union, pursuant to the Treaty establishing the European Communities, as amended by the Treaty on European Union and the Treaty of Amsterdam. Unless otherwise indicated, the financial information in this report has been expressed in U.S. dollars. Unless otherwise stated, the U.S. dollar equivalent information translating euros into U.S. dollars has been made, for convenience purposes, on the basis of the noon buying rate published by the Board of Governors of the Federal Reserve as of March 31, 2015, which was €1.00 = $1.0741. Such translations should not be construed as a representation that the euro has been, could have been or could be converted into U.S. dollars at the rate indicated, any particular rate or at all.

Trademarks appearing in this report are the property of their respective holders.

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Item 1. Financial Statements

Radius Health, Inc.

Condensed Balance Sheets

(In thousands, except share and per share amounts)

	March 31,			December 31,
	2015			2014
	(unaudited)
ASSETS
Current assets:
Cash and cash equivalents	$	34,810		$	28,518
Marketable securities	199,364			76,758
Prepaid expenses and other current assets	2,489			2,057
Total current assets	236,663			107,333
Property and equipment, net	863			842
Marketable securities, long-term	8,904			—
Other assets	261			242
Total assets	$	246,691		$	108,417

LIABILITIES AND STOCKHOLDERS’ EQUITY
Current liabilities:
Accounts payable	$	3,173		$	2,292
Accrued expenses and other current liabilities	12,108			18,267
Current portion of note payable, net of discount	2,446			—
Total current liabilities	17,727			20,559

Note payable, net of current portion and discount	22,016			24,394
Total liabilities	$	39,743		$	44,953
Commitments and contingencies
Stockholders’ equity:
Common stock, $.0001 par value; 200,000,000 shares authorized; 37,882,967 shares and 32,924,535 shares issued and outstanding at March 31, 2015 and December 31, 2014, respectively	$	4		$	3
Additional paid-in-capital	568,198			407,720
Accumulated other comprehensive income (loss)	41			(21		)
Accumulated deficit	(361,295		)	(344,238		)
Total stockholders’ equity	206,948			63,464
Total liabilities and stockholders’ equity	$	246,691		$	108,417

See accompanying notes to unaudited condensed financial statements.

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Radius Health, Inc.

Condensed Statements of Operations and Comprehensive Loss

(Unaudited, in thousands, except share and per share amounts)

	Three Months Ended
	March 31,
	2015			2014
OPERATING EXPENSES:
Research and development	$	11,559		$	9,717
General and administrative	4,756			2,139
Loss from operations	(16,315		)	(11,856		)
OTHER (EXPENSE) INCOME:
Other income (expense), net	(50		)	(2,233		)
Interest income	105			2
Interest expense	(797		)	(401		)
NET LOSS	$	(17,057	)	$	(14,488	)
OTHER COMPREHENSIVE INCOME, NET OF TAX:
Unrealized gain from marketable securities	62			—
COMPREHENSIVE LOSS	$	(16,995	)	$	(14,488	)
LOSS ATTRIBUTABLE TO COMMON STOCKHOLDERS - BASIC AND DILUTED (Note 10):	$	(17,057	)	$	(19,457	)
LOSS PER SHARE:
Basic	$	(0.47	)	$	(50.45	)
Diluted	$	(0.47	)	$	(50.45	)
WEIGHTED AVERAGE SHARES:
Basic	36,268,975			385,664
Diluted	36,268,975			385,664

See accompanying notes to unaudited condensed financial statements.

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Radius Health, Inc.

Statement of Stockholders’ Equity

(Unaudited, in thousands except share amounts)

	Stockholders’ Equity
	Common Stock			Additional Paid-In- Capital		Accumulated Other Comprehensive Income (Loss)			Accumulated Deficit			Total Stockholders’ Equity
	Shares	Amount		Amount		Amount			Amount			Amount
Balance at December 31, 2014	32,924,535	$	3	$	407,720	$	(21	)	$	(344,238	)	$	63,464
Net loss									(17,057		)	(17,057		)
Unrealized gain from available-for-sale securities						62						62
Exercise of warrants	357,029											—
Exercise of options	1,403			4								4
Stock-based compensation expense				2,061								2,061
Issuance of common stock, net	4,600,000	1		158,413								158,414
Balance at March 31, 2015	37,882,967	$	4	$	568,198	$	41		(361,295		)	$	206,948

See accompanying notes to unaudited condensed financial statements.

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Radius Health, Inc.

Statements of Cash Flows

(Unaudited, in thousands)

	Three Months Ended March 31,
	2015			2014
CASH FLOWS USED IN OPERATING ACTIVITIES:
Net loss	$	(17,057	)	$	(14,488	)
Adjustments to reconcile net loss to net cash used in operating activities:
Depreciation and amortization	36			16
Amortization of premium (accretion of discount) on marketable securities, net	290			—
Stock-based compensation expense	2,061			511
Research and development expense settled in stock	—			2,717
Change in fair value of other current assets, warrant liability and other liability	—			2,233
Non-cash interest	78			63
Changes in operating assets and liabilities:
Prepaid expenses and other current assets	(428		)	(690		)
Other long-term assets	(31		)	—
Accounts payable	881			(21		)
Accrued expenses and other current liabilities	(6,159		)	2,453
Net cash used in operating activities	(20,329		)	(7,206		)
CASH FLOWS USED IN INVESTING ACTIVITIES:
Purchases of property and equipment	(56		)	—
Purchases of marketable securities	(170,088		)	—
Sales and maturities of marketable securities	38,351			—
Net cash used in investing activities	(131,793		)	—
CASH FLOWS PROVIDED BY FINANCING ACTIVITIES:
Payments on note payable	—			(2,907		)
Proceeds from the issuance of common stock, net	158,414			—
Proceeds from the issuance of preferred stock, net	—			27,368
Net cash provided by financing activities	158,414			24,461
NET INCREASE IN CASH AND CASH EQUIVALENTS	6,292			17,255
CASH AND CASH EQUIVALENTS AT BEGINNING OF YEAR	28,518			12,303
CASH AND CASH EQUIVALENTS AT END OF PERIOD	$	34,810		$	29,558
SUPPLEMENTAL DISCLOSURES:
Cash paid for interest	$	626		$	310
NON-CASH FINANCING ACTIVITIES:
Accretion of dividends on preferred stock	$	—		$	4,969
Fair value of Series A-6 convertible preferred stock issued as settlement of liability	$	—		$	10,109
Fair value of warrants issued	$	—		$	1,216

See accompanying notes to unaudited condensed financial statements.

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Radius Health, Inc.

Notes to Financial Statements

(Unaudited)

1. Organization

Radius Health, Inc. (the “Company”) is a science-driven biopharmaceutical company focused on developing new therapeutics for patients with osteoporosis as well as other serious endocrine-mediated diseases, including hormone responsive breast cancer. The Company’s lead investigational product candidate is the investigational drug abaloparatide, a bone anabolic for potential use in the reduction of fracture risk in postmenopausal women with severe osteoporosis delivered via subcutaneous injection (“abaloparatide-SC”), which is currently in Phase 3 development. The Company is leveraging its investment in abaloparatide-SC to develop a potential future line extension that is designed to improve patient convenience by enabling administration of abaloparatide through an investigational short-wear-time patch (“abaloparatide-TD”).

The Company’s current clinical product portfolio also includes the investigational drug RAD1901, a selective estrogen receptor down regulator/degrader and RAD140, a nonsteroidal selective androgen receptor modulator. The Company is developing RAD1901 at higher doses for potential use in the treatment of metastatic breast cancer and other estrogen receptor mediated oncology applications. The Company is currently enrolling a Phase 1, multicenter, open-label, two-part, dose-escalation study of RAD1901 in postmenopausal women with advanced estrogen receptor positive and HER2-negative breast cancer. Low-dose RAD1901 has shown potential to be effective for the treatment of vasomotor symptoms, such as hot flashes, in a successful Phase 2 proof of concept study. RAD140 resulted from an internal drug discovery program focused on the androgen receptor pathway, which is highly expressed in many breast cancers. Due to its receptor and tissue selectivity, potent oral activity, and long duration half-life, RAD140 could have clinical potential in the treatment of breast cancer.

The Company is subject to the risks associated with emerging companies with a limited operating history, including dependence on key individuals, a developing business model, the necessity of securing regulatory approval to market its investigational product candidates, market acceptance of the Company’s investigational product candidates following receipt of regulatory approval, competition for its investigational product candidates following receipt of regulatory approval, and the continued ability to obtain adequate financing to fund the Company’s future operations. The Company has incurred losses and expects to continue to incur additional losses for the foreseeable future. As of March 31, 2015, the Company had an accumulated deficit of $361.3 million, and total cash, cash equivalents and short and long-term marketable securities of $243.1 million.

The Company believes that its cash, cash equivalents and short and long-term marketable securities as of March 31, 2015, will be sufficient to fund its operations into the fourth quarter of 2016. The Company expects to finance the future development costs of abaloparatide-SC, abaloparatide-TD and RAD1901 with its existing cash and cash equivalents and marketable securities, or through strategic financing opportunities, future offerings of its equity, or the incurrence of debt. However, there is no guarantee that any of these strategic or financing opportunities will be executed or executed on favorable terms, and some could be dilutive to existing stockholders. If the Company fails to obtain additional future capital, it may be unable to complete its planned preclinical and clinical trials and obtain approval of certain investigational product candidates from the U.S. Food and Drug Administration or other foreign regulatory authorities.

2. Basis of Presentation and Significant Accounting Policies

Basis of Presentation —The accompanying unaudited condensed financial statements and the related disclosures of the Company have been prepared in accordance with accounting principles generally accepted in the United States (“GAAP”) for interim financial reporting and as required by Regulation S-X, Rule 10-01. Accordingly, they do not include all of the information and footnotes required by GAAP for complete financial statements. In the opinion of management, all adjustments (including those which are normal and recurring) considered necessary for a fair presentation of the interim financial information have been included.

When preparing financial statements in conformity with GAAP, the Company must make estimates and assumptions that affect the reported amounts of assets, liabilities, expenses and related disclosures at the date of the financial statements. Actual results could differ from those estimates. Additionally, operating results for the three months ended March 31, 2015 are not necessarily indicative of the results that may be expected for any other interim period or for the fiscal year ending December 31, 2015. Subsequent events have been evaluated up to the date of issuance of these financials. For further information, refer to the financial statements and footnotes included in the Company’s audited financial statements for the year ended December 31, 2014 included in the Company’s Annual Report on Form 10-K, as filed with the Securities and Exchange Commission on March 10, 2015.

Significant Accounting Policies —The significant accounting policies identified in the Company’s most recent Annual Report on Form 10-K for the fiscal year ended December 31, 2014 which require the Company to make estimates and assumptions include:

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research and development costs, stock-based compensation and fair value measures. There were no changes to significant accounting policies during the three months ended March 31, 2015.

Accounting Standards Updates — In August 2014, the Financial Accounting Standards Board (“FASB”) issued Accounting Standards Update No. 2014-15, Disclosures of Uncertainties about an Entity’s Ability to Continue as a Going Concern (“ASU 2014-15”). ASU 2014-15 provides guidance in GAAP about management’s responsibility to evaluate whether there is substantial doubt about an entity’s ability to continue as a going concern and to provide related footnote disclosures. The amendments under ASU 2014-15 are effective for interim and annual fiscal periods beginning after December 15, 2016, with early adoption permitted. The Company does not expect the adoption of ASU 2014-15 to have a material impact on its results of operations, financial position or cash flows.

In January 2015, the FASB issued Accounting Standards Update No. 2015-01, Income Statement—Extraordinary and Unusual Items (Subtopics 225-20) (“ASU 2015-01”). ASU 2015-01 eliminates the concept of extraordinary items from GAAP. The amendments under ASU 2015-01 are effective for interim and annual fiscal periods beginning after December 15, 2015, with early adoption permitted. The Company does not expect the adoption of ASU 2015-01 to have a material impact on its results of operations, financial position or cash flows.

3. Accrued Expenses and Other Current Liabilities

Accrued expenses and other current liabilities consist of the following (in thousands):

	March 31,		December 31,
	2015		2014
Research costs - Nordic (1)	$	6,024	$	11,536
Research costs - other	2,666		3,336
Payroll and employee benefits	652		1,659
Professional fees	2,439		1,304
Accrued interest on notes payable	327		234
Other	—		198
Total accrued expenses and other current liabilities	$	12,108	$	18,267

(1) Includes amounts accrued ratably over the estimated per patient treatment period under the Nordic Bioscience Clinical Development VII A/S (“Nordic”) Work Statement NB-1 and Work Statement NB-3. Amounts do not include pass-through costs which are expensed as incurred or upon delivery. See note 8 for additional information.

4. Loan and Security Agreement

On May 30, 2014, the Company entered into a Loan and Security Agreement (the “Credit Facility), with Solar Capital Ltd. (“Solar”), as collateral agent and a lender, and Oxford Finance LLC (“Oxford”), as a lender (the “Lenders”), pursuant to which Solar and Oxford agreed to make available to the Company $30.0 million in the aggregate subject to certain conditions to funding. An initial term loan was made on May 30, 2014 in an aggregate principal amount equal to $21.0 million (the “Initial Term Loan”).

In addition to the Initial Term Loan, the Company would have been able to request an additional term loan in an aggregate principal amount of $9.0 million (the “Original Term B Loan”) after the completion of its initial public offering if the net cash proceeds were at least $65.0 million, subject to certain customary conditions to funding. Given the net proceeds from the Company’s initial public offering were less than $65.0 million, it was not able to request the Original Term B Loan. The Initial Term Loan bears interest per annum at 9.85% plus one-month LIBOR (customarily defined). All principal and accrued interest on the initial term loan is due on June 1, 2018.

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On July 10, 2014, the Company entered into a first amendment to the Credit Facility (the “First Amendment”). The terms of the First Amendment, among other things, provide the Company with, subject to certain customary funding conditions, additional term loans in an aggregate principal amount of $4.0 million upon the closing of the First Amendment (the “Modified Term B Loan”). All other terms applicable to the Original Term B Loan remain applicable to the Modified Term B Loan and the Modified Term B Loan replaced the Original Term B Loan. The Company borrowed the full amount of the Modified Term B Loan on July 10, 2014.

The Company is required to make interest-only payments through December 1, 2015, and beginning on January 1, 2016, it is required to make payments of principal and accrued interest in equal monthly installments over a term of 30 months.

As security for its obligations under the Credit Facility, the Company granted a security interest in substantially all of its existing and after-acquired assets except for its intellectual property and certain other customary exclusions.

The future principal payments under the Credit Facility, as amended, are as follows, as of March 31, 2015 (in thousands):

Years ending December 31,	Principal Payments
2015	$	—
2016	10,000
2017	10,000
2018	5,000
Total	$	25,000

On May 30, 2014, pursuant to the Credit Facility, the Company issued to Solar and Oxford warrants to purchase an aggregate of up to 10,258 shares of its series B-2 convertible preferred stock (“Series B-2”) at an exercise price equal to $61.42 per share. The warrants were initially classified as liabilities in the Company’s balance sheet and were re-measured at their estimated fair value through completion of the Company’s initial public offering. The changes in fair value were recorded as other (expense) income in the statement of operations. Upon the closing of the Company’s initial public offering at a price of $8.00 per share and the automatic conversion of the Series B-2 into common stock, these warrants became exercisable for up to 78,760 shares of common stock. Subsequent to the initial public offering, the Company’s warrant liability was reclassified to equity. On July 10, 2014, pursuant to the First Amendment and closing of the Modified Term B Loan, the Company issued to Solar and Oxford warrants to purchase up to 4,706 shares of common stock, each at a price per share equal to $12.75.

These warrants are immediately exercisable for cash or by net exercise and will expire five years from their issuance.

The initial fair value of the warrants issued in connection with the Initial Term Loan was $0.3 million and was recorded as a discount to the Initial Term Loan. The initial fair value of the warrants issued in connection with the First Amendment was $41 thousand and was recorded as a discount to the Modified Term B Loan. The Company also paid Solar and Oxford a facility fee of $0.3 million and reimbursed certain costs associated with the Credit Facility of approximately $0.1 million, both of which were also recorded as a discount to the Initial Term Loan. The discount is being amortized to interest expense over the 48 month period that the Initial Term Loan is expected to be outstanding using the effective interest method.

5. Marketable Securities

Available-for-sale marketable securities and cash and cash equivalents consist of the following (in thousands):

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	March 31, 2015
	Amortized Cost Value		Gross Unrealized Gains		Gross Unrealized Losses			Fair Value
Cash and cash equivalents:
Cash	$	2,284	$	—	$	—		$	2,284
Money market funds	32,526		—		—			32,526
Total	$	34,810	$	—	$	—		$	34,810
Marketable securities:
Domestic corporate debt securities	150,058		11		(44		)	150,025
Domestic corporate commercial paper	55,668		72		—			55,740
U.S. Agency bonds	2,501		2		—			2,503
Total	$	208,227	$	85	$	(44	)	$	208,268

	December 31, 2014
	Amortized Cost Value		Gross Unrealized Gains		Gross Unrealized Losses			Fair Value
Cash and cash equivalents:
Cash	$	1,519	$	—	$	—		$	1,519
Money market funds	23,994		—		—			23,994
Domestic corporate debt securities	3,005		—		—			3,005
Total	$	28,518	$	—	$	—		$	28,518
Marketable securities:
Domestic corporate debt securities	69,542		—		(33		)	69,509
Domestic corporate commercial paper	7,237		12		—			7,249
Total	$	76,779	$	12	$	(33	)	$	76,758

There were no debt securities that had been in an unrealized loss position for more than 12 months as of March 31, 2015 or December 31, 2014. There were 38 debt securities in an unrealized loss position for less than 12 months at March 31, 2015 and there were 34 debt securities that had been in an unrealized loss position for less than 12 months at December 31, 2014. The aggregate unrealized loss on these securities as of March 31, 2015 was less than $44 thousand and the fair value was $117.6 million. The Company considered the decline in market value for these securities to be primarily attributable to current economic conditions. As it was not more likely than not that the Company would be required to sell these securities before the recovery of their amortized cost basis, which may be maturity, the Company did not consider these investments to be other-than-temporarily impaired as of March 31, 2015.

As of March 31, 2015, marketable securities consisted of investments that mature within one year, with the exception of certain corporate bonds and U.S. Agency bonds, which have maturities within two years and an aggregate fair value of $8.9 million.

6. Fair Value Measurements

The Company determines the fair values of its financial instruments based upon the fair value hierarchy, which requires an entity to maximize the use of observable inputs and minimize the use of unobservable inputs when measuring fair value. Below are the three levels of inputs that may be used to measure fair value:

· Level 1—Quoted prices in active markets for identical assets or liabilities that the Company has the ability to access at the measurement date.

· Level 2—Observable inputs other than Level 1 prices, such as quoted prices for similar assets or liabilities; quoted prices in markets that are not active; or other inputs that are observable or can be corroborated by observable market data for substantially the full term of the assets or liabilities.

· Level 3—Unobservable inputs that are supported by little or no market activity and that are significant to the fair value of the assets or liabilities.

The following table summarizes the financial instruments measured at fair value on a recurring basis in the accompanying condensed balance sheets as of March 31, 2015 and December 31, 2014 (in thousands):

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	March 31, 2015
	Level 1		Level 2		Level 3		Total
Assets
Cash and cash equivalents:
Cash	$	2,284	$	—	$	—	$	2,284
Money market funds (1)	32,526		—		—		32,526
Total	$	34,810	$	—	$	—	$	34,810
Marketable securities:
Domestic corporate debt securities (2)	—		150,025		—		150,025
Domestic corporate commercial paper (2)	—		55,740		—		55,740
U.S. Agency bonds (2)	—		2,503		—		2,503
Total	$	—	$	208,268	$	—	$	208,268

	December 31, 2014
	Level 1		Level 2		Level 3		Total
Assets
Cash and cash equivalents:
Cash	$	1,519	$	—	$	—	$	1,519
Money market funds (1)	23,994		—		—		23,994
Domestic corporate debt securities (2)	—		3,005		—		3,005
Total	$	25,513	$	3,005	$	—	$	28,518
Marketable securities:
Domestic corporate debt securities (2)	$	—	$	69,509	$	—	$	69,509
Domestic corporate commercial paper (2)	—		7,249		—		7,249
Total	$	—	$	76,758	$	—	$	76,758

(1) Fair value is based upon quoted market prices.

(2) Fair value is based upon quoted prices for similar instruments in active markets, quoted prices for identical or similar instruments in markets that are not active and model-based valuation techniques for which all significant assumptions are observable in the market or can be corroborated by observable market data for substantially the full term of the assets. Inputs are obtained from various sources, including market participants, dealers and brokers.

The fair value of the Company’s note payable is determined using current applicable rates for similar instruments as of the balance sheet date. The carrying value of the Company’s note payable approximated its fair value as of March 31, 2015, as the Company’s interest rate is near current market rates. The fair value of the Company’s notes payable was determined using Level 3 inputs.

7. License Agreements

On September 27, 2005, the Company entered into a license agreement (the “Ipsen Agreement”), as amended, with SCRAS S.A.S, a French corporation on behalf of itself and its affiliates (collectively, “Ipsen”). Under the Ipsen Agreement, Ipsen granted to the Company an exclusive right and license under certain Ipsen compound technology and related patents to research, develop, manufacture and commercialize certain compounds and related products in all countries, except Japan (where the Company does not hold commercialization rights) and France (where the Company’s commercialization rights are subject to certain co-marketing and co-promotion rights retained by Ipsen). With respect to France, if Ipsen exercises its co-marketing and co-promotion rights, then Ipsen may elect to receive a percentage of the aggregate revenue from the sale of products by both parties in France (subject to a mid-double digit percentage cap), and Ipsen shall bear a corresponding percentage of the costs and expenses incurred by both parties with respect to such marketing and promotion efforts in France. Ipsen shall also pay the Company a mid-single digit royalty on Ipsen’s allocable portion of aggregate revenue from the sale of products by both parties in France. Abaloparatide is subject to the Ipsen Agreement. Ipsen also granted the Company an exclusive right and license under the Ipsen compound technology and related patents to make and have made compounds or product in Japan. Ipsen also granted the Company an exclusive right and license under certain Ipsen formulation technology and related patents solely for purposes of enabling the Company to develop, manufacture and commercialize compounds and products covered by the compound technology license in all countries, except Japan (where the Company does not hold commercialization rights) and France (where the Company’s commercialization rights are subject to certain co-marketing and co-promotion rights retained by Ipsen).

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In consideration for these licenses, the Company made a nonrefundable, non-creditable payment of $250.0 thousand to Ipsen, which was expensed during 2005. The Ipsen Agreement provides for further payments in the range of €10.0 million to €36.0 million ($10.7 million to $38.7 million) to Ipsen upon the achievement of certain development and commercialization milestones specified in the Ipsen Agreement, and for the payment of fixed 5% royalties on net sales of any product by the Company or its sublicensees on a country-by-country basis until the later of the last to expire of the licensed patents or for a period of 10 years after the first commercial sale in such country of any product that includes the compound licensed from Ipsen or any analog thereof.

If the Company sublicenses the rights licensed from Ipsen, then the Company will also be required to pay Ipsen a percentage of certain payments received from such sublicensee (in lieu of milestone payments not achieved at the time of such sublicense). The applicable percentage is in the low double digit range. In addition, if the Company or its sublicensees commercialize a product that includes a compound discovered by it based on or derived from confidential Ipsen know-how, it will be obligated to pay to Ipsen a fixed low single digit royalty on net sales of such product on a country-by-country basis until the later of the last to expire of licensed patents that cover such product or for a period of 10 years after the first commercial sale of such product in such country.

In June 2006, the Company entered into a license agreement (the “Eisai Agreement”), with Eisai Co. Ltd., (“Eisai”). Under the Eisai Agreement, Eisai granted to the Company an exclusive right and license to research, develop, manufacture and commercialize RAD1901 and related products from Eisai in all countries, except Japan. In consideration for the rights to RAD1901, the Company paid Eisai an initial license fee of $0.5 million, which was expensed during 2006. The Eisai Agreement provides for further payments in the range of $1.0 million to $20.0 million (inclusive of the $0.5 million initial license fee), payable upon the achievement of certain clinical and regulatory milestones.

On March 9, 2015, the Company entered into an amendment to the Eisai Agreement (the “Eisai Amendment”) in which Eisai granted to the Company the exclusive right and license to research, develop, manufacture and commercialize RAD1901 in Japan. In consideration for the rights to RAD1901 in Japan, the Company paid Eisai an initial license fee of $0.4 million upon execution of the contract, which was recognized as research and development expense during the three months ended March 31, 2015.

Under the Eisai Agreement, as amended, should a product covered by the licensed technology be commercialized, the Company will be obligated to pay to Eisai royalties in a variable mid-single digit range based on net sales of the product on a country-by-country basis until the later of the last to expire of the licensed patents or the expiration of data protection clauses covering such product in such country. The royalty rate shall then be subject to reduction, and the royalty obligation will expire at such time as sales of lawful generic version of such product account for more than a specified minimum percentage of the total sales of all products that contain the licensed compound. The latest valid claim to expire, barring any extension thereof, is expected on August 18, 2026.

The Eisai Agreement also grants the Company the right to grant sublicenses with prior written approval from Eisai. If the Company sublicenses the licensed technology to a third party, the Company will be obligated to pay Eisai, in addition to the milestones referenced above, a fixed low double digit percentage of certain fees received from such sublicensee and royalties in low single digit range based on net sales of the sublicensee. The license agreement expires on a country-by-country basis on the later of (1) the date the last remaining valid claim in the licensed patents expires, lapses or is invalidated in that country, the product is not covered by data protection clauses, and the sales of lawful generic version of the product account for more than a specified percentage of the total sales of all pharmaceutical products containing the licensed compound in that country; or (2) a period of 10 years after the first commercial sale of the licensed products in such country, unless it is sooner terminated.

8. Research Agreements

Abaloparatide-SC Phase 3 Clinical Trial —On March 29, 2011, the Company and Nordic entered into a Clinical Trial Services Agreement (the “Clinical Trial Services Agreement”), a Work Statement NB-1, as amended on December 9, 2011, June 18, 2012, March 28, 2014, May 19, 2014 and July 22, 2014 (the “Work Statement NB-1”) and a Stock Issuance Agreement, as amended and restated on May 16, 2011, and as further amended on February 21, 2013, March 28, 2014, and May 19, 2014 (the “Stock Issuance Agreement”). Pursuant to the Work Statement NB-1, Nordic is managing the Phase 3 clinical trial of abaloparatide-SC (the “Phase 3 Clinical Trial”).

Pursuant to the Work Statement NB-1, the Company was required to make certain per patient payments denominated in both euros and U.S. dollars for each patient enrolled in the Phase 3 Clinical Trial followed by monthly payments for the duration of the study and final payments in two equal euro-denominated installments and two equal U.S. dollar-denominated installments. In addition, the Company agreed to pay to Nordic an additional performance incentive (each a “Performance Incentive Payment”) of $500,000 for every 50 patients that, subsequent to March 28, 2014, completed all end-of-study procedures, up to a maximum aggregate amount of additional payments equal to $5.0 million. The Work Statement NB-1, provided for a total of up to approximately €41.2 million ($44.2 million) of euro-denominated payments and a total of up to approximately $3.2 million of U.S. dollar-denominated payments over the course of the Phase 3 Clinical Trial, plus Performance Incentive Payments.

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The Company recognized research and development expense for the amounts due to Nordic under the Work Statement NB-1 ratably over the estimated per patient treatment period beginning upon enrollment in the Phase 3 Clinical Trial, or a twenty-month period. The Company recognized research and development expense for the amounts due to Nordic under the fourth amendment to the Work Statement NB-1, which is recognized on a per patient basis when the end-of-study visit and all other required procedures are completed. The Company recorded $4.5 million of research and development expense during the three months ended March 31, 2014, for per patient costs incurred for patients that had enrolled in the Phase 3 Clinical Trial. As of March 31, 2015, all obligations due to Nordic under Work Statement NB-1 had been paid.

Abaloparatide-SC Phase 3 Clinical Extension Study — On February 21, 2013, the Company entered into a Work Statement NB-3, as amended on March 4, 2014 (the “Work Statement NB-3”). Pursuant to the Work Statement NB-3, Nordic will perform an extension study to evaluate six months of standard-of-care osteoporosis management following the completion of the Phase 3 Clinical Trial (the “Extension Study”), and, upon completion of this initial six months, an additional period of 18 months of standard-of-care osteoporosis management (the “Second Extension”).

Payments in cash to be made to Nordic under the Work Statement NB-3 are denominated in both euros and U.S. dollars and total up to €7.5 million ($8.0 million) and $1.1 million, respectively. In addition, payments are due to Nordic in connection with the Work Statement NB-3 pursuant to the Stock Issuance Agreement, as discussed below.

The Company recognizes research and development expense for the amounts due to Nordic under the Extension Study and the Second Extension ratably over the estimated per patient treatment periods beginning upon enrollment, or over a nine-month and nineteen-month period, respectively. The Company recorded $1.4 million and $2.5 million of research and development expense during the three months ended March 31, 2015 and 2014, respectively, for per patient costs incurred for patients that had enrolled in the Extension Study and the Second Extension.

As of March 31, 2015, the Company had a liability of $6.0 million reflected in accrued expenses and other current liabilities on the balance sheet resulting from services provided by Nordic, which are payable in cash.

Stock Issuance Agreement —Pursuant to the Stock Issuance Agreement, Nordic agreed to purchase 6,443 shares of the Company’s Series A-5 convertible preferred stock (“Series A-5”) and to receive quarterly stock dividends, payable in shares of the Company’s Series A-6 convertible preferred stock (“Series A-6”). In connection with the Work Statement NB-1, the Stock Issuance Agreement provided that Nordic was entitled to receive stock dividends, having an aggregate value of up to €36.8 million ($39.5 million) (the “NB-1 Accruing Dividend”). In connection with Work Statement NB-3, the Stock Issuance Agreement provided that, beginning with the quarter ended March 31, 2013, Nordic was entitled to receive stock dividends having an aggregate value of up to €7.5 million ($8.0 million) and $0.8 million (the “NB-3 Accruing Dividend” and together with the “NB-1 Accruing Dividend,” the “Nordic Accruing Dividend”). On March 28, 2014, the Company entered into the second amendment to the Stock Issuance Agreement (the “Second Stock Issuance Agreement Amendment”). The Second Stock Issuance Agreement Amendment required that the Company’s Board of Directors declare, as soon as reasonably practical, a stock dividend of twenty-nine (29) shares of its Series A-6 for each share of the Company’s then-outstanding Series A-5, all of which were held by Nordic, for a total of 186,847 shares of Series A-6, in full satisfaction of all stock dividends payable in 2014 under the terms of the Stock Issuance Agreement in connection with Work Statement NB-1 and Work Statement NB-3. In March 2014, Nordic requested that all 186,847 shares of Series A-6 be issued. Accordingly, the Company’s Board of Directors declared and issued a dividend to Nordic of all 186,847 shares on March 31, 2014. The Second Stock Issuance Agreement Amendment further provided that in the event an initial public offering of the Company’s common stock occurred prior to May 31, 2014, any payments owed by the Company to Nordic in relation to Work Statement NB-1 and Work Statement NB-3, excluding Performance Incentive Payments, for all periods of time after 2014, would be changed from the right to receive stock to the right to receive a total cash payment from the Company of $4.3 million payable in ten equal monthly installments of $430,000 beginning on March 31, 2015. On May 19, 2014, the Company entered into the third amendment to the Stock Issuance Agreement, which amended the date prior to which an initial public offering must occur to June 30, 2014. The Second Stock Issuance Agreement Amendment also stipulated that all consideration to be paid to Nordic pursuant to the Stock Issuance Agreement at any time after the consummation of an initial public offering be payable in cash. As the Company completed an initial public offering on June 11, 2014, Nordic no longer has the right to receive stock from the Company and has been paid in cash for all periods after June 11, 2014.

Prior to the issuance of shares of stock to Nordic in satisfaction of the Nordic Accruing Dividend, the liability to issue shares of stock was being accounted for as a liability in the Company’s balance sheet, based upon the fair value of the Series A-6. Changes in the fair value from the date of accrual to the date of issuance of the Series A-6 shares were recorded as a gain or loss in other (expense) income in the statement of operations.

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9. Stock-Based Compensation

A summary of stock option activity during the three months ended March 31, 2015 is as follows (in thousands, except for per share amounts):

			Weighted-
			Average		Weighted-
			Exercise		Average
			Price (in		Contractual	Aggregate
			dollars per		Life (in	Intrinsic
	Shares		share)		years)	Value
Options outstanding at December 31, 2014	3,220		$	13.58
Granted	432		46.29
Exercised	(1	)	2.74
Cancelled	(26	)	13.54
Expired	—		—
Options outstanding at March 31, 2015	3,625		$	17.48	8.51	$	88,050
Options exercisable at March 31, 2015	1,460		$	9.78	7.19	$	45,795
Options vested or expected to vest at March 31, 2015	3,523		$	17.32	8.48	$	86,075

The weighted-average grant-date fair value per share of options granted during the three months ended March 31, 2015 was $24.97. As of March 31, 2015, there was approximately $24.4 million of total unrecognized compensation expense related to unvested stock options, which is expected to be recognized over a weighted-average period of approximately 4 years.

10. Net Loss Per Share

Basic and diluted net loss per share is calculated as follows (in thousands, except share and per share numbers):

	Three Months Ended March 31,
	2015			2014
Numerator:
Net loss	$	(17,057	)	$	(14,488	)
Accretion of Preferred Stock	—			(4,969		)
Loss attributable to common stockholders - basic and diluted	$	(17,057	)	$	(19,457	)

Denominator:
Weighted-average number of common shares used in loss per share - basic and diluted	36,268,975			385,664

Loss per share - basic and diluted	(0.47		)	$	(50.45	)

The following potentially dilutive securities, prior to the use of the treasury stock method, have been excluded from the computation of diluted weighted-average shares outstanding, as they would be anti-dilutive. For the three months ended March 31, 2015 and 2014, all of the Company’s classes of preferred stock, options to purchase common stock and warrants outstanding were assumed to be anti-dilutive as earnings attributable to common stockholders was in a loss position.

	Three Months Ended March 31,
	2015	2014
Convertible preferred stock	—	7,628,051
Options to purchase common stock	3,376,071	2,121,606
Warrants	1,113,622	1,010,257

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11. Commitments and Contingencies

The Company may be exposed, individually or in the aggregate, to certain claims or assessments in the ordinary course of business. In the opinion of management, the outcome of these matters is not likely to have any material effect on the financial statements of the Company.

12. Stockholders’ Equity and Convertible Preferred Stock

Common Stock — On June 11, 2014, the Company completed its initial public offering whereby the Company sold 6,500,000 shares of common stock at a price of $8.00 per share. In connection with the offering, all outstanding shares of its convertible preferred stock converted into 19,465,132 shares of common stock and 2,862,654 shares of common stock were issued in satisfaction of accumulated dividends accrued on the preferred stock.

On June 18, 2014 and June 25, 2014, the underwriters purchased an additional 512,744 shares in the aggregate by exercising a portion of the over-allotment option granted to them in connection with the initial public offering. As a result of the closing of the initial public offering and subsequent exercise of the over-allotment option, the Company received aggregate proceeds, net of underwriting discounts, commissions and offering costs, of approximately $50.4 million.

On October 7, 2014, the Company completed an additional public offering whereby it sold 2,750,000 shares of common stock at a price of $18.25 per share, for aggregate proceeds, net of underwriting discounts, commissions and offering costs, of approximately $46.9 million. On October 7, 2014, the underwriters purchased an additional 378,524 shares in the aggregate by exercising a portion of the over-allotment option granted to them in connection with the offering. As a result of the public offering and subsequent exercise of the over-allotment option, the Company received aggregate proceeds, net of underwriting discounts, commissions and offering costs of approximately $53.4 million.

On January 28, 2015, we completed a public offering of 4,000,000 shares of our common stock at a price of $36.75 per share, for aggregate estimated proceeds, net of underwriting discounts, commissions and offering costs, of approximately $137.8 million. On January 28, 2015, the underwriters purchased an additional 600,000 shares in the aggregate by exercising an option to purchase additional shares that was granted to them in connection with the offering. As a result of the public offering and subsequent exercise of the underwriters’ option, we received aggregate proceeds, net of underwriting discounts, commissions and offering costs of approximately $158.4 million.

Convertible Preferred Stock —On February 14, 2014, the Company entered into a Series B-2 Convertible Preferred Stock and Warrant Purchase Agreement (the “Series B-2 Purchase Agreement”), pursuant to which the Company was able to raise up to approximately $40.2 million through the issuance of (1) up to 655,000 shares of its Series B-2 convertible preferred stock (“Series B-2”) and (2) warrants to acquire up to 718,201 shares of its common stock with an exercise price of $14.004 per share. In February and March 2014, the Company consummated closings under the Series B-2 Purchase Agreement, whereby, in exchange for aggregate gross proceeds to the Company of approximately $27.5 million, the Company issued an aggregate of 448,060 shares of Series B-2 and warrants to purchase up to a total of 491,293 shares of its common stock.

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

Cautionary Statement

This Quarterly Report on Form 10-Q, including the information incorporated by reference herein, contains, in addition to historical information, forward-looking statements. We may, in some cases, use words such as “project,” “believe,” “anticipate,” “plan,” “expect,” “estimate,” “intend,” “continue,” “should,” “would,” “could,” “potentially,” “will,” “may” or similar words and expressions that convey uncertainty of future events or outcomes to identify these forward-looking statements. Forward-looking statements in this Quarterly Report on Form 10-Q may include, among other things, statements about:

· the progress of, timing of and amount of expenses associated with our research, development and commercialization activities;

· the success of our clinical studies for our investigational product candidates;

· our ability to obtain U.S. and foreign regulatory approval for our product candidates and the ability of our product candidates to meet existing or future regulatory standards;

· our expectations regarding federal, state and foreign regulatory requirements;

· the therapeutic benefits and effectiveness of our product candidates;

· the safety profile and related adverse events of our product candidates;

· our ability to manufacture sufficient amounts of abaloparatide, RAD1901, and RAD140 for commercialization activities with target characteristics following regulatory approvals;

· our plans with respect to collaborations and licenses related to the development, manufacture or sale of our product candidates;

· our expectations as to future financial performance, expense levels and liquidity sources;

· our ability to compete with other companies that are or may be developing or selling products that are competitive with our product candidates;

· anticipated trends and challenges in our potential markets; and

· our ability to attract and motivate key personnel.

The outcome of the events described in these forward-looking statements is subject to known and unknown risks, uncertainties and other important factors that could cause actual results to differ materially from the results anticipated by these forward-looking statements. These important factors include our financial performance, our ability to attract and retain customers, our development activities and those factors we discuss in this Quarterly Report on Form 10-Q and in our Annual Report on Form 10-K filed with the Securities and Exchange Commission, or the SEC, on March 10, 2015 under the caption “Risk Factors.” You should read these factors and the other cautionary statements made in this Quarterly Report on Form 10-Q as being applicable to all related forward-looking statements wherever they appear in this Quarterly Report on Form 10-Q. These risk factors are not exhaustive and other sections of this Quarterly Report on Form 10-Q may include additional factors which could adversely impact our business and financial performance.

You should read the following discussion of our financial condition and results of operations in conjunction with our financial statements and related notes set forth in this report. Unless the context otherwise requires, “we,” “our,” “us” and similar expressions used in this Management’s Discussion and Analysis of Financial Condition and Results of Operations section refer to Radius Health, Inc., a Delaware corporation, or Radius.

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Executive Overview

We are a science-driven biopharmaceutical company focused on developing new therapeutics for patients with osteoporosis as well as other serious endocrine-mediated diseases, including hormone responsive breast cancer. Our lead product candidate is the investigational drug abaloparatide, a bone anabolic for potential use in the reduction of fracture risk in postmenopausal women with severe osteoporosis. We are developing two formulations of abaloparatide: abaloparatide-SC, an injectable subcutaneous formulation of abaloparatide, and abaloparatide-TD, a line extension of abaloparatide-SC in the form of a convenient, short-wear-time transdermal patch.

Our current clinical product portfolio also includes the investigational drug RAD1901, a selective estrogen receptor down regulator/degrader, or SERD, and the investigational drug RAD140, a nonsteroidal selective androgen receptor modulator, or SARM. We are developing RAD1901 at higher doses for potential use in the treatment of metastatic breast cancer and other estrogen receptor mediated applications. We are currently enrolling a Phase 1, multicenter, open-label, two-part, dose-escalation study of RAD1901 in postmenopausal women with advanced estrogen receptor positive and HER2-negative breast cancer. Low-dose RAD1901 has shown potential to be effective for the treatment of vasomotor symptoms such as hot flashes in a successful Phase 2 proof of concept study. RAD140 resulted from an internal drug discovery program focused on the androgen receptor pathway which is highly expressed in many breast cancers. Due to its receptor and tissue selectivity, potent oral activity and long duration half-life, RAD140 could have clinical potential in the treatment of breast cancer or possibly other conditions where androgen modulation may offer therapeutic benefit.

Abaloparatide

Abaloparatide is a novel synthetic peptide analog of parathyroid hormone-related protein, or PTHrP, that we are developing as a bone anabolic treatment for potential use in the reduction of fracture risk in postmenopausal women with severe osteoporosis. We also believe that, subject to further research and development, abaloparatide may have potential applications across a variety of skeletal or bone related diseases or medical conditions. We are developing two formulations of abaloparatide:

· Abaloparatide-SC - In December 2014, we announced the 18-month top-line data from our Phase 3 ACTIVE clinical trial of abaloparatide-SC. The study was designed to evaluate whether abaloparatide-SC is superior to placebo for prevention of vertebral fracture. The study was also designed to evaluate whether abaloparatide-SC is superior to open-label teriparatide for greater bone mineral density, or BMD, improvement at major skeletal sites and for a lower occurrence of hypercalcemia, a condition in which the calcium level in a patient’s blood is above normal. The top-line results of the 18-month ACTIVE clinical trial showed that abaloparatide-SC met the primary endpoint with a statistically significant 86% reduction in new vertebral fractures versus placebo, and teriperatide met the same endpoint with a statistically significant 80% reduction. On the secondary endpoints, as compared to placebo, abaloparatide achieved a statistically significant fracture-rate reduction of 43% in the adjudicated non-vertebral fracture subset of patients; a statistically significant reduction of 45% in the adjudicated clinical fracture group; and a significant difference in the time to first incident of non-vertebral fracture in both the adjudicated non-vertebral fracture and the clinical fracture subset of patients in this trial. On April 28, 2015, additional positive data from the Phase 3 ACTIVE study of our investigational drug abaloparatide-SC, "Treatment with Abaloparatide Significantly Reduces Wrist Fractures Compared to Teriparatide", was presented in the HOT TOPICS Session at the ECTS-IBMS 2015 Congress. This presentation focused on data from a post-hoc analysis (not prespecified in the study protocol or the original or amended statistical analysis plan for the ACTIVE trial) relating to the effects seen for abaloparatide on BMD and fracture risk at the wrist. The post-hoc analysis showed that abaloparatide, as compared to teriparatide, showed a significant 72% reduction in wrist fractures. Any potential clinical significance of these data will be evaluated during the anticipated regulatory review of these and all other data from the ACTIVE clinical trial.

We are currently conducting a 6-month extension trial in which patients from the abaloparatide and placebo groups from this trial are receiving an approved alendronate therapy for osteoporosis management. We currently anticipate the first results from the first six months of the extension trial to be available at the end of the second quarter of 2015. Following completion of the first six months of the extension trial, we plan to

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submit a new drug application in the United States, and a marketing authorization application in Europe, during the second half of 2015. We hold worldwide commercialization rights to abaloparatide-SC, other than in Japan, and subject to a regulatory review and favorable regulatory outcome, we anticipate our first commercial sales of abaloparatide-SC will take place in 2016. We believe that, subject to further research and development, abaloparatide may have potential applications across a variety of skeletal or bone related diseases or medical conditions.

· Abaloparatide-TD - During 2014, we reported progress towards the development of an optimized, short-wear-time transdermal patch that may be capable of demonstrating comparability to abaloparatide-SC injection. In preliminary, nonhuman primate pharmacokinetic studies, we achieved a desirable pharmacokinetic profile, with comparable AUC, Cmax, Tmax and T1/2 relative to abaloparatide-SC. We believe that these results support continued clinical development of abaloparatide-TD toward future global regulatory submissions as a potential post-approval line extension of the investigational drug abaloparatide-SC. We expect to commence the clinical evaluation of the optimized abaloparatide-TD patch in the second half of 2015, with the goal of achieving comparability to abaloparatide-SC. We hold worldwide commercialization rights to abaloparatide-TD technology.

RAD1901

RAD1901 is a novel potent SERD that is being evaluated for potential use in the treatment of metastatic breast cancer and other estrogen receptor mediated oncology applications. RAD1901 has been shown to bind with good selectivity to the estrogen receptor and to have both estrogen-like and estrogen-antagonistic effects in different tissues. We hold worldwide commercialization rights to RAD1901.

In June 2014, we commenced a Phase 1 maximum tolerated dose, or MTD, study of RAD1901 in healthy volunteers. The study is designed to evaluate the tolerability, safety and pharmacokinetics of RAD1901, and also to use 18F-estradiol positron emission tomography, or FES-PET, imaging to provide a pharmacodynamic assessment of estrogen receptor turnover following administration of RAD1901. Levels of RAD1901 in cerebrospinal fluid samples taken from study subjects will be measured to confirm that RAD1901 has crossed the blood-brain barrier. Based upon initial study results, FES-PET imaging of RAD1901 has shown potent activity as a SERD. As of March 31, 2015, 40 subjects had completed dose escalation in the ongoing MTD study, and FES-PET imaging had been completed in a total of five subjects across two different doses. Each of these five subjects showed, based on FES-PET imaging, suppression of the FES-PET signal to background levels after six days of dosing. In addition, RAD1901, at the doses that showed suppression of the FES-PET signal, was well tolerated in these subjects.

In December 2014, we commenced a Phase 1, multicenter, open-label, two-part, dose-escalation study of RAD1901 in postmenopausal women with advanced estrogen receptor positive and HER2-negative breast cancer in the United States to determine the recommended dose for a Phase 2 clinical trial and to make a preliminary evaluation of the potential anti-tumor effect of RAD1901. We continue to enroll and dose patients in this study and expect to provide an update at the American Society of Clinical Oncology Annual Meeting in May 2015 and to report further progress in the second half of 2015. We also expect to commence Phase 1 clinical development in the European Union of RAD1901 in metastatic breast cancer patients in 2015.

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Financial Overview

Research and Development Expenses

Research and development expenses consist primarily of clinical testing costs, including payments in cash and stock made to contracts research organizations, or CROs, salaries and related personnel costs, fees paid to consultants and outside service providers for regulatory and quality assurance support, licensing of drug compounds and other expenses relating to the manufacture, development, testing and enhancement of our product candidates. We expense our research and development costs as they are incurred.

None of the research and development expenses in relation to our product candidates are currently borne by third parties. Our lead product candidate is the investigational drug abaloparatide, and it represents the largest portion of our research and development expenses for our product candidates. We began tracking program expenses for abaloparatide-SC in 2005, and program expenses from inception to March 31, 2015 were approximately $181.1 million. We began tracking program expenses for abaloparatide-TD in 2007, and program expenses from inception to March 31, 2015 were approximately $31.6 million. We began tracking program expenses for RAD1901 in 2006, and program expenses from inception to March 31, 2015 were approximately $18.6 million. We began tracking program expenses for RAD140 in 2008, and program expenses from inception to March 31, 2015 were approximately $5.2 million. These expenses relate primarily to external costs associated with manufacturing, preclinical studies and clinical trial costs.

Costs related to facilities, depreciation, stock-based compensation and research and development support services are not directly charged to programs as they benefit multiple research programs that share resources.

We estimate that future development costs for abaloparatide-SC may exceed $47.0 million, including $14.0 million for clinical costs, $21.0 million for license and milestone payments and NDA submission fees, $9.0 million for manufacturing costs and $3.0 million for preclinical costs. For abaloparatide-TD, we estimate that future development costs may exceed $29.0 million, including $18.0 million for clinical costs, $7.0 million for manufacturing costs, and $4.0 million for preclinical costs and NDA submission fees.

In late 2014, we commenced a Phase 1 clinical study of RAD1901 for potential use in the treatment of metastatic breast cancer. However, due to its early stage of development, we are not yet able to determine the possible marketing approval timeline or future development costs at this time. We intend to commence a Phase 2b clinical study of RAD1901 for the potential treatment of vasomotor symptoms in the second half of 2015. We are currently designing the trial and have not finalized the full development plan. In addition, we are currently evaluating alternative development options for RAD140. Therefore, it is currently not possible to project the future development costs or possible marketing approval timelines at this time.

The following table sets forth our research and development expenses related to abaloparatide-SC, abaloparatide-TD, RAD1901 and RAD140 for the three months ended March 31, 2015 and 2014 (in thousands):

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	Three Months Ended March 31,
	2015		2014

Abaloparatide-SC	$	5,134	$	8,107
Abaloparatide-TD	480		185
RAD1901	800		—
RAD140	—		—

General and Administrative Expenses

General and administrative expenses consist primarily of salaries and related expenses for executive, finance and other administrative personnel, professional fees, business insurance, rent, general legal activities, including the cost of maintaining our intellectual property portfolio, and other corporate expenses.

Our results also include stock-based compensation expense as a result of the issuance of stock option grants to employees, directors and consultants. The stock-based compensation expense is included in the respective categories of expense in the statement of operations (research and development and general and administrative expenses). We expect to record additional non-cash stock-based compensation expense in the future, which may be significant.

Interest Income and Interest Expense

Interest income reflects interest earned on our cash, cash equivalents and marketable securities.

Interest expense for the three months ended March 31, 2015 reflects interest due under our loan and security agreement, entered into on May 30, 2014 and amended on July 10, 2014 and February 13, 2015, or the New Credit Facility, with Solar Capital Ltd., or Solar, as agent and lender, and Oxford Finance LLC, or Oxford, as lender. Under the New Credit Facility, we drew $21.0 million under an initial term loan on May 30, 2014 and $4.0 million under a second term loan on July 10, 2014. Interest expense for the three months ended March 31, 2014 reflects interest due under our loan and security agreement, entered into on May 23, 2011 with General Electric Capital Corporation, or GECC, as agent and lender, and Oxford, as a lender, or the Original Credit Facility. Under the Original Credit Facility, we drew $12.5 million under an initial and second term loan during the year ended December 31, 2011 and an additional $12.5 million under a third term loan during the year ended December 31, 2012. On May 30, 2014, we used approximately $9.3 million of the New Credit Facility to repay all the amounts owed under the Original Credit Facility.

Other (Expense) Income

For the three months ended March 31, 2014, other (expense) income reflects changes in the fair value of our warrant liability and the series A-6 convertible preferred stock liability and stock asset from the date of the initial accrual to the reporting date.

Critical Accounting Policies and Estimates

Management’s discussion and analysis of financial condition and results of operations is based upon our condensed consolidated financial statements, which have been prepared in accordance with accounting principles generally accepted in the United States, or

GAAP. The preparation of these financial statements requires us to make estimates and judgments that affect the reported amounts of assets, liabilities and expenses, as well as related disclosures. We evaluate our policies and estimates on an ongoing basis, including those related to accrued clinical expenses, research and development expenses, stock-based compensation and fair value measures, which we discussed in our Annual Report on Form 10-K for the year ended December 31, 2014. Management bases its estimates on historical experience and other various assumptions that are believed to be reasonable under the circumstances. Actual results may differ from these estimates under different assumptions or conditions.

We have reviewed our policies and estimates to determine our critical accounting policies for the three months ended March 31, 2015. We have made no material changes to the critical accounting policies described in our Annual Report on Form 10-K for the year ended December 31, 2014.

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Results of Operations

Three Months Ended March 31, 2015 and March 31, 2014 (in thousands, except percentages)

	Three Months Ended
	March 31,						Change
	2015			2014			$			%

Operating expenses:
Research and development	$	11,559		$	9,717		$	1,842		19	%
General and administrative	4,756			2,139			2,617			122	%
Loss from operations	(16,315		)	(11,856		)	4,459			38	%
Other (expense) income:
Other income (expense), net	(50		)	(2,233		)	(2,183		)	-98	%
Interest (expense) income, net	(692		)	(399		)	293			73	%
Net Loss	$	(17,057	)	$	(14,488	)	$	2,569		18	%

Research and development expenses —For the three months ended March 31, 2015, research and development expense was $11.6 million compared to $9.7 million for the three months ended March 31, 2014, an increase of $1.8 million, or 19%. This increase is primarily a result of an increase in compensation expense as a result of an increase in headcount and an increase in consulting costs incurred to support our NDA submission for our investigational product candidate abaloparatide-SC. These amounts were partially offset by a decrease in the total professional contract service costs associated with the development of abaloparatide-SC resulting from the completion of the Phase 3 18-month fracture study in October 2014. Additionally, fewer patients were enrolled in the extension study of abaloparatide-SC as of March 31, 2015 as compared to the three months ended March 31, 2014. We expect that costs associated with the development of abaloparatide-SC will continue to decrease over the course of the ACTIVExtend clinical trial as patients complete treatment. We expect that the costs associated with the development of abaloparatide-TD will increase as we begin to advance an optimized abaloparatide-TD product in additional clinical studies, followed by a Phase 3 bridging study. There was also an increase in contract service costs associated with the development of our investigational product candidate RAD1901 as a result of the initiation of various preclinical and manufacturing activities in 2014. We expect that the costs associated with the development of RAD1901 will increase as we begin to advance RAD1901 through various preclinical and clinical studies, including a Phase 1 study in metastatic breast cancer, which commenced in late 2014, and a Phase 2b study in vasomotor symptoms, which is expected to commence in the second half of 2015.

General and administrative expenses — For the three months ended March 31, 2015, general and administrative expense was $4.8 million compared to $2.1 million for the three months ended March 31, 2014, an increase of $2.6 million, or 122%. This increase was primarily the result of an increase of approximately $1.5 million in consulting support costs and legal fees during the three months ended March 31, 2015. This increase can also be attributed to higher compensation costs, including non-cash stock-based compensation expense, due to an overall increase in employee headcount.

Other income (expense), net —For the three months ended March 31, 2015, there was other expense, net of other income, of $0.1 million as compared to other expense, net of other income during the three months ended March 31, 2014 of $2.2 million. For the three months ended March 31, 2015, other expense, net of other income, primarily represents state tax expenses. The $2.2 million of other expense, net of income, as of March 31, 2014 was primarily due to an increase in the fair value of our stock liability and other liability as a result of an increase in the fair value of the underlying convertible preferred stock from December 31, 2013 to March 31, 2014.

Interest (expense) income, net —For the three months ended March 31, 2015, interest expense, net of interest income, was $0.7 million compared to $0.4 million for the three months ended March 31, 2014, an increase of $0.3 million, or 73%. This increase was primarily a result of higher average debt outstanding during the three months ended March 31, 2015 as compared to the three months ended March 31, 2014.

Liquidity and Capital Resources

From inception to March 31, 2015, we have incurred an accumulated deficit of $361.3 million, primarily as a result of expenses incurred through a combination of research and development activities related to our various product candidates and expenses supporting those activities. Our total cash, cash equivalents and marketable securities balance as of March 31, 2015 was $243.1 million. We have financed our operations since inception primarily through the public offerings of our common stock, private sale of preferred stock, borrowings under our credit facilities and the receipt of $5.0 million in fees associated with an option agreement.

We believe that our cash, cash equivalents and marketable securities as of March 31, 2015, will be sufficient to fund our operations into the fourth quarter of 2016. We expect to finance the future development costs of abaloparatide-SC, abaloparatide-TD and RAD1901 with our existing cash and cash equivalents and marketable securities, or through strategic financing opportunities that

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could include, but are not limited to, partnering or other collaboration agreements, or the completion of an additional public offering of securities. However, there is no guarantee that any of these financing opportunities will be available to us on favorable terms, and some could be dilutive to existing stockholders. Our future capital requirements will depend on many factors, including the scope and progress made in our research and development and commercialization activities, the results of our clinical trials, and the review and potential approval of our products by the FDA and EMA. If we fail to obtain additional future capital, we may be unable to complete our planned preclinical and clinical trials and obtain approval of any investigational product candidates from the FDA and other foreign regulatory authorities.

The following table sets forth the major sources and uses of cash for each of the periods set forth below (in thousands):

	Three Months Ended March 31,						Change
	2015			2014			$		%

Net cash (used in) provided by:
Operating activities	$	(20,329	)	$	(7,206	)	$	13,123	182	%
Investing activities	(131,793		)	—			131,793		100	%
Financing activities	158,414			24,461			133,953		548	%
Net increase in cash and cash equivalents	$	6,292		$	17,255

Cash Flows from Operating Activities

Net cash used in operating activities during the three months ended March 31, 2015 was $20.3 million, which was primarily the result of a net loss of $17.1 million and net changes in working capital of $5.7 million, partially offset by $2.5 million of net non-cash adjustments to reconcile net loss to net cash used in operations. The $17.1 million net loss was primarily due to abaloparatide-SC program development expenses, including clinical and manufacturing costs, along with employee compensation and consulting costs incurred to support future regulatory submissions and preparation for the potential commercial launch of abaloparatide-SC. The $2.5 million net non-cash adjustments to reconcile net loss to net cash used in operations included stock-based compensation expense of $2.1 million and amortization of premiums (discounts) on marketable securities of $0.3 million.

Net cash used in operating activities for the three months ended March 31, 2014 was $7.2 million, which was primarily the result of a net loss of $14.5 million, partially offset by $5.5 million of net non-cash adjustments to reconcile net loss to net cash used in operations and net changes in working capital of $1.8 million. The $14.5 million net loss was primarily due to expenses incurred in connection with our Phase 3 clinical trial of abaloparatide-SC. The $5.5 million net non-cash adjustments to reconcile net loss to net cash used in operations included $2.7 million of research and development expenses settled in stock, a $2.2 million increase in the fair value of our warrant liability and stock liability as a result of an increase in the fair value of the underlying convertible preferred stock and common stock from December 31, 2013 to March 31, 2014, and stock-based compensation expense of $0.5 million.

Cash Flows from Investing Activities

Net cash used in investing activities during the three months ended March 31, 2015 was $131.8 million, which was primarily the result of $170.1 million of purchases of marketable securities, partially offset by $38.4 million of net proceeds received from the sale or maturity of marketable securities. There was no net cash provided by or used in investing activities for the three months ended March 31, 2014.

Our investing cash flows will be impacted by the timing of purchases and sales of marketable securities. All of our marketable securities have contractual maturities of less than two years. Due to the short-term nature of our marketable securities, we would not expect our operational results or cash flows to be significantly affected by a change in market interest rates.

Cash Flows from Financing Activities

Net cash provided by financing activities during the three months ended March 31, 2015 was $158.4 million, as compared to $24.5 million net cash provided by financing activities during the three months ended March 31, 2014.

Net cash provided by financing activities during the three months ended March 31, 2015 consisted of $158.4 million of net proceeds received from an additional public offering in January of 2015.

Net cash provided by financing activities for the three months ended March 31, 2014 consisted of $27.4 million of net proceeds from the issuance of our series B-2 convertible preferred stock in February and March of 2014, partially offset by payments under our Original Credit Facility of $2.9 million.

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Financings

Future Financing Needs

We expect to finance the future development costs of our investigational product candidates abaloparatide-SC, abaloparatide-TD and RAD1901 with our existing cash and cash equivalents and marketable securities, or through strategic financing opportunities, future offerings of our equity, or the incurrence of debt. We anticipate that we will make determinations as to which additional programs to pursue and how much funding to direct to each program on an ongoing basis in response to the scientific and clinical data of each product candidate, progress on securing third-party collaborators, as well as ongoing assessments of each product candidate’s commercial potential and our ability to fund product development.

The successful development of our investigational product candidates is subject to numerous risks and uncertainties associated with developing drugs, including, but not limited to, the variables listed below. A change in the outcome of any of these variables with respect to the development of any of our product candidates could mean a significant change in the cost and timing associated with the development of that product candidate.

Abaloparatide-SC is our only product candidate in late stage development, and our business currently depends heavily on its successful development, regulatory approval and commercialization. We have not submitted an NDA to the FDA or comparable applications to foreign regulatory authorities. Obtaining approval of a product candidate is an extensive, lengthy, expensive and uncertain process, and any approval of abaloparatide-SC may be delayed, limited or denied for many reasons, including:

· we may not be able to demonstrate that abaloparatide is safe and effective as a treatment for reduction of fracture risk in postmenopausal women with severe osteoporosis to the satisfaction of the FDA or other foreign regulatory authorities;

· the results of our clinical studies may not meet the level of statistical or clinical significance required for marketing approval;

· the FDA or other foreign regulatory authorities may disagree with the number, design, size, conduct or implementation of our clinical studies;

· any clinical research organizations that we have retained or may in the future retain to conduct clinical studies may take actions outside of our control that materially adversely impact our clinical studies;

· the FDA or other foreign regulatory authorities may not find the data from preclinical studies and clinical studies sufficient to demonstrate that abaloparatide’s clinical and other benefits outweigh its safety risks;

· the FDA or other foreign regulatory authorities may disagree with our interpretation of data from our preclinical studies and clinical studies or may require that we conduct additional studies;

· The FDA or other foreign regulatory authorities may not accept data generated at our clinical study sites;

· the FDA or other foreign regulatory authorities may not agree with our proposed labeling and may require labeling that undermines or otherwise significantly impairs the commercial value of the product if it were to be approved with such labeling;

· the FDA may require development of a Risk Evaluation and Mitigation Strategy as a condition of approval;

· if our NDA is reviewed by an advisory committee, the FDA may have difficulties scheduling an advisory committee meeting in a timely manner or the advisory committee may recommend against approval of our application or may recommend that the FDA require, as a condition of approval, additional preclinical studies or clinical studies, limitations on approved labeling or distribution and use restrictions; or

· the FDA or other foreign regulatory authorities may identify deficiencies in the manufacturing processes or facilities of our third-party manufacturers.

In addition, the FDA or other foreign regulatory authorities may change their approval policies or adopt new regulations. For example, on February 15, 2012, we received a letter from the FDA stating that, after internal consideration, the agency believes that a minimum of 24 months of fracture data is necessary for approval of new products for the treatment of postmenopausal osteoporosis, and our ongoing abaloparatide-SC pivotal Phase 3 clinical trial is designed to produce fracture data based on an 18-month primary endpoint. Based on our discussions with the FDA, we believe that continued use of the 18-month primary endpoint will be acceptable, provided that our NDA includes the 24-month fracture data derived from the first 6 months of an extension study of our Phase 3 clinical trial. We cannot be certain that the FDA, or other regulatory authorities, will be supportive of this plan, will not change this approval policy again, or adopt other approval policies or regulations that adversely affect any NDA that we may submit.

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Research and Development Agreements

Abaloparatide-SC Phase 3 Clinical Trial —We have entered into agreements with Nordic Bioscience Clinical Development VII A/S, or Nordic, to conduct our Phase 3 clinical trial of abaloparatide-SC, or the Phase 3 Clinical Trial. On March 29, 2011, we entered into a Clinical Trial Services Agreement, or the Clinical Trial Services Agreement. On the same date, we also entered into Work Statement NB-1, as amended on December 9, 2011, June 18, 2012, March 28, 2014, May 19, 2014 and July 22, 2014, or Work Statement NB-1, and the Stock Issuance Agreement, as amended and restated on May 16, 2011, and as further amended on February 21, 2013, March 28, 2014, and May 19, 2014, or the Stock Issuance Agreement.

Pursuant to the Work Statement NB-1, we were required to make certain per patient payments denominated in both euros and U.S. dollars for each patient enrolled in the Phase 3 Clinical Trial followed by monthly payments for the duration of the study and final payments in two equal euro-denominated installments and two equal U.S. dollar-denominated installments. In addition, Nordic is entitled to a performance incentive payment, or Performance Incentive Payment, of $500,000 for every 50 patients that, subsequent to March 28, 2014, completed all end-of-study procedures, up to a maximum aggregate amount of $5.0 million. The Work Statement NB-1, provided for a total of up to approximately €41.2 million ($44.2 million) of euro-denominated payments and a total of up to approximately $3.2 million of U.S. dollar-denominated payments over the course of the Phase 3 Clinical Trial, plus Performance Incentive Payments.

We recognized research and development expense for the amounts due to Nordic under the Work Statement NB-1 ratably over the estimated per patient treatment period beginning upon enrollment in the Phase 3 Clinical Trial, or a twenty-month period, except for research and development expense for the amounts due under the fourth amendment to the Work Statement NB-1, which we recognized on a per patient basis when the end-of-study visit and all other required procedures were completed. We recorded $4.5 million of research and development expense during the three months ended March 31, 2014, for per patient costs incurred for patients that had enrolled in the Phase 3 Clinical Trial. As of March 31, 2015, all obligations due to Nordic under Work Statement NB-1 had been paid.

Abaloparatide-SC Phase 3 Clinical Extension Study — On February 21, 2013, we entered into the Work Statement NB-3, as amended on March 4, 2014, or the Work Statement NB-3. Pursuant to the Work Statement NB-3, Nordic will perform an extension study to evaluate six months of standard-of-care osteoporosis management following the completion of the Phase 3 Clinical Trial, or the Extension Study, and, upon completion of this initial six months, an additional period of 18 months of standard-of-care osteoporosis management, or the Second Extension.

We recognize research and development expense for the amounts due to Nordic under the Extension Study and the Second Extension ratably over the estimated per patient treatment periods beginning upon enrollment or over a nine-month and nineteen-month period, respectively. We recorded $1.4 million and $2.5 million of research and development expense during the three months ended March 31, 2015 and 2014 for per patient costs incurred for patients that had enrolled in the Extension Study and the Second Extension.

As of March 31, 2015, we had a liability of $6.0 million reflected in accrued expenses and other current liabilities on the balance sheet resulting from services provided by Nordic, which are payable in cash.

Stock Issuance Agreement — Pursuant to the Stock Issuance Agreement, Nordic agreed to purchase 6,443 shares of our Series A-5 convertible preferred stock, or the Series A-5, and to receive quarterly stock dividends, payable in shares of our Series A-6 convertible preferred stock, or the Series A-6. In connection with the Work Statement NB-1, the Stock Issuance Agreement provided that Nordic was entitled to receive stock dividends, having an aggregate value of up to €36.8 million ($39.5 million), or the NB-1 Accruing Dividend. In connection with Work Statement NB-3, the Stock Issuance Agreement provided that, beginning with the quarter ended March 31, 2013, Nordic was entitled to receive stock dividends having an aggregate value of up to €7.5 million ($8.0 million) and $0.8 million, or the NB-3 Accruing Dividend, and together with the NB-1 Accruing Dividend, the Nordic Accruing Dividend. On March 28, 2014, we entered into the second amendment to the Stock Issuance Agreement, or the Second Stock Issuance Agreement Amendment. The Second Stock Issuance Agreement Amendment required that our board of directors declare, as soon as reasonably practical, a stock dividend of twenty-nine (29) shares of its Series A-6 for each share of our then-outstanding Series A-5, all of which were held by Nordic, for a total of 186,847 shares of Series A-6, in full satisfaction of all stock dividends payable in 2014 under the terms of the Stock Issuance Agreement in connection with Work Statement NB-1 and Work Statement NB-3. In March 2014, Nordic requested that all 186,847 shares of Series A-6 be issued. Accordingly, our board of directors declared and issued a dividend to Nordic of all 186,847 shares on March 31, 2014. The Second Stock Issuance Agreement Amendment further provided that in the event an

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initial public offering of our common stock occurred prior to May 31, 2014, any payments owed by us to Nordic in relation to Work Statement NB-1 and Work Statement NB-3, excluding Performance Incentive Payments, for all periods of time after 2014, would be changed from the right to receive stock to the right to receive a total cash payment from us of $4.3 million payable in ten equal monthly installments of $430,000 beginning on March 31, 2015. On May 19, 2014, we entered into the third amendment to the Stock Issuance Agreement, which amended the date prior to which an initial public offering must occur to June 30, 2014. The Second Stock Issuance Agreement Amendment also stipulated that all consideration to be paid to Nordic pursuant to the Stock Issuance Agreement at any time after the consummation of an initial public offering be payable in cash. As we completed an initial public offering on June 11, 2014, Nordic no longer has the right to receive stock from us and has been paid in cash for all periods after June 11, 2014.

Prior to the issuance of shares of stock to Nordic in satisfaction of the Nordic Accruing Dividend, the liability to issue shares of stock was being accounted for as a liability on our balance sheet, based upon the fair value of the Series A-6. Changes in the fair value from the date of accrual to the date of issuance of the Series A-6 shares were recorded as a gain or loss in other (expense) income in the statement of operations.

License Agreement Obligations

Abaloparatide

In September 2005, we exclusively licensed the worldwide rights (except Japan) to abaloparatide and analogs from an affiliate of Ipsen Pharma SAS, or Ipsen.

In consideration for the rights to abaloparatide and in recognition of certain milestones having been met to date, we have paid to Ipsen an aggregate amount of $1.0 million. The license agreement further requires us to make payments upon the achievement of certain future clinical and regulatory milestones. The range of milestone payments that could be paid under the agreement is €10.0 million to €36.0 million ($10.7 million to $38.7 million). Should abaloparatide be approved and subsequently become commercialized, we or our sublicensees will be obligated to pay to Ipsen a fixed five percent royalty based on net sales of the product on a country-by-country basis until the later of the last to expire of the licensed patents or for a period of 10 years after the first commercial sale in such country. The date of the last to expire of the abaloparatide patents licensed from or co-owned with Ipsen, barring any extension thereof, is expected to be March 26, 2028. In the event that we sublicense abaloparatide to a third party, we are obligated to pay a percentage of certain payments received from such sublicensee (in lieu of milestone payments not achieved at the time of such sublicense). The applicable percentage is in the low double digit range. In addition, if we or our sublicensees commercialize a product that includes a compound discovered by us based on or derived from confidential Ipsen know-how, we will be obligated to pay to Ipsen a fixed low single digit royalty on net sales of such product on a country-by-country basis until the later of the last to expire of licensed patents that cover such product or for a period of 10 years after the first commercial sale of such product in such country. The license agreement contains other customary clauses and terms as are common in similar agreements in the industry.

Prior to executing the license agreement for abaloparatide with Radius, Ipsen licensed the Japanese rights for abaloparatide to Teijin Limited, or Teijin, a Japanese pharmaceutical company. It is our understanding that Teijin has fully enrolled a Phase 2 study of abaloparatide, which is expected to report results in mid-2015.

RAD1901

We exclusively licensed the worldwide rights to RAD1901 from Eisai Co. Ltd., or Eisai. On March 9, 2015, we entered into an amendment to the Eisai Agreement in which Eisai granted us an exclusive right and license to research, develop, manufacture and commercialize RAD1901 in Japan. In consideration for the rights to RAD1901 in Japan, we paid Eisai an initial license fee of $0.4 million upon execution of the contract, which was expensed during the three months ended March 31, 2015.

In consideration for the rights to RAD1901 and in recognition of certain milestones having been met to date, we have paid to Eisai an aggregate amount of $1.9 million. The range of milestone payments that could be paid under the agreement is $1.0 million to $20.0 million. The license agreement further requires us to make payments upon the achievement of certain future clinical and regulatory milestones. Should RAD1901 be approved and subsequently become commercialized, we will be obligated to pay to Eisai a royalty in a variable mid-single digit range based on net sales of the product on a country-by-country basis for a period that expires on the later of (1) the date the last remaining valid claim in the licensed patents expires, lapses or is invalidated in that country, the product is not covered by data protection clauses, and the sales of lawful generic version of the product account for more than a specified percentage of the total sales of all pharmaceutical products containing the licensed compound in that country; or (2) a period of 10 years after the first commercial sale of the licensed products in such country, unless it is sooner terminated. The latest valid claim is expected to expire, barring any extension thereof, on August 18, 2026. The royalty rate shall then be subject to reduction and the royalty obligation will expire at such time as sales of lawful generic version of such product account for more than a specified minimum percentage of the total sales of all products that contain the licensed compound. We were also granted the right to grant

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sublicenses with prior written approval from Eisai. If we sublicense RAD1901 to a third party, we will be obligated to pay Eisai, in addition to the milestones referenced above, a fixed low double digit percentage of certain fees we receive from such sublicensee and royalties in a variable mid-single digit range based on net sales of the sublicensee. The license agreement contains other customary clauses and terms as are common in similar agreements in the industry.

Net Operating Loss Carryforwards

As of December 31, 2014, we had federal and state net operating loss carryforwards of approximately $319.7 million and $246.5 million, respectively. If not utilized, the net operating loss carryforwards will expire at various dates through 2034.

Under Section 382 of the Internal Revenue Code of 1986, as amended, or the Code, substantial changes in our ownership may limit the amount of net operating loss carryforwards that could be used annually in the future to offset taxable income. Specifically, this limitation may arise in the event of a cumulative change in ownership of our company of more than 50% within a three-year period. Any such annual limitation may significantly reduce the utilization of the net operating loss carryforwards before they expire. The private placements and other transactions that have occurred since our inception may have triggered an ownership change pursuant to Section 382, which could limit the amount of net operating loss carryforwards that could be utilized annually in the future to offset taxable income, if any. Any such limitation, whether as the result of prior private placements, sales of common stock by our existing stockholders or additional sales of common stock by us, could have a material adverse effect on our results of operations in future years. We have not completed a study to assess whether an ownership change has occurred, or whether there have been multiple ownership changes since our inception, due to the significant costs and complexities associated with such study. In each period since our inception, we have recorded a valuation allowance for the full amount of our deferred tax asset, as the realization of the deferred tax asset is uncertain. As a result, we have not recorded any federal or state income tax benefit in our statement of operations.

Off-Balance Sheet Arrangements

We do not have any off-balance sheet arrangements or any relationships with unconsolidated entities of financial partnerships, such as entities often referred to as structured finance or special purpose entities.

New Accounting Standards

Refer to note 2, Basis of Presentation and Significant Accounting Policies — Accounting Standards Updates and Basis of Presentation and Significant Accounting Policies — Recently Adopted Accounting Standards, in “Notes to Condensed Financial Statements,” for a discussion of new accounting standards.

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Item 3. Quantitative and Qualitative Disclosure about Market Risk

We are exposed to market risk related to changes in interest rates. As of March 31, 2015 and December 31, 2014, we had cash, cash equivalents, and marketable securities of $243.1 million and $105.3 million, respectively, consisting of cash, money market funds, domestic corporate debt securities, domestic corporate commercial paper and U.S. agency bonds. This exposure to market risk is interest rate sensitivity, which is affected by changes in the general level of U.S. interest rates, particularly because our investments are in marketable securities. Due to the short-term duration of our investment portfolio and the low risk profile of our investments, an immediate 10 percent change in interest rates would not have a material effect on the fair market value of our portfolio. We generally have the ability to hold our short-investments until maturity, and therefore we would not expect our operating results or cash flows to be affected by any significant degree by the effect of a change in market interest rates on our investments. We carry our investments based on publicly available information. As of March 31, 2015 and December 31, 2014, we do not have any hard to value investment securities or securities for which a market is not readily available or active.

On May 30, 2014, we entered into a Loan and Security Agreement, which was amended on July 10, 2014 and February 13, 2015, or the Credit Facility, with Solar Capital Ltd., or Solar, as collateral agent and a lender, and Oxford Finance LLC, or Oxford, as a lender, pursuant to which Solar and Oxford agreed to make available to us $30.0 million in the aggregate subject to certain conditions to funding. An initial term loan was made on May 30, 2014 in an aggregate principal amount equal to $21.0 million, or the Initial Term Loan. A second term loan was made on July 10, 2014 in an aggregate principal amount equal to $4.0 million, or the Second Term Loan. The Initial Term Loan and Second Term Loan bear interest per annum at 9.85% plus one-month LIBOR (customarily defined) and mature on June 1, 2018. Changes in interest rates can cause interest charges to fluctuate under our Credit Facility. As of March 31, 2015, principal payable under the Initial Term Loan was $25.0 million. A 10% increase in current interest rates would have resulted in less than $0.1 million in additional cash interest expense for the three months ended March 31, 2015.

We are not subject to significant credit risk as this risk does not have the potential to materially impact the value of assets and liabilities.

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Item 4. Controls and Procedures

Disclosure Controls and Procedures

Our management, with the participation of our principal executive officer and principal financial officer, 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, as of the end of the period covered by this Quarterly Report on Form 10-Q. Based on this evaluation, our principal executive officer and principal financial officer concluded that our disclosure controls and procedures were effective as of March 31, 2015.

Changes in Internal Control over Financial Reporting

There have not been any changes in our internal control over financial reporting during the three months ended March 31, 2015 that have materially affected, or are reasonably likely to materially affect, our internal control over financial reporting.

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PART II— OTHER INFORMATION

Item 1. Legal Proceedings

None.

Item 1A. Risk Factors

Set forth below and elsewhere in this Quarterly Report on Form 10-Q and in other documents we file with the SEC are risks and uncertainties that could cause actual results to differ materially from the results contemplated by the forward-looking statements contained in this Quarterly Report on Form 10-Q. Because of the following important factors, as well as other variables affecting our operating results, past financial performance should not be considered as a reliable indicator of future performance and investors should not use historical trends to anticipate results or trends in future periods.

Risks Related to Our Business

Risks Related to Our Financial Position and Need for Capital

We are not currently profitable and may never become profitable.

We have a history of net losses and expect to incur substantial losses and have negative operating cash flow for the foreseeable future, and may never achieve or maintain profitability. We had net losses of $17.1 million for the three months ended March 31, 2015 and $62.5 million and $60.7 million for the years ended December 31, 2014 and 2013, respectively. As of March 31, 2015, we had an accumulated deficit of $361.3 million. Until we succeed in developing and commercializing one or more of our product candidates, we expect to incur substantial losses. We also expect to continue to incur significant operating and capital expenditures and anticipate that our expenses will increase substantially as we:

· continue to undertake preclinical development and clinical trials for product candidates;

· seek regulatory approvals for product candidates;

· implement additional internal systems and infrastructure; and

· hire additional personnel.

We also expect to experience negative cash flow as we fund our operating losses and capital expenditures. As a result, we will need to generate significant revenues in order to achieve and maintain profitability. Accordingly, unless and until we generate revenues and become profitable, we will need to raise additional capital to continue to operate our business. Our failure to achieve or maintain profitability or to raise additional capital could negatively impact the value of our securities.

We currently have no product revenues and we will need to raise additional capital, which may not be available on favorable terms, if at all, in order to continue operating our business.

To date, we have generated no product revenues. Until, and unless, we receive approval from the U.S. Food and Drug Administration, or FDA, and other foreign regulatory authorities for our product candidates, we will not be permitted to sell our drugs and will not have product revenues. Currently, our only product candidates are abaloparatide-SC, abaloparatide-TD, RAD1901 and RAD140, and none of these product candidates is approved by the FDA or other foreign regulatory authorities for sale. Therefore, for the foreseeable future, we will have to fund our operations and capital expenditures with our existing cash and cash equivalents and marketable securities, or through strategic financing opportunities, future offerings of our equity, and/or the incurrence of debt. We believe that our existing resources will be sufficient to fund our planned operations into the fourth quarter of 2016. We have based this estimate on assumptions that may prove to be wrong, and we could use up our available capital resources sooner than we currently expect. If we fail to obtain additional capital, we may be unable to complete our planned preclinical and clinical trials and obtain approval of any product candidates from the FDA and other foreign regulatory authorities. In addition, we could be forced to discontinue product development, reduce or forego sales and marketing efforts for any product candidate that is approved, forego attractive business opportunities or discontinue our operations entirely. Any additional sources of financing may not be available or may not be available on favorable terms and will likely involve the issuance of additional equity securities, which will have a dilutive effect on stockholders. Our future capital requirements will depend on many factors, including the scope and progress made in our research and development activities and our clinical studies.

Our credit facility imposes significant restrictions on our business, and if we default on our obligations, the lenders would have a right to foreclose on substantially all our assets.

In May 2014, we entered into a new $30.0 million credit facility with Solar Capital Ltd., as collateral agent and lender, and Oxford Finance LLC, as lender. We drew $21.0 million under this credit facility on May 30, 2014. Pursuant to an amendment to the credit facility, we drew an additional $4.0 million on July 10, 2014. Our new credit facility contains a number of covenants that impose significant operating and financial restrictions on us, including covenants that limit our ability to:

· dispose of our business or certain assets;

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· change our business, management, ownership or business locations;

· incur additional debt or liens;

· make certain investments or declare dividends;

· acquire or merge with another entity;

· enter into licensing agreements;

· engage in transactions with affiliates; or

· encumber our intellectual property.

Our credit facility may limit our ability to finance future operations or capital needs or to engage in, expand or pursue our business activities. It may also prevent us from engaging in activities that could be beneficial to our business and our stockholders unless we repay the outstanding debt, which may not be desirable or possible.

We have pledged substantially all of our assets other than our intellectual property to secure our obligations under our credit facility. If we default on our obligations and are unable to obtain a waiver for such a default, the lenders would have a right to accelerate the debt and terminate all commitments under our credit facility. They would also have the right to foreclose on the pledged assets, including our cash and cash equivalents. Any such action on the part of lenders against us would significantly harm our business and our ability to operate.

Raising additional capital may cause dilution to our existing stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates.

Until such time, if ever, as we can generate substantial product revenues, we expect to finance our cash needs through a combination of collaborations, strategic alliances, licensing arrangements, other marketing and distribution arrangements, equity offerings, and debt financings. We do not have any committed external source of funds. To the extent that we raise additional capital through the sale of equity or convertible debt securities, your ownership interest will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect your rights as a stockholder. Debt financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends. If we raise additional funds through marketing and distribution arrangements or other collaborations, strategic alliances or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams, research programs or product candidates, or we may need to 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 commercialization efforts or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.

We are a company with a limited operating history upon which to base an investment decision.

We are a company with a limited operating history and have not demonstrated an ability to perform the functions necessary for the successful commercialization of any product candidates. The successful commercialization of any product candidates will require us to perform a variety of functions, including:

· continuing to undertake preclinical development and clinical trials;

· participating in regulatory approval processes;

· formulating and manufacturing products; and

· conducting sales and marketing activities for products if approved.

Our operations have been limited to organizing and staffing our company, acquiring, developing and securing our proprietary technology and undertaking preclinical and clinical trials of our product candidates. These operations provide a limited basis for you to assess our ability to commercialize our product candidates and the advisability of investing further in our securities.

Our financial results may fluctuate from quarter to quarter, which makes our results difficult to predict and could cause our results to fall short of expectations.

Our financial results may fluctuate as a result of a number of factors, many of which are outside of our control. For these reasons, comparing our financial results on a period-to-period basis may not be meaningful, and you should not rely on our past results as an indication of our future performance. Our revenues, if any, may fluctuate from quarter to quarter and our future quarterly and annual expenses as a percentage of our revenues may be significantly different from those we have recorded in the past or which we expect for the future. Our financial results in some quarters may fall below expectations. Any of these events as well as the various risk factors listed in this “Risk Factors” section could adversely affect our financial results and cause our stock price to fall.

Our cash and cash equivalents could be adversely affected if the financial institutions in which we hold our cash and cash equivalents fail.

We regularly maintain cash balances at third-party financial institutions in excess of the Federal Deposit Insurance Corporation, or FDIC, insurance limit. While we monitor daily the cash balances in the operating accounts and adjust the balances as appropriate, these balances could be impacted, and there could be a material adverse effect on our business, if one or more of the financial institutions with which we deposit fails or is subject to other adverse conditions in the financial or credit markets. To date, we have experienced no loss or lack of access to our invested cash or cash equivalents; however, we can provide no assurance that access to our invested cash and cash equivalents will not be impacted by adverse conditions in the financial and credit markets.

Our investments in marketable securities are subject to market, interest and credit risk that may reduce their value.

The value of our investments in marketable securities may be adversely affected by changes in interest rates, downgrades in the creditworthiness of bonds we hold, turmoil in the credit markets and financial services industry and by other factors which may result in other than temporary declines in the value of our investments. Decreases in the market value of our marketable securities could have an adverse impact on our statements of financial position, results of operations and cash flow.

Risks Related to the Discovery, Development and Commercialization of Our Product Candidates

We are heavily dependent on the success of our investigational product candidate abaloparatide-SC, which is under clinical development. We cannot be certain that abaloparatide-SC will receive regulatory approval or be successfully commercialized even if we receive regulatory approval.

Abaloparatide-SC is our only product candidate in late-stage clinical development, and our business currently depends heavily on its successful development, regulatory approval and commercialization. We have no drug products for sale currently and may never be able to develop approved and marketable drug products. The research, testing, manufacturing, labeling, approval, sale, marketing and

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distribution of drug products are subject to extensive regulation by the FDA and other foreign regulatory authorities in the United States and other countries, which regulations differ from country to country. We are not permitted to market abaloparatide-SC in the United States unless and until we receive approval of a New Drug Application, or NDA, from the FDA, or in any foreign countries unless and until we receive the requisite approval from regulatory authorities in foreign countries. In addition, the approval of abaloparatide-TD as a line extension to abaloparatide-SC is dependent on the earlier approval of abaloparatide-SC. We have not submitted an NDA to the FDA or comparable applications to regulatory authorities in other countries. Obtaining approval of a product candidate is an extensive, lengthy, expensive and uncertain process, and any approval of abaloparatide-SC may be delayed, limited or denied for many reasons, including:

· the results of our clinical studies may not meet the level of statistical or clinical significance required for marketing approval;

· the FDA or other foreign regulatory authorities may disagree with the number, design, size, conduct or implementation of our clinical studies;

· any clinical research organizations, or CROs, that we have retained or may in the future retain, to conduct clinical studies may take actions outside of our control that materially adversely impact our clinical studies;

· the FDA or other foreign regulatory authorities may disagree with our interpretation of data from our preclinical studies and clinical studies or may require that we conduct additional studies;

· the FDA or other foreign regulatory authorities may not accept data generated at our clinical study sites;

· the FDA may require development of a Risk Evaluation and Mitigation Strategy, or REMS, as a condition of approval;

· the FDA or other foreign regulatory authorities may identify deficiencies in the manufacturing processes or facilities of our third-party manufacturers.

In addition, the FDA or other foreign regulatory authorities may change its approval policies or adopt new regulations. For example, on February 15, 2012, we received a letter from the FDA stating that, after internal consideration, the FDA believes that a minimum of 24-month fracture data are necessary for approval of new products for the treatment of postmenopausal osteoporosis. Our abaloparatide-SC pivotal Phase 3 clinical trial is designed to produce fracture data based on an 18-month primary endpoint. Based on our discussions with the FDA, we believe that continued use of the 18-month primary endpoint will be acceptable, provided that our NDA includes the 24-month fracture data derived from the first six months extension of the abaloparatide 80 µg and placebo groups in our Phase 3 study, which groups will receive an approved alendronate (generic Fosamax) therapy for osteoporosis management. We plan to submit our NDA with the 24-month fracture data. We cannot be certain that the FDA will be supportive of this plan, will not change this approval policy again or will not adopt other approval policies or regulations that adversely affect any NDA that we may submit, the occurrence of any of which may further delay FDA approval.

Before we submit an NDA to the FDA for abaloparatide-SC as a proposed treatment for osteoporosis, we must complete the first six months of the alendronate extension study of the abaloparatide and placebo groups from our Phase 3 clinical and submit 24-month fracture data to the FDA. We also must complete several additional studies, including, but not limited to, a thorough QT Phase 1 study and a Phase 1 pharmacokinetic study in renal patients. The results of these studies will have an important bearing on the approval of abaloparatide.

We cannot assure you that we will receive the approvals necessary to commercialize any of our product candidates, including abaloparatide-SC, abaloparatide-TD, RAD1901 and RAD140, or any product candidate we may acquire or develop in the future. We will need FDA approval to commercialize our product candidates in the United States and approvals from the regulatory authorities in foreign jurisdictions to commercialize our product candidates in those jurisdictions. In order to obtain FDA approval of any product candidate, we must submit to the FDA an NDA demonstrating that the product candidate is safe for humans and effective for its indicated use. This demonstration requires significant research and animal tests, which are referred to as preclinical studies, as well as human tests, which are referred to as clinical trials. Satisfaction of the FDA’s regulatory requirements typically takes many years, depends upon the type, complexity and novelty of the product candidate and requires substantial resources for research, development and testing. We cannot predict whether our research and clinical approaches will result in drugs that the FDA considers safe for humans and effective for proposed uses. The FDA has substantial discretion in the drug approval process and may require us to

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conduct additional preclinical and clinical testing or to perform post-marketing studies. The approval process may also be delayed by changes in government regulation, future legislation or administrative action or changes in FDA policy that occur prior to or during its regulatory review, such as the request we received from the FDA with respect to providing a minimum of 24-month fracture data for approval of abaloparatide. Delays in obtaining regulatory approvals may:

· delay commercialization of, and our ability to derive product revenues from, our product candidates;

· impose costly procedures on us; and

· diminish any competitive advantages that we may otherwise enjoy.

The abaloparatide-SC finished product is a drug/device combination product candidate with both a drug and device component and with the primary mode of action being provided by the investigational drug abaloparatide. Based on our discussions to date with the FDA, we believe that abaloparatide-SC will be regulated as a combination product by the FDA, and both drug and device components will be required for review as part of our NDA submission. We expect that our NDA would be submitted to the Center for Drug Evaluation and Research and be reviewed with support from the FDA Office of Combination Products and the FDA Center for Devices and Radiological Health for the device aspects of the abaloparatide-SC product candidate. In addition, there are device-related manufacturing and other regulatory requirements (e.g., cGMPs and adverse event reporting) to which we may be subject by virtue of the product’s status as a drug/device combination product. As a result of these factors, we may experience delays in the product development and regulatory review and approval process in seeking a drug/device combination product approval under an NDA.

Even if we comply with all FDA requests, the FDA may ultimately reject one or more of our NDAs. We may never obtain regulatory clearance for any of our product candidates. Failure to obtain FDA approval of any of our product candidates will severely undermine our business by leaving us without a saleable product, and therefore without any source of revenues, until another product candidate can be developed. There is no guarantee that we will ever be able to develop or acquire any product candidate.

In foreign jurisdictions, we must receive approval from the appropriate regulatory authorities before we can commercialize any drugs. Foreign regulatory approval processes generally include all of the risks associated with the FDA approval procedures described above. We cannot assure you that we will receive the approvals necessary to commercialize any of our product candidates for sale outside the United States.

Clinical trials are very expensive, time-consuming and difficult to design and implement.

Human clinical trials are very expensive and difficult to design and implement, in part because they are subject to rigorous regulatory requirements. A substantial portion of our abaloparatide development costs are denominated in euros and any adverse movement in the dollar/euro exchange rate will result in increased costs and require us to raise additional capital to complete the development of our products. The clinical trial process is also time consuming. Furthermore, failure can occur at any stage of the trials, and we could encounter problems that cause us to abandon or repeat clinical trials. The commencement and completion of clinical trials may be delayed by several factors, including:

· changes in government regulation, administrative action or changes in FDA or other foreign regulatory authority policy with respect to clinical trials that change the requirements for approval;

· unforeseen safety issues;

· determination of dosing issues;

· lack of effectiveness during clinical trials;

· slower than expected rates of patient recruitment and enrollment;

· failure of sites to comply with requirements for conducting clinical trials;

· inability to monitor patients adequately during or after treatment; and

· inability or unwillingness of medical investigators to follow our clinical protocols.

In addition, we, the FDA, or other equivalent regulatory authorities and ethics committees with jurisdiction over our studies may suspend our clinical trials at any time if it appears that we are exposing participants to unacceptable health risks or if the FDA or other foreign regulatory authorities find deficiencies in our regulatory submissions or the conduct of these trials. Therefore, we cannot predict with any certainty the schedule for existing or future clinical trials. Any such unexpected expenses or delays in our clinical trials could increase our need for additional capital, which may not be available on favorable terms or at all.

Most of our investigational product candidates are in early stages of clinical trials.

Except for abaloparatide-SC and abaloparatide-TD, each of our other product candidates (i.e., RAD1901 and RAD140) is in the early stages of development and requires extensive preclinical and clinical testing. We cannot predict with any certainty if or when we might submit an NDA or equivalent application to foreign regulatory authorities for regulatory approval for any of our product candidates or whether any such NDA or equivalent application would be accepted for filing by FDA or other foreign regulatory authorities or approved if filed.

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The results of clinical trials may not support our product candidate claims.

Even if our clinical trials are completed as planned, we cannot be certain that the results will support regulatory approval of our product candidates. Success in preclinical testing and early clinical trials does not ensure that later clinical trials will be successful, and we cannot be sure that the results of later clinical trials will replicate the results of prior clinical trials and preclinical testing. The clinical trial process may fail to demonstrate that our product candidates are safe for humans and effective for proposed uses. This failure would cause us to abandon a product candidate and may delay development of other product candidates. Any delay in, or termination of, our clinical trials will delay the submission of our NDAs to the FDA or equivalent application to foreign regulatory authorities and, ultimately, our ability to commercialize our product candidates and generate product revenues. In addition, our clinical trials to date (other than the ACTIVE Phase 3 Clinical Trial for abaloparatide-SC) have involved small patient populations. Because of the small sample sizes, the results of these clinical trials may not be indicative of future results.

In addition, third parties could conduct clinical trials using the product candidates we license. We would have no control over how these trials are conducted and the results could potentially contradict the results we have obtained, or will obtain from the clinical trials we conduct.

If serious adverse or undesirable side effects are identified during the development of our product candidates, we may need to abandon our development of some of our product candidates.

All of our product candidates are still in preclinical or clinical development. Undesirable side effects caused by our product candidates could cause us, regulatory authorities, and/or ethics committees to interrupt, delay or halt clinical trials and could result in a more restrictive label or cause the delay or denial of regulatory approval by the FDA or other comparable foreign authorities. It is impossible to predict when or if any of our product candidates will prove effective or safe in humans or will receive regulatory approval, if ever. If our product candidates result in undesirable side effects or have characteristics that are unexpected, we may need to abandon their development. Drug-related side effects could affect patient recruitment or the ability of enrolled patients to complete the trial or result in potential product liability claims. Any of these occurrences may harm our business, financial condition and prospects significantly.

Additionally if one or more of our product candidates receives marketing approval, and we or others later identify undesirable side effects caused by such products, a number of potentially significant negative consequences could result, including:

· regulatory authorities may withdraw approvals of such product;

· regulatory authorities may require additional warnings on the label;

· we may be required to create a medication guide outlining the risks of such side effects for distribution to patients;

· we could be sued and held liable for harm caused to patients; and

· our reputation may suffer.

Any of these events could prevent us from achieving or maintaining market acceptance of the particular product candidate, if approved, and could significantly harm our business, results of operations and prospects.

Any product candidate for which we obtain marketing approval could be subject to restrictions or withdrawal from the market and we may be subject to penalties if we fail to comply with regulatory requirements or if we experience unanticipated problems with our products, when and if any of them are approved.

Any product candidate for which we obtain marketing approval, along with the manufacturing processes, post-approval clinical data, labeling, advertising and promotional activities for such product, will be subject to continual requirements of and review by the FDA and other foreign regulatory authorities. These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, current good manufacturing practices, or cGMP, requirements relating to quality control, quality assurance and corresponding maintenance of records and documents, and requirements regarding the distribution of samples to physicians and recordkeeping. Even if we obtain marketing approval of a product candidate, the approval may be subject to limitations on the indicated uses for which the product may be marketed or to the conditions of approval, or contain requirements for costly post-marketing testing and surveillance to monitor the safety and/or efficacy of the product. The FDA closely regulates the post-approval marketing and promotion of drugs to ensure drugs are marketed only for the approved indications and in accordance with the provisions of the approved labeling. The FDA imposes stringent restrictions on manufacturers’ communications regarding off-label

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use and, if we market our products for other than their approved indications, we may be subject to enforcement action for off-label marketing.

In addition, later discovery of previously unknown problems with our products, manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may yield various results, including:

· restrictions on such products, manufacturers or manufacturing processes;

· restrictions on the labeling or marketing of a product;

· restrictions on product distribution or use;

· requirements to conduct post-marketing clinical trials;

· warning or untitled letters;

· withdrawal of the products from the market;

· refusal to approve pending applications or supplements to approved applications that we submit;

· voluntary or mandatory recall of products and related publicity requirements;

· fines, restitution or disgorgement of profits or revenue;

· suspension or withdrawal of marketing approvals;

· refusal to permit the import or export of our products;

· product seizure; or

· injunctions or the imposition of civil or criminal penalties.

In addition, the FDA’s policies may change and additional government regulations may be enacted that could prevent, limit, or delay regulatory approval of our product candidates. We cannot predict the likelihood, nature, or extent of government regulation that may arise from future legislation or administrative action, either in the United States or abroad. If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we may have obtained and we may not achieve or sustain profitability, which would adversely affect our business.

The commercial success of any product candidates that we may develop and that may be approved will depend upon the degree of market acceptance by regulators, key opinion leaders, physicians, patients, healthcare payers and others in the medical community.

Even if the FDA or other foreign regulatory authority approves one or more of our product candidates, physicians and patients may not accept and use them. Acceptance and use of any of our products will depend upon a number of factors including:

· perceptions by members of the healthcare community, including physicians and key opinion leaders, about the safety and effectiveness of our drug;

· cost-effectiveness of our product relative to competing products;

· availability of coverage and reimbursement for our product from government or other healthcare payers; and

· effectiveness of marketing and distribution efforts by us and our licensees and distributors, if any.

If any of our product candidates are commercialized and unexpected adverse events are reported in connection with the use of any of those products, physician and patient acceptance of the product could deteriorate and the commercial success of such product could be adversely affected. We are required to report to the FDA or similar bodies in other countries events associated with our products relating to death or serious injury. Adverse events could result in additional regulatory controls, such as for the imposition of costly post-approval clinical studies or revisions to approved labeling which could limit the indications or patient population for a product or could even lead to the withdrawal of a product from the market. Because we expect sales of our current product candidates, if approved, to generate substantially all of our product revenues for the foreseeable future, the failure of these drugs to gain market acceptance or, once gained, a decrease in market acceptance would harm our business and would require us to seek additional financing.

We may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success.

Because we have limited financial and managerial resources, we narrowly focus on research programs and product candidates that we identify for specific indications. As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on current and future research and development programs and product candidates for specific indications may not yield any commercially viable products. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate.

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If we experience delays in the enrollment of patients in our clinical trials, our receipt of necessary regulatory approvals could be delayed or prevented.

We may not be able to initiate or continue clinical trials for some of our product candidates if we are unable to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA or other foreign regulatory authorities. In addition, many of our competitors have ongoing clinical trials for product candidates that could be competitive with our product candidates, and patients who would otherwise be eligible for our clinical trials may instead enroll in clinical trials of our competitors’ product candidates.

Enrollment delays in our clinical trials may result in increased development costs for our product candidates, which would cause the value of the company to decline and limit our ability to obtain additional financing. Our inability to enroll a sufficient number of patients for any of our current or future clinical trials would result in significant delays or may require us to abandon one or more clinical trials altogether.

Risks Related to Our Dependence on Third Parties

Our drug development program depends upon third-party researchers, investigators and collaborators who are outside our control.

We depend upon independent researchers, investigators and collaborators, to conduct our preclinical and clinical trials under agreements with us. These third parties are not our employees and we cannot control the amount or timing of resources that they devote to our programs. Nevertheless, we are responsible for ensuring that each of our studies is conducted in accordance with the applicable protocol, legal, regulatory and scientific standards and requirements, and our reliance on third parties does not relieve us of our regulatory responsibilities. We and our third party researchers, investigators and collaborators are required to comply with good clinical practice, or GCP, requirements, which are regulations and guidelines enforced by the FDA, the Competent Authorities of the Member States of the European Economic Area, or EEA, and comparable foreign regulatory authorities for all of our products in clinical development. Regulatory authorities enforce these GCPs through periodic inspections of trial sponsors, principal investigators and trial sites. If we or any of our CROs fail to comply with applicable GCPs, the clinical data generated in our clinical trials may be deemed unreliable and the FDA, EMA or other comparable foreign regulatory authorities may require us to perform additional clinical trials before approving our marketing applications. We cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of our clinical trials complies with GCP regulations. In addition, our clinical trials must be conducted with product produced under cGMP regulations. Our failure to comply with these regulations may require us to repeat clinical trials, which would delay the regulatory approval process. In addition, these third parties may not assign as great a priority to our programs or pursue them as diligently as we would if we were undertaking such programs ourselves. If outside collaborators fail to devote sufficient time and resources to our drug-development programs, or if their performance is substandard, the approval of our FDA or foreign regulatory authority applications, if any, and our introduction of new drugs, if any, will be delayed. These collaborators may also have relationships with other commercial entities, some of whom may compete with us. If our collaborators assist competitors at our expense, our competitive position would be harmed.

If a regulatory or governmental authority determines that a financial interest in the outcome of the Phase 3 study of abaloparatide-SC by any of the entities managing our Phase 3 clinical trial affected the reliability of the data from the Phase 3 clinical trial, our ability to use the data for our planned regulatory submissions could be compromised, which could harm our business and the value of our common stock.

The Phase 3 clinical trial and subsequent extension studies of abaloparatide-SC are being managed by Nordic at certain clinical sites operated by the Center for Clinical and Basic Research, or CCBR, a leading global CRO with extensive experience in global osteoporosis registration studies. Nordic controls, and holds an ownership interest in, the local CCBR clinical sites. The clinical trial investigators are employees of CCBR and may also hold an equity interest in the local CCBR clinical trials.

In consideration of Nordic’s management of our Phase 3 clinical trial and subsequent extension studies, we agreed to make various cash payments to Nordic denominated in both euros and U.S. dollars over the course of the Phase 3 study equal to a total of up to approximately €48.6 million ($52.2 million) and a total of up to approximately $4.4 million plus up to an additional $5.0 million in aggregate performance incentive payments, payable in cash or stock depending on the timing of the closing of an underwritten offering of shares of our common stock. We also agreed to sell shares of capital stock to Nordic that were exchanged in May 2011 for 6,443 shares of our series A-5 convertible preferred stock for proceeds of approximately $0.5 million. These shares of our series A-5 convertible preferred stock automatically converted into 28,258 shares of our common stock upon the listing of our common stock on the NASDAQ Global Market. Pursuant to the terms of our agreements with Nordic, we were required to issue to Nordic shares of stock with an aggregate value of up to approximately €44.3 million ($47.6 million) and $0.8 million in consideration of Nordic’s management of the Phase 3 clinical trial. These shares of stock accrued at a quarterly rate based on the progress of the Phase 3 clinical trial and were issuable at a price per share equal to the greater of (1) the fair market value of our common stock as of the applicable

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accrual date or (2) $81.42 and rounding down the resulting quotient to the nearest whole number. On each of December 31, 2013 and March 31, 2014, our Board of Directors declared a stock dividend to pay all shares of stock that had accrued as of such dates and that were anticipated to accrue through December 31, 2014, representing an aggregate of 682,958 shares of our Series A-6 convertible preferred stock that automatically converted into 2,995,453 shares of our common stock upon the listing of our common stock on the NASDAQ Global Market. Following the completion of our initial public offering of shares of our common stock on June 11, 2014, or our initial public offering, all compensation remaining payable to Nordic in consideration of their management of our Phase 3 clinical trial became payable in cash.

The fair market value of our common stock may be subject to wide fluctuations in response to various factors, many of which are beyond our control, including any negative outcome of the Phase 3 study. Accordingly, the shares of stock that we have issued to Nordic in consideration of Nordic’s management of the Phase 3 clinical trial may be less than the full value originally anticipated under our agreements with Nordic, assuming Nordic did not expect the fair market value of our stock to fluctuate widely over the term of such agreements. As a result, the total consideration that Nordic will receive in cash and stock may be viewed to be below the market price paid by other companies for comparable clinical trial services.

Because of the potential decrease in the value of the common stock issued to Nordic upon a negative outcome of the Phase 3 study, Nordic, CCBR and the clinical trial investigators may be viewed as having a financial interest in the outcome of the study. We have obtained written acknowledgments from the clinical trial investigators certifying that they have no financial interest in the outcome of the Phase 3 clinical trial. However, if the FDA, the EMA, or any other similar regulatory or governmental authority determines that Nordic, CCBR or the clinical trial investigators have a financial interest that affected the reliability of the data from the Phase 3 clinical trial, we could be subject to additional regulatory scrutiny and the utility of the Phase 3 clinical trial for purposes of our planned regulatory submissions could be compromised, which could have a material adverse effect on our business and the value of our common stock.

We will rely exclusively on third parties to formulate and manufacture our product candidates.

We have no experience in drug formulation or manufacturing and do not intend to establish our own manufacturing facilities. We lack the resources and expertise to formulate or manufacture our own product candidates. We have entered into agreements with contract manufacturers to manufacture abaloparatide for use in clinical trial activities. These contract manufacturers are currently our only source for the production and formulation of abaloparatide. We may not have sufficient clinical supplies of abaloparatide but believe that our contract manufacturers will be able to produce sufficient supply of abaloparatide to complete all of the planned abaloparatide clinical studies. If our contract manufacturers are unable to produce, in a timely manner, adequate clinical supplies to meet the needs of our clinical studies, we would be required to seek new contract manufacturers that may require us to modify our finished product formulation and modify or terminate our clinical studies for abaloparatide. Any modification of our finished product or modification or termination of our clinical studies could adversely affect our ability to obtain necessary regulatory approvals and significantly delay or prevent the commercial launch of the product if it were to be approved, which would materially harm our business and impair our ability to raise capital. In addition, the facilities and processes and controls used by our contract manufacturers to manufacture our product candidates must be approved by the FDA pursuant to inspections that will be conducted after we submit our NDA to the FDA and our MAA to EMA. We do not control the facilities or manufacturing process and controls of, and are completely dependent on, our contract manufacturing partners for compliance with the regulatory requirements, known as cGMPs, for manufacture of both active drug substances and finished drug products. If our contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the FDA or other regulatory authorities, they will not be able to secure and/or maintain regulatory approval for their manufacturing facilities. In addition, we have no control over the ability of our contract manufacturers to maintain adequate quality control, quality assurance and qualified personnel. If the FDA or a comparable foreign regulatory authority does not approve these for the manufacture of our product candidates or if they withdraw any such approval in the future, we may need to find alternative manufacturing facilities, which would significantly impact our ability to develop, obtain regulatory approval for or market our product candidates, if approved.

We depend on a number of single source contract manufacturers to supply key components of abaloparatide. For example, we depend on Lonza Group Ltd., or Lonza, which produces supplies of bulk drug product of abaloparatide to support the abaloparatide-SC and abaloparatide-TD clinical studies and any potential commercial launch. We also depend on Vetter Pharma Fertigung GmbH & Co, or Vetter, and Ypsomed AG, or Ypsomed, for the production of finished supplies of abaloparatide-SC and we depend on 3M for the production of abaloparatide-TD. Because of our dependence on Vetter for the “fill and finish” part of the manufacturing process for abaloparatide-SC, we are subject to the risk that Vetter may not have the capacity from time to time to produce sufficient quantities of abaloparatide to meet the needs of our clinical studies or be able to scale to commercial production of abaloparatide. Because the manufacturing process for abaloparatide-TD requires the use of 3M’s proprietary technology, 3M is our sole source for finished clinical trial supplies of abaloparatide-TD. To date, we have not entered into a commercial supply agreement with 3M. If we were not able to negotiate commercial supply terms with 3M, as we depend on 3M for production of abaloparatide-TD, we would be unable to commercialize this product if it were to be approved. Or, if we are forced to accept unfavorable terms for our future relationship with 3M, our business and financial condition would be materially harmed.

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While we are currently in discussions, to date, we have not entered into a long-term agreement with any of Lonza, Vetter or Ypsomed, each of whom currently produces abaloparatide or related components on a purchase order basis for us. Accordingly, Lonza, Vetter and Ypsomed could terminate their relationship with us at any time and for any reason. We may not be able to negotiate long-term agreements on acceptable terms, or at all. If our relationship with any of these contract manufacturers is terminated, or if they are unable to produce abaloparatide or related components in required quantities, on a timely basis or at all, or if we are forced to accept unfavorable terms for our future relationship, our business and financial condition would be materially harmed. If any of our current product candidates or any product candidates we may develop or acquire in the future receive FDA or foreign regulatory authority approval, we will rely on one or more third-party contractors to manufacture our drugs or related components. Our anticipated future reliance on a limited number of third-party manufacturers exposes us to the following risks:

· We may be unable to identify manufacturers on acceptable terms, or at all, because the number of potential manufacturers is limited and the FDA must approve any replacement contractor. This approval would require new testing and compliance inspections. In addition, a new manufacturer would have to be educated in, or develop substantially equivalent processes for, production of our products after receipt of FDA approval, if any.

· Our third-party manufacturers might be unable to formulate and manufacture our drugs or related components in the volume and of the quality required to meet our clinical needs and commercial needs, if any.

· Our contract manufacturers may not perform as agreed or may not remain in the contract manufacturing business for the time required to supply our clinical trials or to successfully produce, store and distribute our products.

· Drug manufacturers are subject to ongoing periodic unannounced inspection by the FDA, the Drug Enforcement Administration, for any controlled substances, and corresponding state agencies to ensure strict compliance with cGMP, and other government regulations and corresponding foreign standards, and failure to comply with cGMP or corresponding foreign standards can result in compliance actions that may limit a manufacturer’s production or prohibit a manufacturer from producing some or all products at a facility and/or importing it into the United States or a foreign country. We do not have control over third-party manufacturers’ compliance with these regulations and standards.

· If any third-party manufacturer makes improvements in the manufacturing process for our products, any such improvement(s) could be subject to FDA review and prior approval, and we may not own, or may have to share, the intellectual property rights to the innovation.

Each of these risks could delay our clinical trials, the approval, if any, of our product candidates by the FDA or other foreign regulatory authority or the commercialization of our product candidates or result in higher costs or deprive us of potential product revenues.

If we are not able to establish additional collaborations, we may have to alter our development plans.

Our product development programs and the potential commercialization of our product candidates will require substantial additional cash to fund expenses. For some of our product candidates, we may decide to collaborate with pharmaceutical and biotechnology companies for the development and potential commercialization of those product candidates.

We face significant competition in seeking appropriate collaborators. Collaborations are complex and time-consuming to negotiate and document. We may also be restricted under existing collaboration agreements from entering into agreements on certain terms with other potential collaborators. We may not be able to negotiate collaborations on acceptable terms, or at all. If that were to occur, we may have to curtail the development of a particular product candidate, reduce or delay its development program or one or more of our other development programs, delay its potential commercialization or reduce the scope of our sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to increase our expenditures to fund development or commercialization activities on our own, we may need to obtain additional capital, which may not be available to us on acceptable terms or at all. If we do not have sufficient funds, we will not be able to bring our product candidates to market and generate product revenue.

Risks Related to Marketing and Sale of Our Products

We have no experience selling, marketing or distributing products and currently do not have the internal capability to do so.

We currently have no sales, marketing or distribution capabilities. Our future success depends, in part, on our ability to enter into and maintain collaborative relationships for such capabilities, the collaborators’ strategic interest in the products under development and such collaborators’ ability to successfully market and sell any such products. We intend to build an internal sales force to market and sell our products to specialists within the target indications if approved and to pursue collaborative arrangements to market and sell

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our products to primary care physicians within the target indications if approved. To the extent that we depend on third parties for marketing and distribution, any revenues we receive will depend upon the efforts of such third parties, and we cannot assure you that their efforts will be successful. In addition, we cannot assure you that we will be able to establish or maintain relationships with such third party collaborators or that we would be able to market and sell our products in the United States or overseas through an in-house sales force in lieu of such relationships.

If we cannot compete successfully for market share against other drug companies, we may not achieve sufficient product revenues and our business will suffer.

The market for our product candidates is characterized by intense competition and rapid technological advances. If any of our product candidates receives FDA or other foreign regulatory authority approval, it will compete with a number of existing and future drugs and therapies developed, manufactured and marketed by others. Existing or future competing products may provide greater therapeutic convenience or clinical or other benefits for a specific indication than our products, or may offer comparable performance at a lower cost. If our products fail to capture and maintain market share, we may not achieve sufficient product revenues and our business will suffer.

If approved, we will compete against fully integrated pharmaceutical companies and smaller companies that are collaborating with larger pharmaceutical companies, academic institutions, government agencies and other public and private research organizations. Many of these competitors have compounds already approved or in development. In addition, many of these competitors, either alone or together with their collaborative partners, operate larger research and development programs or have substantially greater financial resources than we do, as well as significantly greater experience in:

· developing drugs;

· undertaking preclinical testing and human clinical trials;

· obtaining FDA and other regulatory approvals of drugs;

· formulating and manufacturing drugs; and

· launching, marketing and selling drugs.

Developments by competitors may render our products or technologies obsolete or non-competitive.

The biotechnology and pharmaceutical industries are intensely competitive and subject to rapid and significant technological change. Some of the drugs that we are attempting to develop, such as our investigational product candidates abaloparatide-SC, abaloparatide-TD, RAD1901 and RAD140, will have to compete against existing therapies if they are approved. In addition, a large number of companies are pursuing the development of pharmaceuticals that target the same diseases and conditions that we are targeting. We face competition from pharmaceutical and biotechnology companies in the United States and abroad. In addition, companies doing business in different but related fields represent substantial competition. Many of these organizations competing with us have substantially greater capital resources, larger research and development staffs and facilities, longer drug development history in obtaining regulatory approvals, and greater manufacturing and marketing capabilities than we do. These organizations also compete with us to attract qualified personnel and parties for acquisitions, joint ventures or other collaborations, and therefore, we may not be able to hire or retain qualified personnel to run all facets of our business. These risks could render our products or technologies obsolete or non-competitive.

Our ability to generate product revenues will be diminished if our drugs sell for inadequate prices or patients are unable to obtain adequate levels of reimbursement.

Our ability to commercialize our product candidates if approved, alone or with collaborators, will depend in large part on the extent to which coverage and reimbursement will be available post-approval from:

· government and health administration authorities;

· private health maintenance organizations and health insurers; and

· other healthcare payers.

Significant uncertainty exists as to the reimbursement status of newly approved healthcare products. Healthcare payers, including Medicare, are challenging the prices charged for medical products and services. Government and other healthcare payers increasingly attempt to contain healthcare costs by limiting both coverage and the level of reimbursement for drugs. Even if one of our product candidates is approved by the FDA or other foreign regulatory authority, insurance coverage may not be available, and reimbursement levels may be inadequate, to cover the costs of our drug. If government and other healthcare payers do not provide adequate coverage and reimbursement levels for our product candidates, once approved, market acceptance of our products could be reduced.

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We may incur substantial liabilities and may be required to limit commercialization of our products in response to product liability lawsuits.

The testing and marketing of medical products entail an inherent risk of product liability. Even if one of our investigational product candidates is approved by the FDA or other foreign regulatory authority, if we cannot successfully defend ourselves against product liability claims, we may incur substantial liabilities or be required to limit commercialization of our products. Our inability to obtain sufficient product liability insurance at an acceptable cost to protect against potential product liability claims could prevent or inhibit the commercialization of pharmaceutical products we develop, alone or with collaborators.

Risks Related to Our Intellectual Property

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

We are a party to a number of intellectual property license agreements with third parties and expect to enter into additional license agreements in the future. Our existing license agreements impose, and we expect that any future license agreements will impose, various diligence, milestone payment, royalty, insurance and other obligations on us. If we fail to comply with these obligations, our licensors may have the right to terminate these agreements, in which event we might not be able to develop and market any product that is covered by these agreements. Termination of these licenses or reduction or elimination of our licensed rights may result in our having to negotiate new or reinstated licenses with less favorable terms. The occurrence of such events could materially harm our business.

If our efforts to protect our intellectual property related to abaloparatide-SC, abaloparatide-TD, RAD1901 and/or RAD140 fail to adequately protect these assets or if we are unable to secure all necessary intellectual property, we may lose the ability to license or successfully commercialize one or more of these candidates.

Our commercial success is significantly dependent on intellectual property related to our product portfolio of product candidates. We are either the licensee or assignee of numerous issued and pending patent applications that cover various aspects of our assets, including abaloparatide-SC, abaloparatide-TD, RAD1901 and RAD140.

Patents covering abaloparatide as a composition of matter have been issued in the United States (US Patent No. 5,969,095) and several additional countries. Because the abaloparatide composition of matter patent was filed in 1996, it is expected to have an expiration in 2016 in the United States (this date does not include the possibility of Hatch-Waxman patent term extension, which could extend the expiration in the United States into the first quarter of 2021 if an application for extension is made and the maximum extension is granted by the United States Patent and Trademark Office, USPTO), and additional countries where it has issued. European Patent No. 0847278, which was included in the license from Ipsen and claimed the composition of matter of abaloparatide, lapsed due to Ipsen’s failure to pay annuities. We are pursuing restoration of those patent rights. To date, the patent rights in Finland, France, Germany, the Netherlands, Portugal, Spain, Sweden and United Kingdom have been restored. We believe that the data and market exclusivity provided in Europe for a new chemical entity, coupled with the need for a potential competitor to conduct clinical trials, will likely provide a longer barrier to entry than the patent protection provided by the original European patent term, which would have expired in 2016, plus a five year maximum Supplemental Protection Certificate.

We and Ipsen are also co-assignees to US Patent No. 7,803,770 that we believe provides exclusivity until October 3, 2027 and may be extended to March 26, 2028 in the United States (absent any Hatch-Waxman patent term extension) for the method of treating osteoporosis with the intended therapeutic dose for abaloparatide-SC.

We and Ipsen Pharma SAS, or Ipsen, are also co-assignees to US Patent No. 8,148,333 that we believe provides exclusivity until 2027 in the United States (absent any Hatch-Waxman patent term extension) for the intended therapeutic formulation for abaloparatide-SC.

We and 3M are co-assignees to several foreign and corresponding U.S. patent applications with the earliest priority date of April 22, 2011, which cover various aspects of abaloparatide for microneedle application. Any issued patents resulting from these applications will expire in 2032. However, pending patent applications in the United States and elsewhere may not issue since the interpretation of the legal requirements of patentability in view of claimed inventions are not always predictable. Additional intellectual property covering abaloparatide-TD technology exists in the form of proprietary information protected as trade secrets. These can be accidentally disclosed to, independently derived by or misappropriated by competitors, possibly reducing or eliminating the exclusivity advantages of this form of intellectual property, thereby allowing those competitors more rapid entry into the marketplace with a competitive product thus reducing our advantage with abaloparatide-TD. In addition, trade secrets may in some instances become publicly available through required disclosures in regulatory files. Alternatively, competitors may sometimes reverse engineer a product once it becomes available on the market. Even where a competitor does not use an identical technology for the delivery of abaloparatide, it is possible that they could achieve an equivalent or even superior result using another technology. Such occurrences could lead to either one or more alternative competitor products becoming available on the market and/or one or more generic competitor products on the market gaining market share and causing a corresponding decrease in market share and/or price for abaloparatide-TD even if it were to be successfully developed and approved by FDA.

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Patents covering RAD1901 as a composition of matter, as well as the use of RAD1901 for the treatment of estrogen-dependent breast cancer, have been issued in the United States, Canada, Australia, and Europe, and are pending in India. The RAD1901 composition of matter patents in the United States expire in 2023 and 2026 (absent any Hatch-Waxman patent term extension). One patent has been issued in the United States (the US Patent No. 8,933,130) for treating vasomotor disturbances or hot flashes on January 13, 2015 (statutory term expires on June 22, 2027, and may be extended to October 19, 2031 with 1,580 days of patent term adjustment due to delays in patent prosecution by the USPTO). Additional patent applications relating to methods of treating vasomotor symptoms and clinical dosage strengths using RAD1901 have been filed. Pending patent applications in the United States and elsewhere may not issue since the interpretation of the legal requirements of patentability in view of any claimed invention before a patent office are not always predictable. As a result, we could encounter challenges or difficulties in building, maintaining and/or defending our intellectual property both in the United States and abroad.

Patent applications covering RAD140 and other SARM compounds have been granted in the United States, Europe, Canada, Mexico, Japan and Australia, and are pending in the United States and elsewhere. The RAD140 composition of matter patents expire in 2029 in the United States (absent any Hatch-Waxman patent term extension) and additional countries if and when it issues.

Since patents are technical legal documents that are frequently subject to intense litigation pressure, there is risk that even if one or more patents related to our products does issue and is asserted that the patent(s) will be found invalid, unenforceable and/or not infringed when subject to said litigation. Finally, the intellectual property laws and practices can vary considerably from one country to another and also can change with time. As a result, we could encounter challenges or difficulties in building, maintaining and defending our intellectual property both in the United States and abroad.

We may become party to, or threatened with, future adversarial proceedings or litigation regarding intellectual property rights with respect to patents issued or licensed to us, including interference proceedings before the USPTO. Third parties also may assert infringement claims against us. 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. However, we may not be able to obtain any 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. In addition, we could be found liable for monetary damages. A finding of infringement could prevent us from commercializing our product candidates or force us to cease 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 a provisional patent application filed with the USPTO that could be relevant to the use of RAD1901 to treat indications for which we are developing RAD1901. If a patent issues from this patent application with claims covering the use of RAD1901 to treat indications for which we are developing RAD1901, we may need to license the patent in order to commercialize RAD1901 specifically for the treatment of such indications even if RAD1901 were successfully developed and approved. We cannot assure you that we will be able to secure a license on reasonable terms, if at all. If we need a license of such patent in order to commercialize RAD1901 and are unable to secure one on reasonable terms, our business would be materially harmed.

If we are unable to obtain and maintain patent protection for our technology and products, or if our licensors are unable to obtain and maintain patent protection for the technology or products that we license from them, our competitors could develop and commercialize technology and products similar or identical to ours, and our ability to successfully commercialize our technology and products may be adversely affected.

Our success depends in large part on our and our licensors’ ability to obtain and maintain patent protection in the United States and other countries with respect to our proprietary technology and products. 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 or products that we license from third parties. 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 these patents, or lose rights to those patents, the rights we have licensed may be reduced or eliminated.

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. As a result, the issuance, scope, validity, enforceability and commercial value of our and our licensors’ patent rights are highly uncertain. Our and our licensors’ pending and future patent applications may not result in patents being issued that protect our technology or products or that effectively prevent others from commercializing competitive technologies and products. Changes in either the patent laws or interpretation of the patent laws in the United States and other countries may diminish the value of our patents or narrow the scope of our patent protection. The laws of foreign countries may not protect our rights to the same extent as the laws of the United States. Assuming the other requirements for patentability are met, in the United States, prior to March 16, 2013, the first to make the claimed invention was entitled to the patent (a “first-to-invent” system), while outside the United States, the first to file a patent application is entitled to the patent (a “first-to-file” system). With the implementation of the Leahy-Smith America Invents Act, the United States now has a first-to-file system for patent applications filed on or after March 16, 2013. We may become involved in opposition, interference or derivation proceedings

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challenging our patent rights or the patent rights of others. 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 filing, or in some cases not at all. Therefore, we cannot be certain that we or our licensors were the first to make the inventions claimed in our owned and licensed patents or pending patent applications, or that we or our licensors were the first to file for patent protection of such inventions. An adverse determination in any such proceeding could reduce the scope of, or invalidate our patent rights, allow third parties to commercialize our technology or products and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize products without infringing third-party patent rights.

Even if our owned and licensed patent applications issue as patents, they may not issue in a form that will provide us with any meaningful 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. The issuance of a patent is not conclusive as to its scope, validity or enforceability, and our owned and licensed patents may be challenged in the courts or patent offices in the United States and abroad. Any challenges may result in patent claims being narrowed, invalidated or held unenforceable, which could limit our ability to stop or prevent us from stopping others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our technology and products. 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 approved or commercialized. As a result, our owned and licensed patents may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.

Payments, fees, submissions and various additional requirements must be met in order for pending patent applications to advance in prosecution and issued patents to be maintained. Rigorous compliance with these requirements is essential to procurement and maintenance of patents integral to our product portfolio.

Periodic maintenance fees, renewal fees, annuity fees and various other governmental fees on patents and/or patent applications will come due for payment periodically throughout the lifecycle of patent applications and issued patents. In order to help ensure that we comply with any required fee payment, documentary and/or procedural requirements as they might relate to any patents for which we are an assignee or co-assignee, we employ competent legal help and related professionals as needed to comply with those requirements. Our outside patent counsel uses Computer Packages, Inc. for patent annuity payments. We depend on Eisai and/or Ipsen to comply with any required fee payment, documentary and/or procedural requirements as they might relate to any patents we have licensed from them. Failure to meet a required fee payment, document production or procedural requirement can result in the abandonment of a pending patent application or the lapse of an issued patent. In some instances the defect can be cured through late compliance but there are situations where the failure to meet the required event cannot be cured. Any failures could compromise the intellectual property protection around our preclinical or clinical candidates and possibly weaken or eliminate our ability to protect our eventual market share for that product.

If we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.

In addition to our patented technology and products, we rely on trade secrets, including unpatented know-how, technology and other proprietary information, to maintain our competitive position. We seek to protect these trade secrets, in part, by entering into non-disclosure and confidentiality agreements with parties that have access to our trade secrets, such as our corporate collaborators, outside scientific collaborators, sponsored researchers, contract manufacturers, consultants, advisors and other third parties. We also enter into confidentiality and invention or patent assignment agreements with our employees and consultants. However, any of these parties may breach the agreements and disclose our proprietary information, and we may not be able to obtain adequate remedies for any breaches. Enforcing a claim that a party illegally disclosed or misappropriated a trade secret is difficult, expensive and time-consuming, and the outcome is unpredictable. In addition, 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 have no right to prevent them from using that technology or information to compete with us. If any of our trade secrets were to be disclosed to, or independently developed by a competitor, our competitive position would be harmed.

If we infringe the rights of third parties, we could be prevented from selling products and could be forced to pay damages and defend against litigation.

If our products, methods, processes and other technologies infringe the proprietary rights of other parties, we could incur substantial costs and may have to:

· obtain licenses, which may not be available on commercially reasonable terms, if at all;

· abandon an infringing drug candidate;

· redesign our products or processes to avoid infringement;

· stop using the subject matter claimed in the patents held by others;

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· pay damages; or

· defend litigation or administrative proceedings which may be costly whether we win or lose, which could result in a substantial diversion of our financial and management resources.

We may become involved in lawsuits to protect or enforce our patents, which could be expensive, time consuming and unsuccessful.

Competitors may infringe our patents. To counter infringement or unauthorized use, we may be required to file infringement claims, which can be expensive and time consuming. In addition, in an infringement proceeding, a court may decide that a patent of ours is invalid and/or unenforceable, or may refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question. An adverse result in any litigation proceeding could put one or more of our patents at risk of being invalidated and/or interpreted narrowly. Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation. In addition, our licensors may have rights to file and prosecute these types of claims, and we may be reliant on them to do so.

We may be subject to claims that our employees have wrongfully used or disclosed alleged trade secrets of their former employers.

Some of our employees were previously employed at universities or other biotechnology or pharmaceutical companies, including our competitors or potential competitors. Although we try to ensure that our employees do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that we or these employees have used or disclosed intellectual property, including trade secrets or other proprietary information, of any such employee’s former employer. Litigation may be necessary to defend against these claims. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management.

Intellectual property litigation could cause us to spend substantial resources and distract our personnel from their normal responsibilities.

Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses, and could distract our technical and management personnel from their normal responsibilities, delaying the development of our product candidates. In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments, and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock. Litigation or other proceedings could substantially increase our operating losses and reduce our resources available for development activities. We may not have sufficient financial or other resources to adequately conduct any litigation or proceedings. Some of our competitors may be able to sustain the costs of any litigation or proceedings more effectively than we can because of their substantially greater financial resources. Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could have a material adverse effect on our ability to compete in the marketplace.

Risks Related to Legislation and Administrative Actions

Healthcare reform may have a material adverse effect on our industry and our results of operations.

From time to time, legislation is implemented to reign in rising healthcare expenditures. In March 2010, President Obama signed into law the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or PPACA. PPACA includes a number of provisions affecting the pharmaceutical industry, including annual, non-deductible fees on any entity that manufactures or imports some types of branded prescription drugs and biologics and increases in Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program. In addition, among other things, PPACA also establishes a new Patient-Centered Outcomes Research Institute to oversee, identify priorities and conduct comparative clinical effectiveness research. In addition, other legislative changes have been proposed and adopted since PPACA was enacted. The full impact on our business of these new laws is uncertain. We cannot predict whether other legislative changes will be adopted, if any, or how such changes would affect the pharmaceutical industry generally or our business in particular.

We are subject to healthcare laws, regulation and enforcement, and our failure to comply with those laws could have a material adverse effect on our results of operations and financial conditions.

We are subject to several healthcare regulations and enforcement by the federal government and the states and foreign governments in which we conduct our business. The laws that may affect our ability to operate include:

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· the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of various electronic healthcare transactions and protects the security and privacy of protected health information;

· the federal healthcare programs’ Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, in exchange for or to induce either the referral of an individual for, or the purchase, order or recommendation of, any good or service for which payment may be made under federal healthcare programs such as the Medicare and Medicaid programs. A person or entity does not need to have actual knowledge of the federal Anti-Kickback Statute or specific intent to violate it to have committed a violation; in addition, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the False Claims Act;

· federal false claims laws, which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid, or other third-party payers that are false or fraudulent;

· federal criminal laws that prohibit executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters. Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the federal Anti-Kickback Statute or specific intent to violate it to have committed a violation;

· the federal Physician Payment Sunshine Act, or the Sunshine Act, requires applicable manufacturers of covered drugs to report payments and other transfers of value to physicians and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members. Data from the first reporting period, which began in August 2013, is now publicly available. Manufacturers will be required to submit subsequent reports to the government by the 90 th day of each calendar year; and

· state law equivalents of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items or services reimbursed by any third-party payer, including commercial insurers; state laws that require pharmaceutical companies to comply with the industry’s voluntary compliance guidelines and the applicable compliance guidance promulgated by the federal government or otherwise restrict payments that may be made to healthcare providers and other potential referral sources; state laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures; and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

Our operations and future commercial activities in connection with any product candidate that is approved will be subject to comprehensive compliance obligations under state and federal fraud and abuse, false claims, physician payment transparency laws and government pricing regulations, as described above. If we are found to be in violation of these regulations, we may be subject to penalties, including civil and criminal penalties, damages, fines, the curtailment or restructuring of our operations, the exclusion from participation in federal and state healthcare programs and imprisonment, any of which could adversely affect our ability to operate our business and our financial results.

We may be exposed to liability claims associated with the use of hazardous materials and chemicals.

Our research and development activities may involve the controlled use of hazardous materials and chemicals. Although we believe that our safety procedures for using, storing, handling and disposing of these materials comply with federal, state and local laws and regulations, we cannot completely eliminate the risk of accidental injury or contamination from these materials. In the event of such an accident, we could be held liable for any resulting damages and any liability could materially adversely affect our business, financial condition and results of operations. In addition, the federal, state and local laws and regulations governing the use, manufacture, storage, handling and disposal of hazardous or radioactive materials and waste products may require us to incur substantial compliance costs that could materially adversely affect our business, financial condition and results of operations.

Risks Related to Employee Matters and Managing Growth

As we evolve from a company primarily involved in drug discovery and development into one that is also involved in the commercialization of pharmaceutical products, we may have difficulty managing our growth and expanding our operations successfully.

Our success will depend upon the expansion of our operations and the effective management of our growth, and if we are unable to manage this growth effectively, our business will be harmed. As we advance our product candidates through the development process,

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we will need to expand our development, regulatory, manufacturing, quality, distribution, sales and marketing capabilities or contract with other organizations to provide these capabilities for us. As our operations expand, we expect that we will need to manage additional relationships with various collaborators, suppliers and other organizations. Our ability to manage our operations and growth requires us to continue to improve our operational, financial and management controls, reporting systems and procedures. For example, some jurisdictions, such as the District of Columbia, have imposed licensing requirements for sales representatives. In addition, the District of Columbia and the Commonwealth of Massachusetts, as well as the federal government by way of the Sunshine Act, have established reporting requirements that would require public reporting of compensation and other “transfers of value” paid to health care professionals and teaching hospitals, as well as ownership and investment interests held by such professionals and their immediate family members. Because the reporting requirements vary in each jurisdiction, compliance will be complex and expensive and may create barriers to entering the commercialization phase. The need to build new systems as part of our growth could place a strain on our administrative and operational infrastructure. We may not be able to make improvements to our management information and control systems in an efficient or timely manner and may discover deficiencies in existing systems and controls. Such requirements may also impact our opportunities to collaborate with physicians at academic research centers as new restrictions on academic-industry relationships are put in place. In the past, collaborations between academia and industry have led to important new innovations, but the new laws may have an effect on these activities. While we cannot predict whether any legislative or regulatory changes will have negative or positive effects, they could have a material adverse effect on our business, financial condition and potential profitability.

We may enter into or seek to enter into business combinations and acquisitions which may be difficult to integrate, disrupt our business, divert management attention or dilute stockholder value.

We may enter into business combinations and acquisitions. We have limited experience in making acquisitions, which are typically accompanied by a number of risks, including:

· the difficulty of integrating the operations and personnel of the acquired companies;

· the potential disruption of our ongoing business and distraction of management;

· the potential for unknown liabilities and expenses;

· the failure to achieve the expected benefits of the combination or acquisition;

· the maintenance of acceptable standards, controls, procedures and policies; and

· the impairment of relationships with employees as a result of any integration of new management and other personnel.

If we are not successful in completing acquisitions that we may pursue in the future, we would be required to reevaluate our business strategy and we may have incurred substantial expenses and devoted significant management time and resources in seeking to complete the acquisitions. In addition, we could use substantial portions of our available cash as all or a portion of the purchase price, or we could issue additional securities as consideration for these acquisitions, which could cause our stockholders to suffer significant dilution.

We rely on key executive officers and scientific and medical advisors, and their knowledge of our business and technical expertise would be difficult to replace.

We are highly dependent on our chief executive officer and our principal scientific, regulatory and medical advisors. We do not have “key person” life insurance policies for any of our officers. The loss of the technical knowledge and management and industry expertise of any of our key personnel could result in delays in product development, loss of customers and sales and diversion of management resources, which could adversely affect our operating results.

If we are unable to hire additional qualified personnel, our ability to grow our business may be harmed.

We will need to hire additional qualified personnel with expertise in preclinical testing, clinical research and testing, government regulation, formulation and manufacturing and sales and marketing. We compete for qualified individuals with numerous biopharmaceutical companies, universities and other research institutions. Competition for such individuals is intense, and we cannot be certain that our search for such personnel will be successful. Attracting and retaining qualified personnel will be critical to our success.

Risks Relating to Our Securities

Our stock price may be volatile, and the value of an investment in our common stock may decline.

The trading price of our common stock may be subject to wide fluctuations in response to various factors, some of which are beyond our control, including:

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

· our operating performance and the operating performance of similar companies;

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· the success of competitive products;

· the overall performance of the equity markets;

· the number of shares of our common stock publicly owned and available for trading;

· threatened or actual litigation;

· changes in laws or regulations relating to our products, including changes in the structure of healthcare payment systems;

· any major change in our board of directors or management;

· publication of research reports about us or our industry or positive or negative recommendations or withdrawal of research coverage by securities analysts;

· large volumes of sales of our shares of common stock by existing stockholders;

· general political, economic and market conditions; and

· the other factors described in this “Risk Factors” section.

In addition, the stock market in general has experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of the companies whose shares trade in the stock market. These fluctuations may be even more pronounced in the trading market for our stock shortly following the initial public offering. Securities class action litigation has often been instituted against companies following periods of volatility in the overall market and in the market price of a company’s securities. Such litigation, if instituted against us, could result in very substantial costs, divert our management’s attention and resources and harm our business, operating results and financial condition.

Because we do not anticipate paying any cash dividends on our common stock in the foreseeable future, capital appreciation, if any, will be your sole source of gain.

We have never declared or paid cash dividends on our common stock. We currently intend to retain all of our future earnings, if any, to finance the growth and development of our business. In addition, the terms of our credit facility preclude us from paying cash dividends. As a result, capital appreciation, if any, of our common stock will be your sole source of gain for the foreseeable future.

We have incurred and will continue to incur increased costs as a result of operating as a public company, and our management is required to devote substantial time to new compliance initiatives.

As a public company listed on the NASDAQ Global Market, we have incurred and will continue to incur significant legal, accounting and other expenses that we did not incur as a private company and prior to the listing of our common stock on the NASDAQ Global Market. In addition, the Sarbanes-Oxley Act of 2002 and rules subsequently implemented by the Securities and Exchange Commission, or the SEC, and NASDAQ have imposed various requirements on public companies, including establishment and maintenance of effective disclosure and financial controls and corporate governance practices. Our management and other personnel will need to devote a substantial amount of time to these compliance initiatives. Moreover, these rules and regulations have increased our legal and financial compliance costs and are making some activities more time-consuming and costly.

Pursuant to Section 404 of the Sarbanes-Oxley Act of 2002, or Section 404, we are required to furnish a report by our management on our internal control over financial reporting, and are required to include an attestation report on internal control over financial reporting issued by our independent registered public accounting firm. If we are unable to maintain effective internal controls, we may not have adequate, accurate or timely financial information, and we may be unable to meet our reporting obligations as a publicly traded company or comply with the requirements of the SEC or Section 404. This could result in a restatement of our financial statements, the imposition of sanctions, including the inability of registered broker dealers to make a market in our common shares, or investigation by regulatory authorities. Any such action or other negative results caused by our inability to meet our reporting requirements or comply with legal and regulatory requirements or by disclosure of an accounting, reporting or control issue could adversely affect the trading price of our securities and our business. Material weaknesses in our internal control over financial reporting could also reduce our ability to obtain financing or could increase the cost of any financing we obtain.

Our directors and executive officers, together with their affiliates, have substantial influence over us and could delay or prevent a change in corporate control.

Our directors and executive officers, together with their affiliates, beneficially own a significant portion of our outstanding common stock. As a result, these stockholders, acting together, would have the ability to significantly influence the outcome of matters submitted to our stockholders for approval, including the election of directors and any merger, consolidation or sale of all or substantially all of our assets. In addition, these stockholders, acting together, would have the ability to significantly influence the management and affairs of our company. Accordingly, this concentration of ownership might harm the market price of our common stock by:

· delaying, deferring or preventing a change in corporate control;

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· impeding a merger, consolidation, takeover or other business combination involving us; or

· discouraging a potential acquirer from making a tender offer or otherwise attempting to obtain control of us.

Future sales and issuances of our common stock or rights to purchase common stock, including pursuant to our equity incentive plans, could result in additional dilution of the percentage ownership of our stockholders and could cause our stock price to fall.

Additional capital will be needed in the future to continue our planned operations. To the extent we raise additional capital by issuing equity securities, our stockholders may experience substantial dilution. We may sell common stock, convertible securities or other equity securities in one or more transactions at prices and in a manner we determine from time to time. If we sell common stock, convertible securities or other equity securities in more than one transaction, investors may be materially diluted by subsequent sales. These sales may also result in material dilution to our existing stockholders, and new investors could gain rights superior to our existing stockholders.

Pursuant to our equity incentive plans, our management is authorized to grant stock options and other equity-based awards to our employees, directors and consultants. We have reserved 4,559,510 shares of our common stock for issuance under our equity incentive plans as of March 31, 2015, which includes 3,625,200 shares of common stock issuable upon the exercise of options outstanding as of March 31, 2015, and will become eligible for sale in the public market in the future, subject to certain legal and contractual limitations. In addition, as of March 31, 2015, warrants to purchase 848,616 shares of our common stock were outstanding. Shares of our common stock issued upon exercise of these warrants may be sold in the public market, subject to prior registration, or under an exemption from registration. If any of these additional shares are sold, or if it is perceived that they will be sold, the price of our common stock could decline substantially.

If securities or industry analysts cease to publish research or publish inaccurate or unfavorable research about our business, our stock price and trading volume could decline.

The trading market for our common stock depends in part on the research and reports that securities or industry analysts publish about us or our business. If one or more of the analysts who cover us downgrade our stock or publish inaccurate or unfavorable research about our business, our stock price would likely decline. If one or more of these analysts cease coverage of our company or fail to publish reports on us regularly, demand for our stock could decrease, which might cause our stock price and trading volume to decline.

Anti-takeover provisions contained in our restated certificate of incorporation and amended and restated bylaws, as well as provisions of Delaware law, could impair a takeover attempt.

Our restated certificate of incorporation and our amended and restated bylaws contain provisions that could delay or prevent a change in control of our company. These provisions could also make it more difficult for stockholders to elect directors and take other corporate actions. These provisions include:

· a staggered board of directors;

· authorizing the board to issue, without stockholder approval, preferred stock with rights senior to those of our common stock;

· authorizing the board to amend our bylaws and to fill board vacancies until the next annual meeting of the stockholders;

· prohibiting stockholder action by written consent;

· limiting the liability of, and providing indemnification to, our directors and officers;

· eliminating the ability of our stockholders to call special meetings; and

· requiring advance notification of stockholder nominations and proposals.

Section 203 of the Delaware General Corporation Law, or DGCL, prohibits, subject to some exceptions, “business combinations” between a Delaware corporation and an “interested stockholder,” which is generally defined as a stockholder who becomes a beneficial owner of 15% or more of a Delaware corporation’s voting stock, for a three-year period following the date that the stockholder became an interested stockholder.

These and other provisions in our restated certificate of incorporation and our amended and restated bylaws under Delaware law could discourage potential takeover attempts, reduce the price that investors might be willing to pay in the future for shares of our common stock and result in the market price of our common stock being lower than it would be without these provisions.

Our ability to utilize our net operating loss carryforwards and certain other tax attributes may be limited.

As of December 31, 2014, we had $319.7 million of federal and $246.5 million of state net operating loss carryforwards available to offset future taxable income. Under Section 382 of the Internal Revenue Code of 1986, as amended, or the Code, if a corporation

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undergoes an “ownership change” (generally defined as a greater than 50% change (by value) in its equity ownership over a three year period), the corporation’s ability to use its pre-change net operating loss carryforwards and other pre-change tax attributes to offset its post-change income may be limited. We have not performed a detailed analysis to determine whether an ownership change under Section 382 of the Code has previously occurred. As a result, if we earn net taxable income, our ability to use our pre-change net operating loss carryforwards to offset U.S. federal taxable income may become subject to limitations, which could potentially result in increased future tax liability to us.

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

Use of Proceeds from Public Offering of Common Stock

On June 5, 2014, the Securities and Exchange Commission, or SEC, declared effective our Registration Statement on Form S-1 (File No. 333-194150), as amended, or Registration Statement, filed in connection with the initial public offering of our common stock. Pursuant to the Registration Statement, we registered the offer and sale of 7,475,000 shares of common stock with an aggregate offering price of approximately $59.8 million.

There has been no material change in the expected use of the net proceeds from our initial public offering as described in our final prospectus, dated June 5, 2014, filed with the SEC pursuant to Rule 424(b) relating to our Registration Statement.

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.

The following is an index of the exhibits included in this report:

Incorporated by Reference

Filed/

Exhibit
Number

Exhibit Description

Form

File No.

Exhibit

Filing
Date

Furnished
Herewith

3.1

Restated Certificate of Incorporation, filed on June 11, 2014

8-K

001-35726

3.1

6/13/14

3.2

Amended and Restated By-Laws

8-K

001-35726

3.2

6/13/14

10.1

Second Amendment to Loan and Security Agreement, dated February 13, 2015, by and among the Company, Solar Capital Ltd., and Oxford Finance LLC

10.2

Third Amendment to Loan and Security Agreement, dated April 8, 2015, by and among the Company, Solar Capital Ltd., and Oxford Finance LLC

10.3†

License Agreement Amendment No. 1, dated March 9, 2015, by and between the Company and Eisai Co., Ltd.

10.4

Amendment No. 9 to Work Statement NB-1, effective as of March 12, 2015, by and between the Company and Nordic Bioscience Clinical Development VII A/S

10.5

Amendment No. 2 to Work Statement NB-3, effective as of March 23, 2015, by and between the Company and Nordic Bioscience Clinical Development VII A/S

10.6

Change Order Form #22, dated March 2, 2015, to the Development and Clinical Supplies Agreement, dated June 19, 2009, by and among the Company and 3M Co. and 3M Innovative Properties Co.

10-K

001-35716

10.18

3/10/15

10.7

Work Order #7, dated February 24, 2015, to the Development and Manufacturing Agreement, dated October 16, 2007, by and between the Company, as successor to Radius Health, Inc., and LONZA Sales Ltd.

10-K

001-35716

10.17

3/10/15

31.1

Certification of Chief Executive Officer pursuant to Exchange Act Rule 13a-14(a)/15d-14(a)

31.2

Certification of Chief Financial Officer pursuant to Exchange Act Rule 13a-14(a)/15d-

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14(a)

32.1

Certification of Chief Executive Officer and Chief Financial Officer Pursuant to 18 U.S.C. Section 1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002

101.INS

XBRL Instance Document

101.SCH

XBRL Taxonomy Extension Schema Document

101.CAL

XBRL Taxonomy Extension Calculation Linkbase Document

101.DEF

XBRL Taxonomy Extension Definition Linkbase Document

101.LAB

XBRL Taxonomy Extension Label Linkbase Document

101.PRE

XBRL Taxonomy Extension Presentation Linkbase Document

* Filed herewith.

** Furnished herewith.

† Confidential treatment has been requested with respect to certain portions of this exhibit, which portions have been filed separately with the Securities and Exchange Commission.

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SIGNATURES

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

	RADIUS HEALTH, INC.

	By:	/s/ Robert E. Ward
		Robert E. Ward
		President and Chief Executive Officer
		(Principal Executive Officer)

Date: May 6, 2015


	By:	/s/ B. Nicholas Harvey
		B. Nicholas Harvey
		Chief Financial Officer
		(Principal Accounting and Financial Officer)

Date: May 6, 2015

Exhibit 10.1

Execution Version

SECOND AMENDMENT TO LOAN AND SECURITY AGREEMENT

THIS SECOND AMENDMENT TO LOAN AND SECURITY AGREEMENT (this “ Amendment ”), dated as of February 13, 2015, is made among Radius Health, Inc., a Delaware corporation (the “ Borrower ”), Solar Capital Ltd., a Maryland corporation, in its capacity as collateral agent (in such capacity, “ Collateral Agent ”) and as a lender, and Oxford Finance LLC, a Delaware limited liability company (each a “ Lender ” and, collectively, the “ Lenders ”).

The Borrower, the Lenders and the Collateral Agent are parties to a Loan and Security Agreement dated as of May 30, 2014, as amended by that certain First Amendment to Loan and Security Agreement dated July 10, 2014 (as the same may be amended, restated, supplemented, or otherwise modified from time to time, the “ Loan and Security Agreement ”). The Borrower and Lenders agree to certain amendments to the Loan and Security Agreement, subject to the terms and conditions hereof.

Accordingly, the parties hereto agree as follows:

SECTION 1 Definitions; Interpretation.

(a) Terms Defined in Loan and Security Agreement . All capitalized terms used in this Amendment (including in the recitals hereof) and not otherwise defined herein shall have the meanings assigned to them in the Loan and Security Agreement.

(b) Interpretation . The rules of interpretation set forth in Section 1.1 of the Loan and Security Agreement shall be applicable to this Amendment and are incorporated herein by this reference.

SECTION 2 Amendments to the Loan and Security Agreement.

(a) Amendments . The Loan and Security Agreement shall be amended as follows, upon satisfaction of the conditions set forth in Section 3 (such date being the “ Second Amendment Effective Date ”, which shall be deemed to have occurred on the date hereof):

Section 1.3. The table in Section 1.3 is amended by adding “Notice of Resumption/ Section 6.2(d)” in its proper alphabetical position.

Section 6.2(a). Section 6.2(a) is hereby amended by inserting the following language immediately prior to the lead in thereof “Subject to Section 6.2(d),”.

Section 6.2(d). A new Section 6.2(d) is hereby inserted to read as follows:

Notwithstanding anything to the contrary herein, commencing as of February 13, 2015, Borrower shall not deliver any items, notices or other materials under Section 6.2 or any other provision of this Agreement to Collateral Agent or any Lender until the Collateral Agent or such Lender has requested the resumption of deliveries of such items, notice or materials by providing Borrower with thirty (30) days’ prior written notice that such Person will require that Borrower resume delivery of all items, notices or materials that are otherwise required to be delivered pursuant to the terms of this Agreement (a “Notice of Resumption”). Any Notice of Resumption shall be applicable only to the Person providing such Notice of Resumption, and Borrower shall not provide any such items, notices or materials to the Collateral Agent or a Lender if such Person has not provided a Notice of Resumption. Within thirty (30) days of receipt of a Notice of Resumption by the Borrower: (1) the

Borrower shall provide to the Person that sent such Notice of Resumption an updated Perfection Certificate and Disclosure Schedules as of such date to reflect any amendments, modifications and updates; (2) the Borrower shall provide to the Person that sent such Notice of Resumption copies of all Compliance Certificates, notices and other information that would have otherwise been required to be delivered absent this Section 6.2(d); and (3) Borrower’s obligation to deliver all future items, notices or other materials required under Section 6.2 or any other provision of this Agreement shall be fully reinstated in respect of the Person providing the Notice of Resumption and this Section 6.2(d) shall no longer be applicable with respect to such Person.

(b) References Within Loan and Security Agreement . Each reference in the Loan and Security Agreement to “this Agreement” and the words “hereof,” “herein,” “hereunder,” or words of like import, shall mean and be a reference to the Loan and Security Agreement as amended by this Amendment.

SECTION 3 Conditions of Effectiveness. The effectiveness of Section 2 of this Amendment shall be subject to the satisfaction of each of the following conditions precedent:

(a) This Amendment . The Collateral Agent shall have received this Amendment, executed by the Lenders and the Borrower.

(b) Representations and Warranties; No Default . On the Second Amendment Effective Date, after giving effect to the amendment of the Loan and Security Agreement contemplated hereby:

(i) The representations and warranties contained in Section 4 shall be true and correct on and as of the Second Amendment Effective Date as though made on and as of such date; and

(ii) There exists no Events of Default or events that with the passage of time would result in an Event of Default.

SECTION 4 Representations and Warranties . The Borrower hereby confirms, as of the date hereof, that the representations and warranties made by it in Section 5 of the Loan and Security Agreement and in the other Loan Documents are true and correct in all material respects; provided , however , that such materiality qualifier shall not be applicable to any representations and warranties that already are qualified or modified by materiality in the text thereof. For the purposes of this Section 4, (i) each reference in Section 5 of the Loan and Security Agreement to “this Agreement,” and the words “hereof,” “herein,” “hereunder,” or words of like import in such Section, shall mean and be a reference to the Loan and Security Agreement as amended by this Amendment, and (ii) any representations and warranties which relate solely to an earlier date shall not be deemed confirmed and restated as of the date hereof (provided that such representations and warranties shall be true, correct and complete as of such earlier date).

SECTION 5 Miscellaneous.

(a) Loan Documents Otherwise Not Affected . Except as expressly amended pursuant hereto, the Loan and Security Agreement and the other Loan Documents shall remain unchanged and in full force and effect and are hereby ratified and confirmed in all respects. The Lenders’ and the Collateral Agent’s execution and delivery of, or acceptance of, this Amendment shall not be deemed to create a course of dealing or otherwise create any express or implied duty by any of them to provide any other or further amendments, consents or waivers in the future.

(b) Conditions . For purposes of determining compliance with the conditions specified in Section 3, each Lender that has signed this Amendment shall be deemed to have consented to, approved or accepted or to be satisfied with, each document or other matter required thereunder to be consented to or approved by or acceptable or satisfactory to a Lender unless the Collateral Agent shall have received notice from such Lender prior to the Second Amendment Effective Date specifying its objection thereto.

(c) No Reliance . The Borrower hereby acknowledges and confirms to the Collateral Agent and the Lenders that the Borrower is executing this Amendment on the basis of its own investigation and for its own reasons without reliance upon any agreement, representation, understanding or communication by or on behalf of any other Person.

(d) Costs and Expenses . The Borrower agrees to pay to the Collateral Agent on demand the reasonable out-of-pocket costs and expenses of the Collateral Agent and the Lenders party hereto, and the reasonable fees and disbursements of counsel to the Collateral Agent and the Lenders party hereto (including allocated costs of internal counsel), in connection with the negotiation, preparation, execution and delivery of this Amendment and any other documents to be delivered in connection herewith.

(e) Binding Effect . This Amendment binds and is for the benefit of the successors and permitted assigns of each party.

(f) Governing Law . THIS AMENDMENT AND THE RIGHTS AND OBLIGATIONS OF THE PARTIES HEREUNDER AND THEREUNDER SHALL IN ALL RESPECTS BE GOVERNED BY AND CONSTRUED IN ACCORDANCE WITH, THE INTERNAL LAWS OF THE STATE OF NEW YORK (WITHOUT REGARD TO THE CONFLICT OF LAWS PRINCIPLES OF SUCH STATE), INCLUDING ALL MATTERS OF CONSTRUCTION, VALIDITY AND PERFORMANCE, REGARDLESS OF THE LOCATION OF THE COLLATERAL.

(g) Complete Agreement; Amendments . This Amendment and the Loan Documents represent the entire agreement about this subject matter and supersede prior negotiations or agreements with respect to such subject matter. All prior agreements, understandings, representations, warranties, and negotiations between the parties about the subject matter of this Amendment and the Loan Documents merge into this Agreement and the Loan Documents.

(h) Severability of Provisions. Each provision of this Amendment is severable from every other provision in determining the enforceability of any provision.

(i) Counterparts . This Amendment may be executed in any number of counterparts and by different parties on separate counterparts, each of which, when executed and delivered, is an original, and all taken together, constitute one Agreement.

(j) Loan Documents . This Amendment shall constitute a Loan Document.

[Balance of Page Intentionally Left Blank; Signature Pages Follow]

IN WITNESS WHEREOF, the parties hereto have duly executed this Amendment, as of the date first above written.

	BORROWER:

	RADIUS HEALTH, INC.
	as Borrower


	By:	/s/ B. Nicholas Harvey
	Title:	Chief Financial Officer


	COLLATERAL AGENT AND LENDERS:

	SOLAR CAPITAL LTD. ,
	as Collateral Agent and a Lender


	By:	/s/ Anthony J. Storino
	Name:	Anthony J. Storino
	Title:	Authorized Signatory


	OXFORD FINANCE LLC ,
	as a Lender


	By	/s/ Mark Davis
	Name:	Mark Davis
	Title:	Vice President of Finance

Exhibit 10.2

Execution Copy

THIRD AMENDMENT TO LOAN AND SECURITY AGREEMENT

THIS THIRD AMENDMENT TO LOAN AND SECURITY AGREEMENT (this “ Amendment ”), dated as of April 8, 2015, is made among Radius Health, Inc., a Delaware corporation (the “ Borrower ”), Solar Capital Ltd., a Maryland corporation, in its capacity as collateral agent (in such capacity, “ Collateral Agent ”) and as a lender, and Oxford Finance LLC, a Delaware limited liability company (each a “ Lender ” and, collectively, the “ Lenders ”).

The Borrower, the Lenders and the Collateral Agent are parties to a Loan and Security Agreement dated as of May 30, 2014, as amended by that certain First Amendment to Loan and Security Agreement dated July 10, 2014 and Second Amendment to Loan and Security Agreement dated February 13, 2015 (as the same may be amended, restated, supplemented, or otherwise modified from time to time, the “ Loan and Security Agreement ”). The Borrower and Lenders agree to certain amendments to the Loan and Security Agreement, subject to the terms and conditions hereof.

Accordingly, the parties hereto agree as follows:

SECTION 1 Definitions; Interpretation.

(b) Interpretation . The rules of interpretation set forth in Section 1.1 of the Loan and Security Agreement shall be applicable to this Amendment and are incorporated herein by this reference.

SECTION 2 Amendments to the Loan and Security Agreement.

Amendments . The Loan and Security Agreement shall be amended as follows, upon satisfaction of the conditions set forth in Section 3 (such date being the “ Third Amendment Effective Date ”, which shall be deemed to have occurred on the date hereof):

(a) Section 1.3 . The cross-reference for the definition of “Notice of Resumption” is hereby amended to be Section 6.2(e).

(b) Section 6.2(a) . The lead in to Section 6.2(a) is hereby amended and restated in its entirety as follows:

“(a) Subject to Section 6.2(e), deliver to Collateral Agent and each Lender:”

“(i) as soon as available, but no later than forty five (45) days after the last day of each quarter, a company prepared consolidated and, if prepared by Borrower or if reasonably requested by the Lenders, consolidating balance sheet, income statement and cash flow statement covering the consolidated operations of Borrower and its consolidated Subsidiaries for such quarter certified by a Responsible Officer and in a form reasonably acceptable to the Collateral Agent and the Lenders;”

(d) Section 6.2(b) . Section 6.2(b) is hereby amended and restated in its entirety as follows:

“(b) Subject to Section 6.2(e), concurrently with the delivery of the financial statements specified in Section 6.2(a)(i) above (if applicable) but no later than forty five (45) days after the last day of each month, deliver to Collateral Agent and each Lender:

(i) written notice of the commencement of, and any material development in, the proceedings contemplated by Section 5.8 hereof; and

(i) written notice of any litigation or governmental proceedings pending or threatened (in writing) against Borrower or any of its Subsidiaries, which could reasonably be expected to result in damages or costs to Borrower or any of its Subsidiaries of Two Hundred Fifty Thousand Dollars ($250,000.00).”

(e) Section 6.2(d) . Section 6.2(d) is hereby amended and restated in its entirety as follows:

“(d) Subject to Section 6.2(e), concurrently with the delivery of the financial statements specified in Section 6.2(a)(i) above but no later than forty five (45) days after the last day of each quarter, deliver to Collateral Agent and each Lender:

(i) an updated Perfection Certificate and Disclosure Schedules to reflect any amendments, modifications and updates, if any, to certain information in the Perfection Certificate and Disclosure Schedule;

(ii) a duly completed Compliance Certificate signed by a Responsible Officer;

(iii) copies of any material Governmental Approvals obtained by Borrower or any of its Subsidiaries; and

(iv) written notice of all returns, recoveries, disputes and claims regarding Inventory that involve more than Two Hundred Fifty Thousand Dollars ($250,000.00) individually or in the aggregate in any calendar year.”

(f) Section 6.2(e) . A new Section 6.2(e) is hereby inserted to read as follows:

“(e) Notwithstanding anything to the contrary herein, commencing as of February 13, 2015, Borrower shall not deliver any items, notices or other materials under Section 6.2 or any other provision of this Agreement to Collateral Agent or any Lender until the Collateral Agent or such Lender has requested the resumption of deliveries of such items, notice or materials by providing Borrower with thirty (30) days’ prior written notice that such Person will require that Borrower resume delivery of all items, notices or materials that are otherwise required to be delivered pursuant to the terms of this Agreement (a “Notice of Resumption”). Any Notice of Resumption shall be applicable only to the Person providing such Notice of Resumption, and Borrower shall not provide any such items, notices or materials to the Collateral Agent or a Lender if such Person has not provided a Notice of Resumption. Within thirty (30) days of receipt of a Notice of Resumption by the Borrower: (1) the Borrower shall provide to the Person that sent such Notice of Resumption an updated Perfection Certificate and Disclosure Schedules as of such date to reflect any amendments,

modifications and updates; (2) the Borrower shall provide to the Person that sent such Notice of Resumption copies of all Compliance Certificates, notices and other information that would have otherwise been required to be delivered absent this Section 6.2(e); and (3) Borrower’s obligation to deliver all future items, notices or other materials required under Section 6.2 or any other provision of this Agreement shall be fully reinstated in respect of the Person providing the Notice of Resumption and this Section 6.2(e) shall no longer be applicable with respect to such Person.”

(g) Exhibit D . The Compliance Certificate is hereby amended by replacing each instance of the word “monthly” with the word “quarterly”.

(h) References Within Loan and Security Agreement . Each reference in the Loan and Security Agreement to “this Agreement” and the words “hereof,” “herein,” “hereunder,” or words of like import, shall mean and be a reference to the Loan and Security Agreement as amended by this Amendment.

SECTION 3 Conditions of Effectiveness. The effectiveness of Section 2 of this Amendment shall be subject to the satisfaction of each of the following conditions precedent:

(a) This Amendment . The Collateral Agent shall have received this Amendment, executed by the Lenders and the Borrower.

(b) Representations and Warranties; No Default . On the Third Amendment Effective Date, after giving effect to the amendment of the Loan and Security Agreement contemplated hereby:

(i) The representations and warranties contained in Section 4 shall be true and correct on and as of the Third Amendment Effective Date as though made on and as of such date; and

(ii) There exists no Events of Default or events that with the passage of time would result in an Event of Default.

SECTION 5 Miscellaneous.

satisfactory to a Lender unless the Collateral Agent shall have received notice from such Lender prior to the Third Amendment Effective Date specifying its objection thereto.

(e) Binding Effect . This Amendment binds and is for the benefit of the successors and permitted assigns of each party.

(h) Severability of Provisions. Each provision of this Amendment is severable from every other provision in determining the enforceability of any provision.

(j) Loan Documents . This Amendment shall constitute a Loan Document.

[Balance of Page Intentionally Left Blank; Signature Pages Follow]

IN WITNESS WHEREOF, the parties hereto have duly executed this Amendment, as of the date first above written.

	BORROWER:

	RADIUS HEALTH, INC.
	as Borrower


	By:	/s/ B. Nicholas Harvey
	Title:	Chief Financial Officer


	COLLATERAL AGENT AND LENDERS:

	SOLAR CAPITAL LTD. ,
	as Collateral Agent and a Lender


	By:	/s/ Anthony J. Storino
	Name:	Anthony J. Storino
	Title:	Authorized Signatory


	OXFORD FINANCE LLC ,
	as a Lender


	By	/s/ Mark Davis
	Name:	Mark Davis
	Title:	Vice President - Finance, Secretary & Treasurer

Exhibit 10.3

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

LICENSE AGREEMENT AMENDMENT NO. 1

Eisai Co., Ltd., a corporation organized and existing under the laws of Japan, with its registered office at 6-10 Koishikawa 4-chome, Bunkyo-ku, Tokyo, 112-8088, Japan (“Eisai”) and Radius Health, Inc., with its registered office at 950 Winter Street, Waltham. MA 02451, U.S.A. (“Radius”) entered into the certain License Agreement effective as of June 29, 2006 (respectively, the “Agreement” and the “Effective Date”).

Pursuant to Article 16.1 of the Agreement, the Parties wish to enter into this Amendment No. 1 to the Agreement (“Amendment No. 1”) effective as of February 26, 2015 (the “Amendment Date”). Capitalized terms used in this Amendment No. 1 and not defined herein are used with the meanings ascribed to them in the Agreement.

NOW THEREFORE, in consideration of the mutual covenants and promises contained in this Amendment No. 1, the Parties agree as follows:

1. Defined Terms. Article 1.17 of the Agreement is hereby amended to read in full as follows:

“1.17 “Territory” shall mean all the countries of the world.”

2. Scope of Licenses.

(a) Article 2.1 of the Agreement is hereby amended to read in full as follows:

“2.1 Eisai hereby grants Radius, an exclusive license, under Eisai Patents and Eisai Know-How and Eisai’s undivided interest in Joint Patents, during the term of this Agreement, within the Territory, to research, Develop (to the extent permitted in this Agreement), have Developed, make, have made, use, promote, market, distribute, offer for sale, sell, have sold, import, export and otherwise commercialize the Compound and/or Product. If Radius indicates that it wishes to Develop Combination Product, Radius shall have prior written approval of Eisai, which shall not be unreasonably withheld. The license under this Article 2.1 includes the right to grant sublicenses (without the right of such sublicensees to grant further sublicenses); provided that: (a) with respect to any sublicensee (excluding any contract research organization, contract manufacturer or other contractor of Radius granted rights solely for use on behalf of Radius) of the rights to research, Develop, have Developed, make, have made, use, promote, market, distribute, offer for sale, sell, have sold, import, export or otherwise commercialize the Product, Radius shall have prior written approval of Eisai before granting such sublicense which approval shall not be unreasonably withheld, or delayed with such determination being made with reference to the following criteria with respect to the sublicensee: (1) whether such sublicensee has the financial resources to assume the obligations of Radius with respect to the rights that are the subject of the sublicense; and (2) whether such sublicensee has personnel with skill and experience adequate to perform the obligations of Radius that are the subject of the sublicense. It is understood and agreed that Eisai may withhold such approval if such sublicensee has any material and active litigations with Eisai. Eisai shall have twenty (20) business days to notify Radius whether it is granting or withholding its approval after Radius submits the identity of the proposed sublicensee and a summary of the material terms of the proposed sublicense agreement to Eisai, and if Eisai does not provide such notice within such 20-business day period, Eisai shall be deemed to have granted its approval; (b) Radius obtains each sublicensee’s written agreement to be subject to the same obligations as is Radius under the relevant terms of this Agreement (including Articles 6.1, 8.5, 9.5 and 11.1); (c) Radius shall remain responsible for the performance of all of its obligations under this Agreement, whether such obligations are performed by Radius, its Affiliates or any of its sublicensees; and (d) Radius shall pay Eisai [*] percent ([*]%) of upfront and milestone payments received from its

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

sublicensees pursuant to Article 4.1. No license is granted with respect to activities of Radius outside of the purposes as expressly provided in this Article 2.1. Radius shall provide to Eisai a fully signed copy of all sublicense agreements, within thirty (30) days of executing the same.”

(b) Article 2.2 of the Agreement is hereby amended to read in full as follows:

“2.2 This Article Intentionally Omitted.”

(c) Article 2.3 of the Agreement is hereby amended to read in full as follows:

“2.3 It is acknowledged and agreed that Radius will use its trademark for Product in the Territory. Eisai acknowledges that all right, title and interest in and to Radius’ trademarks, including all goodwill related thereto, are and shall remain owned solely and exclusively by Radius.”

(d) Appendix B to the Agreement is hereby amended to read in full as follows:

“This Appendix B Intentionally Omitted.”

3. Steering Committee.

(a) Article 3.5 of the Agreement is hereby amended to read in full as follows:

“3.5 Radius shall give a written report to Eisai on a quarterly basis with respect to the progress on the pre-clinical and clinical portions of the Development of Products in the Territory from the Effective Date.”

(b) Article 3.6 of the Agreement is hereby amended to read in full as follows:

“3.6 This Article Intentionally Omitted.”

4. Fees. Article 4.1 of the Agreement is hereby amended to read in full as follows:

“4.1 In consideration for the licenses set forth Article 2 herein, Radius shall pay Eisai the following nonrefundable milestone payments, regardless of whether or not Radius has sublicensed any of its rights under this Agreement:

Milestone Event		Payment
Execution of this Agreement		US$0.5 Million
Execution of this Amendment No. 1		US$0.4 Million
Acceptance of IND submission		US$[] Million*
the first Phase I completion		US$[] Million*
the first Phase II completion		US$[] Million*
the first Phase III completion		US$[]Million*
US NDA approval for Planned Indication		US$[]Million*
EMEA marketing approval for Planned Indication		US$[]Million*
Japanese Pharmaceuticals and Medical Devices Agency marketing approval for the first indication (this includes indications other than the Planned Indication)		US$[]Million*
each US NDA approval for indication other than Planned Indication		US$[] Million*
each EMEA marketing approval for indication other than Planned Indication		US$[]Million*
Each Japanese Pharmaceuticals and Medical Devices Agency marketing approval for indication other than the first Indication (this includes indications other than the Planned Indication)		US$[]Million*

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

Each milestone payment shall be due and payable within thirty (30) days after the achievement of the applicable milestone. The milestones shall be due only for the first Product that achieves the milestone regardless of the number of Products that achieve such milestone; provided, that if the first Product does not achieve any milestone(s), such non-achieved milestones shall be paid on any subsequent Product that achieves such milestone.

In addition, in the event that Radius grants the sublicenses to any third parties pursuant to Article 2, in consideration for the sublicenses set forth Article 2 herein, Radius shall pay Eisai [*] percent ([*]%) of upfront and milestone payments received from such third parties within thirty (30) days after the receipt of such milestone payments.

All payments shall be paid by wire transfer of funds to an account at Eisai’s designated bank in Tokyo, and shall be paid in US dollars.”

5. Supply of Compound.

(a) Article 5.1 of the Agreement is hereby amended to read in full as follows:

“ 5.1 This Article Intentionally Omitted.”

(b) Article 5.2 of the Agreement is hereby amended to read in full as follows:

“5.2 This Article Intentionally Omitted.”

(c) Article 5.3 of the Agreement is hereby amended to read in full as follows:

“5.3 This Article Intentionally Omitted.”

(d) Article 5.4 of the Agreement is hereby amended to read in full as follows:

“5.4 As manufacturer of the Product, Radius shall be responsible for: the control of the quality of the Product promoted and sold under the Radius trademarks; as provided in Article 2.3. Radius shall resolve any product liability issues in the Territory relating to the Product at its own expense and subject to Article 5.5.”

(e) Article 5.5 of the Agreement is hereby amended to read in full as follows:

“5.5 Radius’ obligations with respect to product liability in the Territory shall include the following responsibilities, each to be taken at Radius’ expense:

(a) Radius shall report, at its expense, to appropriate authorities, in accordance with local requirements, all adverse events related to use of the Product in the Territory.

(b) In the event that (i) Radius determines that an event, incident, or circumstance may result in the need for a recall or other removal of the Product or any lot or lots thereof from the market; (ii) any regulatory authority in the Territory threatens to remove a Product from the market; or (iii) any regulatory authority in the Territory requires distribution of a “Dear Doctor” letter or its equivalent regarding the use of Product, Radius shall promptly advise Eisai in writing, and shall provide Eisai with copies of all relevant correspondence, notices and the like. Notwithstanding anything the contrary herein, Radius shall have final authority to make all decisions relating to any recall, market withdrawal or other corrective action with respect to the Product in the Territory.”

6. Data. Article 6.2 of the Agreement is hereby amended to read in full as follows:

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

“6.2 Notwithstanding the Article 6.1 above, Eisai and Radius shall share all preclinical and clinical data, including safety data post-approval. All such data generated by Radius shall be owned by Radius. All such data generated by Eisai in Japan during the period prior to the Amendment Date shall be owned by Eisai; provided that Radius can access and use such data without compensation.”

7. Infringement Proceeds. Article 6.12 of the Agreement is hereby amended to read in full as follows:

“6.12 In the event that either Party becomes aware of actual or threatened infringement of Eisai Patents, Radius Patents or Joint Patents anywhere in the world, it shall promptly notify the other Party thereof in writing, which such notice shall include all information available to the notifying Party regarding such alleged infringement. With respect to infringement of Eisai Patents anywhere in the world, Eisai shall have the first right (but not the obligation) to pursue any and all injunctive, compensatory and other remedies (collectively, “Remedies”) against the infringing third party. Eisai shall have a period of forty-five (45) days after delivery to it of such notice and information to elect to so enforce such Eisai Patents. In the event Eisai does not so elect, it shall so notify Radius in writing within such 45-day period, and Radius shall have the right to commence a suit or take action to enforce the applicable Eisai Patents against such infringing third party in the Territory. In the event Eisai has a reasonable business basis not to enforce such Eisai Patents in the Territory, with the determination of reasonableness taking into account the costs of such litigation, its likelihood for success, the potential damages or settlement recovery, and the potential for exposure to counterclaims and defenses against Eisai with respect to the validity of the Eisai Patents, it shall provide Radius such basis in writing within such forty-five (45) day period, in which case Radius shall not have such enforcement right in the Territory; provided that, if the Parties discuss in good faith and agree that there could have a big negative impact on the Net Sales by such infringement, Radius shall thereafter be entitled to the royalty adjustment(s) described in Article 4.3 with respect to the applicable country(ies) where such infringement exists as if no patent protection or data protection clauses are in effect for such country(ies). The Party pursuing Remedies pursuant to this Article 6.12 in respect of Eisai Patents, Radius Patents or Joint Patents shall bear its own costs and expenses relating to such pursuit.

Any damages and other amounts collected in any suit or the settlement thereof that is the subject of this Article 6.12 shall be distributed first, to the Party that pursued Remedies to cover its costs and expenses and, second, to the other Party to cover its unreimbursed costs and expenses, if any, relating to the pursuit of such Remedies. The balance, if any remaining after the Parties have been compensated for expenses shall be distributed to Radius in an amount equal to its lost profits or a reasonable royalty on the sales of the infringer with respect to activity in the Territory (whichever measure the court or settlement agreement uses to determine damages). The balance, if any, remaining after Radius has been compensated for lost profits or lost sales and Eisai has been compensated for lost royalties with respect to infringement in the Territory shall be distributed: (i) [*] ([*]) percent to Radius and [*] ([*]) percent to Eisai in case of Radius pursuing Remedies, and (ii) [*] ([*]) percent to Eisai and [*] ([*]) percent to Radius in case of Eisai pursuing Remedies.

With respect to infringement of Radius Patents anywhere in the world, Radius shall have the first right (but not the obligation) to pursue any and all Remedies against the infringing third party. Radius shall have a period of forty-five (45) days after delivery to it of such notice and information to elect to so enforce such Radius Patents. In the event Radius does not so elect, it shall so notify Eisai in writing within such 45-day period.

In the event that a third party infringes any Joint Patents, Radius shall have the first right (but not the obligation) to pursue Remedies against the infringing third party.

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

In any event as set forth in this Article 6.12, upon request from the other Party, Eisai and Radius shall assist one another and cooperate in the pursuit of Remedies, including without limitation joining such action as a party plaintiff if required by applicable law to pursue such action, without charge to the other Party for costs and expenses incurred thereby.”

8. Risk Allocation with respect to Japan. Article 11.2 of the Agreement is hereby amended to read in full as follows:

“11.2 Eisai shall indemnify and hold harmless Radius, its officers, directors, shareholders, employees, successors and assigns from any loss, damage, or liability, including attorney fees, resulting from any claim, complaint, suit, proceeding or cause of action against any of them by a third party arising out of or resulting from: (i) the negligence, recklessness or intentional acts or omissions of Eisai, its Affiliates, and licensees, and their respective directors, officers, employees, and agents; and (ii) any breach of a representation, warranty, covenant or agreement of Eisai hereunder; provided:

(a) Eisai shall not be obligated to indemnify or hold harmless Radius under this Article 11.2 to the extent that:

(i) such claim arose out of or was the result of the negligence, recklessness, or willful misconduct or intentional acts or omissions of any employee or agent of Radius; or

(ii) the injury was the result of any defect attributable to the act or failure to act by Radius; and

(b) Eisai shall not have any obligation to indemnify or hold harmless Radius under this Article 11.2 unless (i) Radius gives Eisai prompt written notice of any claim or lawsuit or other action for which it seeks to be indemnified under this Agreement, (ii) Eisai is given the opportunity to assume full authority and control over the defense, including settlement (provided that any settlement shall not result in any remaining obligation or liability on the part of Radius), against such claim or lawsuit or other action, and (iii) Radius cooperates fully with Eisai and its agents in defense of the claims or lawsuit or other action; and

(c) Radius shall have the right to participate solely at its own expense, in the defense of any such claim, complaint, suit, proceeding and its agents in d or cause of action, including any settlement or other disposition thereof, for which Radius seeks indemnification under this Agreement.”

9. Change of Control. Article 7.6 of the Agreement is hereby amended to read in full as follows:

“7.6 Radius shall notify Eisai in advance if Radius proposes to be acquired by or to transfer all of its pharmaceutical business assets (or an essential part of such assets) or fifty (50) percent or more of its voting stock to any third party person or organization, or to otherwise come under the control of, such a person or organization, whether resulting from merger, acquisition, consolidation or otherwise. Eisai shall have twenty (20) business days following the receipt of such notice from Radius to notify Radius whether Eisai will deem the proposed change a termination event based on the criteria listed in items (1)-(3) below as well as the criteria listed in items (a)-(b) below and if Eisai does not provide such notice within such 20 business day period it will be deemed to have agreed that such change will not entitle Eisai to seek termination under this Article 7.6. In the event that Radius gives such prior notice and is notified by Eisai that Eisai will deem the proposed change a termination event or Radius without giving such prior notice is acquired by or transfers all of its pharmaceutical business assets or an essential part of such assets to, or if fifty (50) percent or more of its voting stock is acquired by, or otherwise comes under the control of, a person or an organization, whether resulting from merger, acquisition, consolidation or otherwise, Radius shall promptly notify Eisai of such change and Eisai shall have the right to terminate this Agreement with notice to Radius delivered within thirty (30) days of the occurrence of such change in the event that Eisai reasonably determines that the person or organization assuming control of Radius is not able to perform this Agreement with the same degree of skill and diligence that Radius shall use, such determination being made with reference to the following criteria with respect to the person or organization assuming control of Radius: (1) whether such person or organization has the financial

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

resources to assume the obligations of Radius with respect to Development and commercialization of Products; (2) whether such person or organization has personnel with skill and experience adequate to assume the obligations of Radius with respect to Development and commercialization of Products at the stage of Development and commercialization as of the date of such change; and (3) whether such person or organization expressly assumes all obligations imposed on Radius by this Agreement in writing and agrees to dedicate personnel and financial resources to the Development and commercialization of the Product that are at least as great as those provided by Radius. Radius shall give Eisai information by which Eisai can reasonably determine whether such person or organization satisfies the above criteria together with the notice of such change. It is understood and agreed that notwithstanding the above criteria listed in (1)-(3), Eisai shall have the right to terminate under this Article 7.6 if such person or organization: (a) has any material and active litigations with Eisai or (b) such person or organization is a hostile takeover bidder against Radius which has not been approved by the Board of Directors of Radius as constituted immediately prior to such change of control. It is understood and agreed that an underwritten public offering of Radius’ common stock pursuant to a Registration Statement on Form S-1 under the Securities Act of 1933, as amended, will not be considered a change of control triggering a termination right under this Article 7.6.”

10. Ratification . Except to the extent expressly amended by this Amendment No. 1, all of the terms, provisions and conditions of the Agreement are hereby ratified and confirmed and shall remain in full force and effect. The term “Agreement”, as used in the Agreement, shall henceforth be deemed to be a reference to the Agreement as amended by this Amendment No. 1.

11. General. This Amendment No. 1 may be executed in counterparts, each of which will be deemed an original with all such counterparts together constituting one instrument

[Remainder of this page intentionally left blank — signature page follows]

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

IN WITNESS WHEREOF, the Parties, through their authorized representatives, have executed this Amendment No. 1 as of the Amendment Date.

EISAI CO., LTD.		RADIUS HEALTH, INC.


By:	/s/ Rami Suzuki	By:	/s/ Robert Ward
Name: Rami Suzuki		Name: Robert Ward
Title: President, Senior Group Officer,		Title: Chief Executive Officer
Global Business Development Unit

Exhibit 10.4

Execution copy

CLINICAL TRIAL SERVICES AGREEMENT AMENDMENT NO. 9 TO WORK STATEMENT NB-1

RADIUS HEALTH, INC., a Delaware corporation (“ Radius ”) and NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S, a Danish corporation (“ NB ”) that is a wholly-owned subsidiary of Nordic Bioscience Clinical Development A/S entered into the certain Clinical Trial Services Agreement ( “Agreement” ) and that certain Work Statement NB-1 under the Agreement as of March 29, 2011 ( “Effective Date” ), and entered into an Amendment No. 1, Amendment No. 2, Amendment No. 3, Amendment No. 4, Amendment No. 5, Amendment No. 6,Amendment No. 7 and Amendment No. 8 to Work Statement NB-1 as of December 9, 2011, June 18, 2012, November 6, 2013, March 28, 2014, May 19, 2014, July 22, 2014, July 22, 2014 and August 15, 2014 respectively, (as amended, “Work Statement NB-1” ).

Pursuant to Section 2.3, 2.11 and 11.7 of the Agreement, the parties wish to enter into this Amendment No. 9 to Work Statement NB-1 ( “Amendment No. 9” ) effective as of 12 March, 2015 ( “Amendment Date” ). Capitalized terms used in this Amendment No. 9 and not defined herein are used with the meanings ascribed to them in the Agreement and Work Statement NB-1.

NOW THEREFORE , in consideration of the mutual covenants and promises contained in this Amendment No. 9, the parties agree as follows:

1. Additional bioanalytical activities

At Radius request, NB will perform additional testing of bone biomarkers (CTX-I and P1NP) in the biomarker subgroup samples obtained at 1 months and 3 months of treatment with Abaloparathide as well as baseline samples obtained at 6, 12 and 18 months stored at -20°C.

(b) A new section at the bottom Attachment B to Work Statement NB-1 ( Budgets, Fees, Pass-through Costs, and Payment Schedule ) is hereby amended to read in full as follows:

Budget	Euro
Test fee, subtotal	€	183,600
Sample/Study Management	€	1,800
Data transfer	€	2,200
TOTAL	€	187,600

(c) The “Payment Schedule” set forth in Attachment B to Work Statement NB-1 ( Attachment 2 to the Agreement) is amended to add a new Paragraph (17) immediately following Paragraph (16) of the Payment Schedule, which shall read in full as follows:

“(17) Payment for “Additional bioanalytical activities” will be paid upon receipt of invoice after delivery of final report.”

2. Ratification. Except to the extent expressly amended by this Amendment No. 9, all of the terms, provisions and conditions of the Agreement and Work Statement NB-1 are hereby ratified and confirmed and shall remain in full force and effect. The term “Work Statement NB-1”, as used in the Agreement, shall henceforth be deemed to be a reference to Work Statement NB-1 as amended by this Amendment No. 9.

3. General. This Amendment No. 9 may be executed in counterparts, each of which will be deemed an original with all such counterparts together constituting one instrument.

IN WITNESS WHEREOF the parties have caused this Amendment No. 9 under Work Statement NB-1 to be executed by their respective duly authorized officers, and have duly delivered and executed this Amendment No. 9 under seal as of the Amendment Date.

RADIUS HEALTH, INC.		NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S


/s/ Gregory C. Williams		/s/ Jeppe Ragnar Andersen
By: Gregory C. Williams		By:
Title: 12 March 2015		Title: CEO 12 March, 2015

Notice Address		Notice Address
Radius Health, Inc.		Nordic Bioscience Clinical Development VII A/S
950 Winter Street		Herlev Hovedgade 207
Waltham, MA 02451		2730 Herlev
USA		Denmark
Attn: President & CEO		Attn: CEO
Phone: 01.617.551.4000		Phone: 45.4452.5251
Fax: 01.617.551.4701		Fax: 45.4452.525

Exhibit 10.5

CLINICAL TRIAL SERVICES AGREEMENT AMENDMENT NO. 2 TO WORK STATEMENT NB-3

RADIUS HEALTH, INC., a Delaware corporation (“ Radius ”) and NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S, a Danish corporation (“ NB ”) that is a wholly-owned subsidiary of Nordic Bioscience Clinical Development A/S entered into a Clinical Trial Services Agreement dated March 29, 2011 ( “Agreement” ) and Work Statement NB-3 under the Agreement ( “Work Statement NB-3” ) as of February 21, 2013 ( “Effective Date” ), and entered into an Amendment No. 1 to Work Statement NB-3 as of February 28, 2014 (as amended, “Work Statement NB-3”).

Pursuant to Section 2.3, 2.11 and 11.7 of the Agreement, the parties wish to enter into this Amendment No. 2 to Work Statement NB-3 ( “ Amendment No. 2” ) effective as of March 23, 2015 ( “Amendment Date” ). Capitalized terms used in this Amendment No. 2 and not defined herein are used with the meanings ascribed to them in the Agreement and Work Statement NB-3.

NOW THEREFORE , in consideration of the mutual promises contained in the Agreement and for other good and valuable consideration the receipt and adequacy of which each of the parties does hereby acknowledge, the parties hereby agree to the terms of this Amendment No. 2 to Work Statement NB-3 as follows:

1. Additional Services in period 2 of the BA058-05-005 study:

(a) At Radius’ request, NB will perform monitoring in the period from the 6 month visit until the 24 month visit in a Period 2 extension of the clinical study that is the subject of Work Statement NB-3 entitled: BA058-05-005 “An Extension Study to Evaluate 24 Months of Standard-of-Care Osteoporosis Management Following Completion of 18 Months of BA058 or Placebo Treatment in Protocol BA058-05-00” . Radius wishes to provide for payment to NB for Services during Period 2 under this Amendment No. 2. The purpose of this Amendment no. 2 is to introduce the same level of monitoring activities in period 2 as in period 1 of the extension, including alendronate accountability to the best possible extent.

(b) At Radius’ request, NB will perform two (2) data base locks after all patients have completed month 12 and month 18, respectively.

(c) At Radius’ request, NB will contract with up to 28 CCBR and non-CCBR Sites to perform additional blood samples for safety and efficacy at months 12, 18 and 24 and DXA scans at months 12 and 18 as outlined in Amendment 3 to the protocol for study BA058-05-003 (Attachment 3).

(d) At Radius’ request, NB will contract with BioClinica-Synarc to perform analysis of the additional DXA scans from months 12 and 18 as well as additional data transfers for the two extra data base locks mentioned in 1(b).

(e) At Radius’ request, NB will contract with Nordic Bioscience Laboratory A/S to perform analysis on the blood samples collected according to 1(c).

This Amendment No. 2 to Work Statement NB-3 contains the following Attachments, each of which is made a part hereof:

Attachment 1	—	Key Assumptions and time lines
Attachment 2	—	Budget Summary including pricing, pass-through costs and Payment Schedule
Attachment 3	—	Protocol

2. Ratification. Except to the extent expressly amended by this Amendment No. 2, all of the terms, provisions and conditions of the Agreement and Work Statement NB-3 are hereby ratified and confirmed and shall remain in full force and effect. The term “Work Statement NB-3” , as used in the Agreement, shall henceforth be deemed to be a reference to Work Statement NB-3 as amended by this Amendment No. 2.

3. General. This Amendment No. 2 may be executed in counterparts, each of which will be deemed an original with all such counterparts together constituting one instrument.

IN WITNESS WHEREOF the parties have caused this Amendment No. 2 under Work Statement NB-3 to be executed by their respective duly authorized officers, and have duly delivered and executed this Amendment No. 2 under seal as of the Amendment Date.

RADIUS HEALTH, INC.		NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S


/s/ Gregory C. Williams		/s/ Jeppe Ragnar Andersen
By: Gregory C. Williams		By: Jeppe Ragnar Andersen
Title: Chief Development Officer		Title: CEO

Notice Address		Notice Address
Radius Health, Inc.		Nordic Bioscience Clinical Development VII A/S
201 Broadway, 6 th Floor		Herlev Hovedgade 207
Cambridge, MA 02139		2730 Herlev
USA		Denmark
Attn: President & CEO		Attn: CEO
Phone: 01.617.551.4700		Phone: 45.4452.5251
Fax: 01.617.551.4701		Fax: 45.4452.525

Attachment 1 — Key Assumptions and time lines

	BUDGET
	PROPOSAL	Notes

SPONSOR	Radius Health, Inc

Protocol ID	BA058-05-005 Period 2	In addition to Amendment 1 to NB-3

Development Phase:	Phase III

Disease:	OP

Expected Date of FPFV:	Q2-2015

Request for proposal date	14-jan-14

Cost Proposal date	23-mar-15

Total # of Randomized Subjects:	1.139

Number of Countries:	10

Number of research sites	24

Nordic preparation time (months)	4,0

Expected Length of Screening and enrollment (months):	0

Treatment Duration + FU (months):	18

Close Out (months)	2

Nordic paid involvement time (months):	24

Number of Visits per randomized patient	3

TOTAL BUDGET PROPOSAL EXCL. PASS-THROUGH (EURO)	4.116.224

TOTAL BUDGET PROPOSAL PER SUBJECT (EURO)	3.614

TOTAL BUDGET PROPOSAL PER MONTH (EURO)	170.798

*PASS-THROUGH ESTIMATED (EURO)*	*809.568*	Not including fracture adjudication

Attachment 2 - Budget

DETAILED BUDGET SUMMARY	Total Budget (EURO)	Notes

CRO Activities	2.834.811

Prepare site contracts	33.600	for new ICF + DXA/Xray
Prepare New Study Materials	20.432
Study specific training activities	25.800
Project Coordination	511.723	Incl. coordination of eCRF update + Narratives
Regulatory	203.090	Inc. submission of amendment
Review of Monitoring visit reports	77.035
Medical monitoring activities (medical advisor)	88.880
Centralized monitoring	223.339	2 additional DB locks
On site Monitoring	1.272.615	509 monitor days, incl. drug accountability
Site contact and administration	168.980
Close-Out activities	90.520	2 additional DB locks
Close out visits	59.990
QA and audit related activities	58.808

Investigator Activities	546.000		Adjustment rate +/- assumption #
Reconsent Amendment 3 (Additional DXA, Estimated 800 subjects)	120.000	To be adjusted according to actual	EUR 150 per patient
Month 12 DXA (Estimated 300 subjects)	90.000	To be adjusted according to actual	EUR 300 per 12 M DXA
Month 18 DXA (Estimated 700 subjects)	210.000	To be adjusted according to actual	EUR 300 per 18 M DXA
Blood sample collection for safety, efficacy and hematology - 12 M	21.000	Assumes 300 subjects. To be adjusted	EUR 70 per 12 M sample collection
Blood sample collection for safety, efficacy and hematology - 18 M	49.000	Assumes 700 subjects.To be adjusted	EUR 70 per 18 M sample collection
Blood sample collection for safety, efficacy and hematology - 24 M	56.000	Assumes 800 subjects.To be adjusted	EUR 70 per 24 M sample collection
The provided costs are based on the assumption that all procedures will be performed on already planned visits

Central Laboratory Activities	735.413		Adjustment rate +/- assumption #
Laboratory Tests, Safety	402.759	Assumes 300, 700 and 800 subjects as above	EUR 250 per visit
Laboratory Tests, Biomarkers (Efficacy)	114.754	Assumes 339 subjects. To be adjusted	EUR 204 per patient
Additional Cost’s, Study & Sample management	217.900		Fixed cost, no adjustment

Pass-through Activities
Collection of discharge letters (or similar) for fracture adjudication	310 EUR / Fracture
Analysis of 12 and 18 months DXA (BioClinica-Synarc)	USD 245.154	Estimated, Pass-through based on actual
Additional data transfers (BioClinica-Synarc)	USD 5.700 / transfer	Pass-through based on actual
Updating the eCRF and database (Medidata)	30.000	Pass-through based on actual
Shipment of lab samples and lab kits	427.219	Presumes monthly shipments. Pass-through based on actual

Pass Through Cost		Included in budget?
Monitoring Travel Expenses & Accommodations/ other travels		Included
Translation		Included
Investigator Meeting		N/A
Alendronate and calcium/ D supplement		Not included
Image shipments		Not included
Submission Fee to ERC and CA		Not included
EDC system		Not included
Data Monitoring Committee		Not included
Patient insurance		Not included
Medical writing		Not included
External advisory Board		Not included
Statistical Data analysis and Clinical Study Report		Not included

If there are no changes to the current assumptions, Nordic will cover the costs for additional monitoring visits in order to complete monitoring as per the monitoring plan. The assumptions are to introduce the same level of monitoring activities in period 2 as in period 1 of the extension, including alendronate accountability to the best possible extent

The pricing for Investigator Activities and Central Lab Activities specified in the Budget is based on the assumption that approximately 300 study subjects will complete the month-12-DXA and blood samples, that 700 study subjects will complete the month-18-DXA and blood samples and that 800 study subjects will complete the month-24 blood sampling. Upon completion of the Services, the Budget will be adjusted in a pro rata fashion according to the Adjustment Rates in the table above, to reflect the actual study activities completed.

The adjustments will be made in the invoice relating to Final Payment.

Payment Schedule

Radius shall make payment to NB in accordance with the below Payment Schedule upon receipt of invoice:

	Occurrence	Amount
Non-refundable up-front payment (7.5%)	1	EUR	308,716.80
Monthly payments	24	EUR	132,919.73
Final Payment (15%)	1	EUR	617,433.60
	Total	EUR	4,116,224.00

Attachment 3 - Protocol

CLINICAL STUDY PROTOCOL

An Extension Study to Evaluate 24 Months of Standard-of-Care Osteoporosis Management Following Completion of 18 Months of BA058 or Placebo Treatment in Protocol BA058-05-003

This study will be conducted according to the protocol and in compliance with Good Clinical Practice, the ethical principles stated in the Declaration of Helsinki, and other applicable regulatory requirements.

Protocol Number:	Protocol BA058-05-005
Protocol Date (Version):	Original (23 July 2012) Amendment 1, Version 1 (13 February 2013) Amendment 2, Version 1 (31 March 2014) Amendment 3, Version 1 (3 March 2015)
EudraCT Number	2012-002216-10
IND Number:	73,176
Study Sponsor:	Radius Health, Inc. 950 Winter Street Waltham, MA 02451 Tel: 617.551.4000. Fax: 617.551.4701
Sponsor Medical Monitor/Study Safety Officer:	Alan Harris, MD Chief Medical Officer, Radius Health, Inc. Tel: XXXX Fax: XXXX Email: XXXX@XXXX.com

Contract Research Organization (CRO):	Nordic Bioscience A/S Herlev Hovedgade 207 2730 Herlev, Denmark Tel: +XXXX Fax: +XXXX

Disclosure Statement
This document contains information that is confidential and proprietary to Radius Health, Incorporated (RADIUS). This information is being provided to you solely for the purpose of evaluation and/or conducting a clinical trial for RADIUS. You may disclose the contents of this document only to study personnel under your supervision and/or to your institutional review board(s) or ethics committee(s) who need to know the contents for this purpose and who have been advised on the confidential nature of the document.

Radius Health, Inc.

Confidential

PROTOCOL SYNOPSIS

Title: An Extension Study to Evaluate 24 Months of Standard-of-Care Osteoporosis Management Following Completion of 18 Months of BA058 or Placebo Treatment in Protocol BA058-05-003

Protocol Number: BA058-05-005

Test Drug: Alendronate

Study Objectives:

Please note that the name of BA058 Injection 80 µg has been changed to Abaloparatide-SC, therefore the name has been changed throughout the document.

The primary objective of this study is to collect clinical information regarding six months of treatment with alendronate, in subjects who have previously received 18 months of blinded treatment with Abaloparatide-SC or Placebo in Study BA058-05-003. Safety data will be obtained via clinical, laboratory and radiologic assessments. Following the initial six months of treatment in the study, subjects will then enter the long-term observational phase of the study during which subjects will continue to receive alendronate treatment for an additional 18 months (for a total of 24 months).

The specific objectives of this study are to:

· Provide additional information on safety in study subjects receiving six months of treatment with alendronate following 18 months of treatment with Abaloparatide-SC/Placebo.

· Provide information on the vertebral fracture rate in subjects receiving six months of treatment with alendronate following 18 months of treatment with Abaloparatide-SC/Placebo.

· Provide additional information on non-vertebral fractures and BMD change associated with six months of treatment with alendronate following 18 months of treatment with Abaloparatide-SC/Placebo.

· Provide additional information on BMD change and osteoporosis status associated with 24 months of treatment with alendronate after 18 months of treatment with Abaloparatide-SC/Placebo.

The analysis performed at six months of this Extension Study will be used as a follow-up to the 18 month fracture endpoint for Study BA058-05-003. Vertebral fractures based on radiologic assessments will also be analyzed at Month 24. Additional analyses for other endpoints will be conducted cumulatively at Months 12, 18, and 24 (i.e., Visits 4, 5, and 6). Full details of the statistical procedures to be used will be provided in the Statistical Analysis Plan.

Study Population:

Subjects with postmenopausal osteoporosis who completed the End-of-Treatment Visit (Visit 9) for Study BA058-05-003 and were previously randomized to either blinded Abaloparatide-SC or blinded Placebo are eligible for inclusion into this Extension Study provided that they fulfill the Inclusion/Exclusion criteria described below.

Inclusion/Exclusion Criteria

Otherwise healthy ambulatory postmenopausal women who participated in, and who completed 18 months of treatment with either blinded Abaloparatide-SC or blinded Placebo in Study BA058-05-003, are scheduled to complete or have completed the End-of-Treatment visit (Visit 9 in Study BA058-05-003), and who have provided a new written informed consent for the Extension Study, are eligible for enrollment into this study. Participants must be no more than 40 days from Visit 9 in Study BA058-05-003 to be eligible for this study. The physical examinations and clinical laboratory

Protocol BA058-05-005 Amendment 3, Version 1 (3 March 2015)

measurements from the End-of-Treatment visit from Protocol BA058-05-003 (Visit 9) of the BA058-05-003 study will provide baseline data for this Extension Study. In addition, the subjects must, in the opinion of the Investigator, be appropriate candidates for treatment with alendronate.

Subjects will not be enrolled if they experienced a treatment-related SAE as assessed by the Investigator, or if they were withdrawn from Study BA058-05-003 for any reason. Specific inclusion and exclusion criteria are described in Section 4.1 and Section 4.2, respectively.

Study Design and Methodology:

Number of Subjects

All subjects who were randomized to the Abaloparatide-SC/Placebo arms in Study BA058-05-003, and who completed 18 months of treatment will be offered the opportunity to participate in this study. There will, therefore, be a potential maximum of 1,600 subjects eligible to be enrolled in this study.

Design

This study will be an open-label extension of Study BA058-05-003. The purpose of the study is to provide longer term safety data, fracture data and BMD data after treatment with alendronate, in otherwise healthy ambulatory postmenopausal women with severe osteoporosis who have previously received 18 months of blinded treatment with Abaloparatide-SC or Placebo. The analysis performed at six months will be used as a follow-up to the 18 month fracture endpoint for Study BA058-05-003. In addition, this study will examine changes in osteoporosis status after 12, 18, and 24 months of treatment with alendronate in otherwise healthy ambulatory women with severe osteoporosis who have previously received 18 months of blinded treatment with Abaloparatide-SC/Placebo.

Subjects randomized to Abaloparatide-SC/Placebo in Study BA058-05-003 and who are candidates for alendronate treatment, will receive six months of treatment with oral alendronate at a total dose of 70 mg once per week. Following the initial six months of treatment in the study, subjects will then enter the long-term observational phase of the study during which subjects will continue to receive alendronate treatment for an additional 18 months (for a total of 24 months). All subjects will undergo protocol specified procedures (Section 7.0, Appendix 14.1 and 14.2) including BMD and fracture assessment. The study design is presented in Figure 1, below.

Figure 1: Protocol BA058-05-005 Study Design

In this study, the Follow-up Visit from the 18 month study (Visit 10 from Study BA058-05-003) will serve as the Day 1 Visit (Visit 1) for this six month Extension Study (Study BA058-05-005).

Following the initial six months of treatment, subjects will enter the long-term observational phase of this study during which the subjects will continue to receive alendronate treatment for an additional 18 months. During the long-term follow-up of this study, subjects will continue to undergo study related procedures as outlined in Section 14.1 and Section 14.2.

All subjects will continue to take calcium and vitamin D supplementation throughout the Extension Study.

Study Visits

At the End-of-Treatment Visit (Visit 9) for Study BA058-05-003, the possibility of participating in the Extension Study will be discussed with subjects randomized to Abaloparatide-SC/Placebo. This Extension Study will be comprised of 24 months of treatment with alendronate. In the month between Visit 9 and Visit 10 (between months 18 and 19 of Study BA058-05-003), the Investigator will consider the results of the assessments performed at Visit 9, including a local review of BMD, and determine if alendronate is appropriate for the subject, as part of this Extension Study.

At the Follow-up (Visit 10 for Protocol BA058-05-003, Day 1 for Protocol BA058-05-005) subjects; who were randomized to Abaloparatide-SC/Placebo, who fulfill the inclusion/exclusion criteria (Section 4.1 and Section 4.2), and who have agreed to participate in the Extension Study; will sign the Informed Consent Form and be enrolled in the study.

Subjects who have been determined by the Investigator to be candidates for alendronate therapy will receive open-label oral alendronate treatment at a total dose of 70 mg once per week for 24 months. Subjects will be instructed to take their first dose of alendronate for Study BA058-05-005 in the morning, within a week of their Day 1 visit. Following the initial six months of treatment in this study, subjects will enter the long-term observational phase of this study, during which subjects will continue to receive alendronate treatment for an additional 18 months.

All subjects will have clinic visits for study related procedures at Day 1, Month 3, Month 6, Month 12, Month 18 and Month 24. For the purpose of this study one month is equal to 30 days.

Statistical Considerations:

The statistical analyses will assess longer term safety, fracture incidence (including vertebral and non-vertebral fracture), and BMD change following treatment with alendronate for six months after the completion of a subject’s participation of 18 months in study BA058-05-003.

The efficacy and safety analyses performed at six months will be used as a follow-up to the 18 month fracture endpoint for Study BA058-05-003. At this time-point, subjects will be analyzed based on the randomization assignment in the BA058-05-003 study.

Fractures and BMD Analyses

All specified endpoints will be summarized by treatment group and study period using standard descriptive statistics (n, mean, SD, median, minimum, maximum or n and %, as appropriate). The fracture incidence; either clinically or radiologically determined, based on clinical events or protocol-directed vertebral x-rays at Month 6 of this Extension Study; will be analyzed. In addition, BMD results from the six months of treatment with alendronate will also be analyzed based on the treatment arm they were randomized to in the BA058-05-003 study. These analyses will be conducted on all subjects with baseline and post-baseline data.

In addition to the 6-month assessment, vertebral fractures based on radiologic assessments will also be analyzed at Month 24. Additional analyses for the other endpoints will be cumulatively at Months 12, 18 and 24 (i.e., Visits 4, 5 and 6). Full details of these analyses will be provided in the Statistical Analysis Plan.

Safety Analysis

Data will be summarized and tabulated based on the enrolled population for this Extension Study. All subjects enrolled in the Extension Study will be included in the safety analysis that will be performed on the following parameters:

· Incidence and severity of AEs.

· Pathological changes in hematology, chemistry and urinalysis data based on normal ranges supplied by the clinical laboratory, if applicable.

Safety assessments for changes in physical examination, vital signs, ECG, and laboratory tests will be descriptively summarized by treatment and study periods. Concomitant medication classes will be categorized using World Health Organization (WHO) drug dictionary and summarized by number and percent of subjects using each class by treatment group. All treatment emergent adverse events (TEAEs) will be coded for system organ class (SOC) and preferred term (PT) using MedDRA and the number (%) of subjects experiencing each AE (SOC/PT) will be summarized by treatment, relationship to treatment, and severity. All serious adverse events (SAE) will be listed and the number (%) of subjects with an SAE presented by treatment group.

Similar safety analyses will be conducted cumulatively at Months 12, 18, and 24 (i.e., Visits 4, 5, and 6). Full details of these analyses will be provided in the Statistical Analysis Plan.

Procedures and Assessments

Fractures and BMD

The End-of-Treatment (Visit 9) evaluations for vertebral fracture assessment, non-vertebral fracture assessment and BMD from Study BA058-05-003 will serve as the baseline evaluations in this study. The Day 1 assessment will be concurrent with the Follow-up Visit (Visit 10) for Study BA058-05-003. Subjects will return to the clinic for assessment of BMD at spine, hip and wrist (for those subjects who had wrist DXAs performed in Study BA058-05-003) at Month 6, Month 12, Month 18, and at Month 24. Any patient who shows a continuing significant deterioration (>7%) of BMD at

spine or hip from the Day 1 assessment of Study BA058-05-005 will have the assessment repeated and, if confirmed, will be discontinued from the study. Clinical and radiographic assessments for fractures will be performed at Month 6 and Month 24, and bone marker assessments of anabolism (PINP, bone-specific alkaline phosphatase and osteocalcin) and resorption (CTX) will be performed at Day 1 and Months 6, 12, 18 and 24.

Safety

Safety evaluations performed will include physical examinations, vital signs, 12-lead ECGs, clinical laboratory tests, and monitoring and recording of adverse events.

Complete details of the study assessments are provided in Section 7.0, in the Schedule of Visits and Procedures (Appendix 14.1) and in the Suggested Schedule of Events and Procedures by Study Visit (Appendix 14.2).

Treatments Administered

Alendronate sodium (Fosamax®, Merck & Co., Inc., or other approved generic manufacturer) 70 mg tablets for oral administration contain 91.35 mg of alendronate monosodium salt trihydrate which is the molar equivalent of 70 mg free acid and excipients. Alendronate should be stored in a well-closed container at room temperature, 15-30ºC. The alendronate may be generic substitutable approved versions which contain different inactive ingredients, but the amount of active free alendronate must be equivalent to 70 mg. Alendronate for Europe, Hong Kong and the US will be sourced centrally; alendronate for South America will be sourced locally by the medical center and reimbursed by the Sponsor. However, alendronate may be locally sourced in all venues when centrally supplied alendronate is unavailable due to unforeseen delays. The local source will be documented in the study drug logs.

Calcium (500—1000 mg) and vitamin D (400—800 IU) supplements will be sourced locally by the medical center and provided to the subjects at the expense of the Sponsor. Subjects will continue to take calcium and vitamin D as they did in Study BA058-05-003.

Duration of Subject Participation:

Participation in the initial phase of this study will be approximately six months from enrollment to completion of the six month study evaluations. Participation for both the initial and observational phases of the study will be approximately 24 months. In combination with Study BA058-05-003, subjects will participate in this clinical postmenopausal osteoporosis program for 43 to 44 months. The first visit of Study BA058-05-005 will be concurrent with Visit 10 of Study BA058-05-003.

TABLE OF CONTENTS

PROTOCOL SYNOPSIS					2

TABLE OF CONTENTS					7

LIST OF ABBREVIATIONS					10

1.0	INTRODUCTION				12

1.1	BACKGROUND INFORMATION				12
1.2	DRUG UNDER STUDY				12
1.2.1			Efficacy of Alendronate		12
1.2.2			Safety of Alendronate Sodium		13
1.3	STUDY RATIONALE AND SELECTION OF DOSES				14
1.3.1		Study Rationale			14
1.3.2		Study Design			14
1.3.3		Study Population			15
1.3.4		Selection of Endpoints			15
1.3.5		Selection of Dose			15

2.0	STUDY OBJECTIVES				15

3.0	INVESTIGATIONAL PLAN				16

3.1	OVERALL DESIGN AND STUDY PLAN				16
3.1.1			Treatment Period		17

4.0	SELECTION OF STUDY POPULATION				18

4.1	NUMBER OF SUBJECTS				18
4.2	INCLUSION CRITERIA				18
4.3	EXCLUSION CRITERIA				19
4.4	WITHDRAWAL OF SUBJECTS FROM THE STUDY				19
4.5	TEMPORARY SUSPENSION OF TREATMENT				19
4.6	REPLACEMENT OF SUBJECTS				20

5.0	STUDY TREATMENTS				20

5.1	STUDY MEDICATIONS				20
5.1.1			Alendronate		20
5.1.1.1				Restrictions on Alendronate Use	20
5.1.2			Calcium and Vitamin D Supplements		20
5.2	PACKAGING, LABELING AND STORAGE				20
5.2.1			Storage		21
5.3	TREATMENT ASSIGNMENT				21
5.4	STUDY MEDICATION ADMINISTRATION				21
5.4.1			Alendronate Administration		21
5.5	TREATMENT COMPLIANCE				21
5.6	UNBLINDING OF STUDY MEDICATION				21

6.0	CONCOMITANT MEDICATIONS				22

6.1	CONCOMITANT MEDICATIONS				22
6.2	PROHIBITED MEDICATIONS				22

7.0	STUDY ASSESSMENTS				22

7.1	CLINICAL PROCEDURES/ASSESSMENTS				23
7.1.1			Informed Consent		23
7.1.2			Recent Health Status		23
7.1.3			Vital Signs		23
7.1.4			Height and Weight		23
7.1.5			Orthostatic Blood Pressure and Heart Rate		23

7.1.6		Electrocardiogram	23
7.1.7		Clinical Laboratory Evaluations	24
7.1.8		Clinical Chemistry and Urinalysis (Dipstick)	24
7.1.9		Hematology	25
7.1.10		Coagulation	25
7.1.11		24-Hour Urine Collection	25
7.1.12		Bone Mineral Density	25
7.1.13		Serum Markers of Bone Metabolism	26
7.1.14		Clinical and Radiologic Evaluation of Fractures	26
7.1.15		Abaloparatide Antibody Assessments	26
7.1.16		Subject Diaries	27
7.1.17		Activity and Diet	27

8.0	ADVERSE EVENTS AND SAFETY EVALUATION		27

8.1	DEFINITIONS, DOCUMENTATION, AND REPORTING		27
8.1.1		Adverse Event Definition	27
8.1.2		Serious Adverse Event Definition	27
8.2	MONITORING OF ADVERSE EVENTS AND PERIOD OF OBSERVATION		28
8.3	PROCEDURES FOR RECORDING AND REPORTING AES AND SAES		28
8.4	RULES FOR SUSPENSION OF THE STUDY		30

9.0	STATISTICAL PROCEDURES		30

9.1	SAMPLE SIZE		31
9.2	RANDOMIZATION, STRATIFICATION AND BLINDING		31
9.3	POPULATIONS FOR ANALYSIS		31
9.3.1		ITT (Safety) Population	31
9.3.2		Modified Intent-to-Treat Population	31
9.3.3		Per Protocol Population	31
9.4	PROCEDURES FOR HANDLING MISSING, UNUSED, AND SPURIOUS DATA		31
9.5	STATISTICAL METHODS		31
9.5.1		Statistical Considerations	31
9.5.2		Baseline Comparisons	32
9.5.3		Fractures and BMD Analysis	32
9.5.4		Safety Analysis	32
9.5.5		Procedures for Reporting Deviations to Original Statistical Analysis Plan	32
9.6	DATA OVERSIGHT		33
9.6.1		Central Review of Radiographs and DXA Scans	33

10.0	ADMINISTRATIVE REQUIREMENTS		33

10.1	GOOD CLINICAL PRACTICE		33
10.2	ETHICAL CONSIDERATIONS		33
10.3	SUBJECT INFORMATION AND INFORMED CONSENT		33
10.4	PROTOCOL COMPLIANCE		34
10.5	CASE REPORT FORM COMPLETION		34
10.6	SOURCE DOCUMENTS		34
10.7	STUDY MONITORING		35
10.8	ON-SITE AUDITS		35
10.9	DRUG ACCOUNTABILITY		35
10.10	RECORD RETENTION		35
10.11	STUDY TERMINATION		36
10.12	LIABILITY AND INSURANCE		36

11.0	USE OF INFORMATION AND PUBLICATION OF STUDY FINDINGS		36

11.1	USE OF INFORMATION		36
11.2	PUBLICATION		37

12.0	INVESTIGATOR AGREEMENT	38

13.0	REFERENCES	39

14.0	APPENDICES	41

14.1	SCHEDULE OF VISITS AND PROCEDURES	42
14.2	SUGGESTED SCHEDULE OF EVENTS AND PROCEDURES BY STUDY VISIT	44
14.3	EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) COMMON TOXICITY CRITERIA	52

LIST OF ABBREVIATIONS

Abbreviation		Term
°C		Degree Celsius
°F		Degree Fahrenheit
µg		Microgram
µmol		Micromole
AE		Adverse event
ALT		Alanine aminotransferase
AST		Aspartate aminotransferase
BMD		Bone mineral density
BMI		Body mass index
bpm		Beats per minute
BSAP		Bone-specific alkaline phosphatase
BUN		Blood urea nitrogen
cm		Centimeter
CPK		Creatine phosphokinase
CRF		Case report form
CRO		Contract research organization
CTX		C-telopeptides of type 1 collagen crosslinks (serum)
DXA		Dual energy x-ray absorptiometry
ECG		Electrocardiogram
eCRF		Electronic case report form
FDA		Food and Drug Administration
g		Gram
GCP		Good clinical practice
GGT		Gamma-glutamyltranspeptidase
GLP		Good laboratory practice
GMP		Good manufacturing practice
ICH		International Conference on Harmonization
IEC		Independent ethics committee
IRB		Institutional review board
ITT		Intent-to-treat
IU		International unit
IV		Intravenous
IVRS		Interactive voice response system
kg		Kilogram
L		Liter
LDH		Lactate dehydrogenase
MCH		Mean corpuscular hemoglobin
MCHC		Mean corpuscular hemoglobin concentration
MCV		Mean corpuscular volume

Abbreviation		Term
MedDRA		Medical dictionary for regulatory activities
µL		Microliter
mg		Milligram
mL		Milliliter
mmHg		Millimeter of mercury
msec		Millisecond
NPO		Nothing by mouth
ng		Nanogram
ONJ		Osteonecrosis of the jaw
PA		Posterior-anterior
PD		Pharmacodynamic
pg		Picogram
PINP		N-terminal propeptide of type I procollagen
PK		Pharmacokinetic
PT		Prothrombin time
PTH		Parathyroid hormone
PTHrP		Parathyroid hormone related peptide
PTT		Partial thromboplastin time
PUBs		Upper gastrointestinal perforations, ulcers and bleeds
QT		Total depolarization and repolarization time
QTc		Total depolarization and repolarization time corrected with heart rate
RBC		Red blood cell
SAE		Serious adverse event
SC		Subcutaneous
SD		Standard deviation
SERMs		Selective estrogen receptor modulators
SOC		System organ class
SOP		Standard operating procedure
TEAEs		Treatment emergent adverse events
ULN		Upper Limit of Normal
WBC		White blood cells
WHO		World Health Organization

1.0 INTRODUCTION

1.1 Background Information

Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue which leads to enhanced fragility and increased risk of fractures (Rizzoli, 2001). It is estimated that over 200 million people worldwide have osteoporosis (Reginster, 2006) and osteoporosis causes more than 8.9 million fractures worldwide, of which more than 4.5 million occur in the Americas and Europe (WHO Scientific Group, 2007). The vast majority of osteoporotic fractures occur in elderly women and incidence increases markedly with age. Most fractures occur at the spine, wrist and hip. Of these, hip fractures carry the highest morbidity and mortality. In 1990, the total number of hip fractures in men and women was estimated to be 1.26 million worldwide, and it is estimated that this number will increase to 3.6 million by 2025 and to 4.5 million by 2050 (Gullberg, 1997).

Subjects enrolled in this Extension Study will have completed 18 months of treatment with Abaloparatide-SC/Placebo. Abaloparatide is a synthetic 34 amino acid analog of parathyroid hormone related peptide(PTHrP), with molecular modifications of specific amino acids, and is under clinical development for the prevention of fractures in postmenopausal women with severe osteoporosis who are at a risk for fracture. Abaloparatide shows particular potential for reversing bone loss at both the spine and the hip, the site of the most debilitating osteoporotic fractures in elderly women. Abaloparatide is a synthetic analog of PTHrP (1-34) designed to give a greater anabolic effect than human parathyroid hormone (hPTH). Initial in vitro and in vivo studies identified abaloparatide as displaying bone anabolic properties without a significant hypercalcemic effect. In humans, abaloparatide has different pharmacokinetics (PK) and pharmacodynamics (PD) properties than hPTH(1-34) and has been shown in a Phase 2 study (BA058-05-002) to have similar or greater efficacy in restoring bone mineral density (BMD) in individuals with osteoporosis than hPTH(1-34). Overall, abaloparatide has been well tolerated in previous studies.

This is an open-label extension of Study BA058-05-003. Enrollment requires previous participation in, and successful completion of, 18 months of treatment with Abaloparatide-SC/Placebo in Study BA058-05-003. The purpose of this extension is to accumulate longer-term safety, fracture, and BMD data in subjects who receive six months of treatment with alendronate, following 18 months of treatment with blinded Abaloparatide-SC/Placebo treatment. Following the initial six months of treatment in this study, subjects will then enter the long-term observational phase of this study during which the subjects will continue to receive alendronate treatment for an additional 18 months. The analyses performed at six months will be used as a follow-up to the 18 month fracture endpoint for Study BA058-05-003. Additional analyses will be cumulatively at Months 12, 18, and 24 (i.e., Visits 4, 5, and 6. Full details of the statistical procedures to be used will be provided in the Statistical Analysis Plan. Alendronate, a bisphosphonate, is approved and marketed world-wide for the treatment and prevention of osteoporosis in postmenopausal women.

1.2 Drug Under Study

1.2.1 Efficacy of Alendronate

Alendronate is a bisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the

hydroxyapatite found in bone. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. (Fosamax Package Insert)

Bisphosphonates including alendronate are widely used to treat osteoporosis. In animal models, minipigs treated with alendronate exhibited a direct correlation between cancellous bone volume and bone strength (Lefage 1995). In primates, treatment with alendronate increased the strength of cancellous bone between 44 and 100% (the effect was dose dependent) when compared to vehicle, and also increased bone mass (Balena 1993). In dogs, this increase in bone mass occurred without causing abnormalities in bone modeling of bone structure (Balena, 1996).

In postmenopausal women, alendronate has been demonstrated to increase bone mineral density, decrease bone turnover and reduce the risk of fracture among women with osteoporosis (Tucci, 1996; Devogelaer, 1996; Liberman, 1995). The therapeutic effects on bone density, remodeling and fracture prevention persist following daily treatment at an oral dose of 10 mg for up to 10 years (Bone, 2004). Studies have demonstrated that sequential treatment of osteoporosis with one year of treatment with PTH followed by one year of treatment with alendronate resulted in an increase in vertebral bone density that was considerably greater than previously reported for alendronate alone (Rittmaster, 2000). In subjects receiving PTH(1-84) followed by alendronate, there were significant increases in BMD, in particular trabecular spine, when compared to PTH(1-84) followed by placebo (31% vs. 14%, p<0.001) (Black, 2005).

1.2.2 Safety of Alendronate Sodium

According to the US package insert for Fosamax® (alendronate sodium), in studies of up to five years duration, adverse experiences usually were mild and generally did not require discontinuation of therapy. In a three-year, placebo-controlled, double blind study in which 196 subjects were treated with 10 mg/day, discontinuation due to any adverse experience occurred in 4.1% of subjects treated with alendronate, and 6% of 397 subjects treated with placebo. The most frequently reported adverse event (occurring in > 2% of subjects treated with alendronate) in this study were abdominal pain, musculoskeletal pain, nausea, dyspepsia, constipation, diarrhea, flatulence, headache and acid regurgitation.

Alendronate may cause local irritation of the upper gastrointestinal mucosa. Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions occasionally with bleeding and rarely followed by esophageal stricture or perforation have been reported. Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, has been reported in subjects taking alendronate. For subjects requiring dental procedures, discontinuation of alendronate therapy may reduce the risk for ONJ.

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been

established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.

Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.

According to the Summary of Product Characteristics for alendronate from the EMA, the following adverse experiences have been reported in alendronate treated subject during clinical trials and/or post-marketing use:

Common: Headache, abdominal pain, dyspepsia, constipation, diarrhea, flatulence, esophageal ulcer, dysphagia, abdominal distension, acid regurgitation and musculoskeletal pain.

Uncommon: Nausea, vomiting, gastritis, esophagitis, esophageal erosions, melena, rash, pruritus and erythema.

Rare: Hypersensitivity reactions including urticarial and angioedema, symptomatic hypocalcemia (often in association with predisposing conditions), uveitis, scleritis, episcleritis, esophageal stricture, oropharyngeal ulceration, upper gastrointestinal perforations, ulcers and bleeds (PUBs), rash with photosensitivity, osteonecrosis of the jaw, atypical subtrochanteric and diaphyseal femoral fractures and transient symptoms as in an acute-phase response (myalgia, malaise and rarely, fever), typically associated with initiation of treatment.

1.3 Study Rationale and Selection of Doses

1.3.1 Study Rationale

The purpose of the study is to provide longer term safety data, fracture data and BMD data after six months of treatment with alendronate, in otherwise healthy ambulatory postmenopausal women with severe osteoporosis who have previously received 18 months of blinded treatment with Abaloparatide-SC or Placebo. Following the initial six months of treatment in this study, subjects will enter the long-term observational phase of the study during which the subjects will continue to receive alendronate for an additional 18 months.

1.3.2 Study Design

Subjects randomized to Abaloparatide-SC/Placebo, who have completed 18 months of treatment in Protocol BA058-05-003 and, who meet the Inclusion/Exclusion criteria (Sections 4.2 and 4.3) are eligible to participate in this study. Subjects originally randomized to Abaloparatide-SC/Placebo in Study BA058-05-003 and who are candidates for ongoing

osteoporosis care, will receive 24 months of weekly open-label alendronate treatment at a dose of 70 mg/week.

1.3.3 Study Population

The study population in this protocol is comprised of otherwise healthy ambulatory postmenopausal women who:

1. have participated in Study BA058-05-003,

2. were randomized to either Abaloparatide/Placebo,

3. have completed the End-of-Treatment Visit (Visit 9 in Study BA058-05-003), and

4. have provided a new written informed consent for this protocol.

Subjects will not be enrolled if they experienced treatment-related SAE or were withdrawn from Study BA058-05-003 for any reason.

1.3.4 Selection of Endpoints

The fracture incidence; either clinically or radiologically determined, based on clinical events or protocol-directed vertebral x-rays at Month 6 of this Extension Study; will be analyzed. In addition, BMD results from the six months of treatment with alendronate will also be analyzed. Bone formation (PINP, osteocalcin, BSAP) and resorption (CTX) markers will also be assessed. Clinical incidence of any fracture and radiologic incidence of vertebral fracture will also be evaluated at Month 24. The End-of-Treatment (Visit 9) evaluations for BMD, vertebral fracture, and non-vertebral fracture assessments from BA058-05-003 will serve as the baseline evaluations in this study.

In addition to the 6-month assessment, clinical and radiologic assessment of the spine for assessment of fractures will be performed at Month 24. At Months 6, 12, 18 and 24, BMD by DXA, as well as clinical assessments of fractures will be performed. Bone formation and resorption markers will also be assessed at Day 1 and Months 6, 12 18 and 24. Further details of these assessments are in Section 7.0, and in Appendix 14.1 and 14.2.

Subjects will be monitored for safety events and will have safety assessments performed at each study visit.

1.3.5 Selection of Dose

The dose of alendronate (70 mg per week, oral) selected for this study is based upon the recommended daily dose in the product’s prescribing information.

All enrolled subjects will also continue to receive calcium (500-1000 mg) and vitamin D (400-800 IU) supplementation.

2.0 STUDY OBJECTIVES

The primary objective of this study is to evaluate data obtained following six months of treatment with alendronate, in subjects who have previously received 18 months of blinded Abaloparatide -SC/Placebo. Safety will be evaluated with clinical, laboratory and radiologic assessment. The analysis at six months will be based on the treatment that subjects were randomized to in the BA058-05-003 study. Following the initial six months of treatment in this study, subjects will then enter the long-term observational phase of the study during

which the subjects will continue to receive alendronate treatment for an additional 18 months.

The specific objectives of this study are to:

· Provide additional information on safety in study subjects receiving six months of treatment with alendronate following 18 months of treatment with Abaloparatide-SC/Placebo.

· Provide information on the vertebral fracture rate in subjects receiving six months of treatment with alendronate following 18 months of treatment with Abaloparatide-SC/Placebo.

· Provide additional information on non-vertebral fractures and BMD change associated with six months of treatment with alendronate following 18 months of treatment with Abaloparatide-SC/Placebo.

· Provide additional information on BMD change and osteoporosis status associated with 24 months of treatment with alendronate after 18 months of Abaloparatide-SC/Placebo.

The analysis performed at six months will be used as a follow-up to the 18 month fracture endpoint for Study BA058-05-003. Vertebral fractures based on radiologic assessments will also be analyzed at Month 24. Additional analyses for other endpoints will be conducted cumulatively at Months 12, 18, and 24 (i.e., Visits 4, 5, and 6). Full details of the statistical procedures to be used will be provided in the Statistical Analysis Plan.

3.0 INVESTIGATIONAL PLAN

3.1 Overall Design and Study Plan

This study is an open-label extension of Study BA058-05-003. Subjects and Investigators who participate in Study BA058-05-005 will remain blinded to prior treatment assignment as part of BA058-05-003. At the End-of-Treatment visit (Visit 9) for Study BA058-05-003, the possibility of participating in the Extension Study will be discussed with subjects randomized to Abaloparatide-SC/Placebo. The Extension Study will be comprised of an initial six months of treatment with alendronate. In the month between Visit 9 and Visit 10, the Investigator will review the results of the assessments performed at Visit 9, including a local interpretation of BMD, and determine if alendronate is appropriate for the subject. All subjects will continue to receive vitamin D and calcium supplementation as they did in Study BA058-05-003. The study design is presented in Figure 2, below.

Figure 2: Protocol BA058-05-005 Study Design

Participation for both the initial and observational phases of the will be approximately 24 months. There are a total of six clinic visits during the course of the study.

A brief summary of the study is provided below. For a summary of the study assessments to be performed, refer to Section 7.0 (Study Assessments) and to the Schedule of Visits and Procedures (Appendix 14.1). A more detailed description of the study procedures on a by-visit basis is provided in Appendix 14.2 (Suggested Schedule of Events and Procedures by Study Visit). A suggested order of procedures is also provided in this schedule.

3.1.1 Treatment Period

Subjects will enter into Study BA058-05-005 on Day 1, and Day 1 will also serve as Visit 10 (the Follow-up Visit) for Study BA058-05-003. The Informed Consent must be signed prior to undergoing any BA058-05-005 study related procedures, and may be signed at either Visit 9 or Visit 10 of Study BA058-05-003. Subjects who received Abaloparatide-SC/Placebo in Study BA058-05-003 will receive six months of open-label oral alendronate treatment as part of this study (BA058-05-005). Following the initial six months of treatment in this study, subjects will then enter the long-term observational phase of this study during which the subjects will continue to receive alendronate care for an additional 18 months.

If determined by the Investigator to be appropriate, treatment will be by oral administration of alendronate at a total dose of 70 mg once per week. Subjects will be given a weekly diary card to record missed doses of medication including calcium and vitamin D.

A total of six clinic visits are scheduled during the study (Day 1, Month 3, Month 6, Month 12, Month 18 and Month 24).

Subjects will be instructed to take their first dose of study drug for Study BA058-05-005 in the morning, within a week of their Day 1 visit (Day 2 of this study). Study subjects will

continue calcium and vitamin D supplementation during this study as was administered during BA058-05-003 (Section 6.1).

At Month 3, subjects will return to the clinic for medication resupply, subject diary review and questioning as to their use of concomitant medications and the occurrence of adverse events.

At the Month 6 visit ECG, and safety labs will be performed. Vertebral fractures will be determined clinically and via protocol directed x-ray evaluation; non-vertebral fractures will be determined clinically. In addition, subjects will undergo a DXA of the hip and spine (and wrist, if the subject was enrolled in the wrist DXA sub-study in Study BA058-05-003), and have samples drawn for bone markers and anti-abaloparatide antibodies. Procedures are to be performed as described in Section 7.0, Appendix 14.1 and Appendix 14.2.

At Months 12 and 18, subjects will return to the clinic for safety labs, DXA of the hip and spine (and wrist, if the subject was enrolled in the wrist DXA sub-study in Study BA058-05-003), medication resupply, subject diary review and questioning as to their use of concomitant medications and occurrence of adverse events. Serum samples for bone markers will also be drawn.

At Month 24, subjects will return to the clinic for safety labs, and will undergo clinical and radiologic fracture assessments and have DXA of the hip and spine (and wrist, if the subject was enrolled in the wrist DXA sub-study in Study BA058-05-003). Serum samples for bone markers will also be drawn. Any adverse event or clinical laboratory abnormality recorded at the Month 24 Visit will be monitored until it has resolved, become chronic or stable.

4.0 SELECTION OF STUDY POPULATION

4.1 Number of Subjects

Subjects who completed 18 months of treatment with either Abaloparatide-SC/Placebo in Study BA058-05-003 will be given the opportunity to participate in the Extension Study at all participating centers. Based on randomization to the Abaloparatide-SC/Placebo arms in Study BA058-05-003, up to 1,600 subjects may be entered into this study.

The specific inclusion and exclusion criteria for enrolling subjects in this study are presented below in Sections 4.2 and 4.3, respectively. Exceptions to these criteria should occur infrequently and should be discussed in advance and approved by the Sponsor Medical Monitor.

4.2 Inclusion Criteria

Subjects must meet all of the following criteria to be eligible to participate in this study:

1. The subject was enrolled, randomized to Abaloparatide-SC/Placebo and completed 18-months of blinded treatment within Study BA058-05-003.

2. The subject is no more than 40 days from Visit 9 in Study BA058-05-003.

3. The subject has read, understood, and signed the written informed consent form for the Extension Study.

4.3 Exclusion Criteria

Subjects with any of the following characteristics are not eligible to participate in the study:

1. Subjects who were withdrawn from Study BA058-05-003 for any reason.

2. Subjects who experienced a treatment-related SAE during Study BA058-05-003.

4.4 Withdrawal of Subjects from the Study

Subjects will be informed that they have the right to withdraw from the study at any time for any reason without prejudice to their medical care.

Consistent with the prior protocol, BA058-05-003, the Investigator must withdraw subjects from the study prior at any time in the study for the following reasons:

· Continuing significant deterioration from the Day 1 assessment of Study BA058-05-005 (>7%) of BMD at spine or hip (after confirmation of the finding);

· Treatment-related SAEs;

· Refusal of treatment;

· Refusal or inability to complete study procedures;

· Lost to follow-up.

The Investigator should exercise his/her best judgment and also has the right to withdraw subjects from the study during the study for any of the following reasons:

· ECOG Grade 3 or 4 adverse events [Refer to Appendix14.3];

· A complex of adverse events which, in the judgment of the Investigator justifies treatment cessation;

· Serious intercurrent illness;

· Non-compliance;

· Protocol violations;

· Administrative reasons.

If a subject is withdrawn or discontinued from the study, the reason for withdrawal is to be recorded in the source documents and on the case report form. All subjects withdrawn prior to completing the study should be encouraged to complete the Month 6 or Month 24 Visit (depending on the length of time on study) including any outstanding radiologic assessment or BMD assessment by DXA.

4.5 Temporary Suspension of Treatment

The Investigator has the right to suspend treatment with alendronate without withdrawal of the subject from the study. Reasons for temporary suspension of treatment may include a medical reason unrelated to an adverse event (e.g., a planned procedure), or important social or administrative events. The reason for the suspension of treatment is to be documented in the electronic case report form (eCRF) and in source documents.

When treatment with alendronate is restarted, the subject should resume treatment with the next scheduled dose (as if treatment had not been interrupted).

4.6 Replacement of Subjects

Subjects who have been enrolled into the study and subsequently withdraw or drop out of the study will not be replaced.

5.0 STUDY TREATMENTS

5.1 Study Medications

Alendronate will be sourced locally. Calcium and vitamin D will be provided by the study centers, similar to their provision in Study BA058-05-003.

5.1.1 Alendronate

Alendronate will be sourced centrally for Europe, Hong Kong and the US, and will be sourced locally for South America at the expense of the Sponsor. However, alendronate may be locally sourced in all venues when centrally supplied alendronate is unavailable due to unforeseen delays. The local source will be documented in the study drug logs.

Subjects will receive oral alendronate at a dose of 70 mg once per week beginning on Day 2 for 24 months. Additional provisions for dosing of alendronate should be followed based on the prescribing information. Alendronate provided will be in the approved, marketed formulation. The alendronate may be generic substitutable approved versions which contain different inactive ingredients, but the amount of active free alendronate must be equivalent to 70 mg per week.

5.1.1.1 Restrictions on Alendronate Use

Subjects should not receive alendronate if they have the following conditions/limitations:

· Abnormalities of the esophagus and other factors which delay esophageal emptying such as stricture or achalasia.

· Inability to stand or sit upright for at least 30 minutes.

· Hypocalcemia.

· Known history of hypersensitivity to alendronate, alendronate excipients, or related compounds.

5.1.2 Calcium and Vitamin D Supplements

Calcium and vitamin D supplements will be sourced locally and provided by the sites at the expense of the Sponsor.

5.2 Packaging, Labeling and Storage

Centrally supplied alendronate will not be repackaged for the study, but will be over-labeled according to local regulatory requirements as necessary.

Calcium and vitamin D supplements will not be relabeled for the study.

5.2.1 Storage

Alendronate must be kept in a secure, limited-access storage area until dispensed for use to a study subject. Alendronate sodium should be stored in the container provided at room temperature, 15-30ºC (59-86ºF).

Calcium and vitamin D supplements may be stored at room temperature.

5.3 Treatment Assignment

All subjects who participate will continue to be identified by the same 7-digit subject number that was assigned upon enrollment into Study BA058-05-003 throughout the study and on the eCRF.

5.4 Study Medication Administration

5.4.1 Alendronate Administration

Alendronate must be taken with water only (not mineral water) at least 30 minutes before the first food, beverage or medicinal product (including antacids, calcium supplements and vitamins) of the day. Other beverages (including mineral water), food and some medicinal products are likely to reduce the absorption of alendronate.

The following instructions should be followed exactly in order to minimize the risk of esophageal irritation and related adverse reactions.

· Alendronate should only be swallowed after getting up for the day with a full glass of water (not less than 200 mL or 7 fl. oz.).

· Subjects should only swallow alendronate whole. Subjects should not crush or chew the tablet or allow the tablet to dissolve in their mouths because of a potential for oropharyngeal ulceration.

· Subjects should not lie down until after their first food of the day.

· Subjects should not lie down for at least 30 minutes after taking alendronate.

· Alendronate should not be taken at bedtime or before arising for the day.

At the Month 3, Month 6, Month 12 and Month 18 visits, the unused alendronate tablets are to be returned to the clinic for counting and the subject will be dispensed additional alendronate. At the Month 24 visit, all unused alendronate tablets are to be returned to the study site.

5.5 Treatment Compliance

The study site personnel will perform drug accountability at each clinic visit and review each subject diary (refer to Section 7.1.16). Accountability will be documented on the appropriate forms and subjects will be re-trained on administration as appropriate. All doses of study medication are to be self-administered.

If a subject does not administer or take all study medication including vitamin D or calcium, the reason for the missed dosing is to be recorded in source documents and on the eCRF.

Returned, unused alendronate will be accounted for by the study site and destroyed as appropriate.

5.6 Unblinding of Study Medication

Not applicable.

6.0 CONCOMITANT MEDICATIONS

6.1 Concomitant Medications

Vitamin D and calcium supplements are required to be administered daily from Day 1 (continuing from Protocol BA058-05-003) until the Month 6 Visit. Vitamin D and calcium supplements will be administered in the following doses: 400-800 IU/day (Vitamin D) and 500-100mg/day (calcium), or at a dose to be determined by the Investigator according to the subjects need. The doses and schedule of Vitamin D and calcium supplements, which are part of the study medication protocol, should be adhered to and not be changed other than for medical necessity. The supplements should be taken in the evening with or without food or as otherwise instructed by the Investigator.

For any required concomitant medication, such as statins or antihypertensives, the subject must be on a stable dose at study entry and every effort should be made to maintain a stable dose during study participation.

The occasional use of over-the-counter medications at approved doses (e.g., ibuprofen or acetaminophen) for headache or minor discomfort is allowed. Occasional short term ( < 3 months) use of corticosteroids for seasonal allergies or asthma is also allowed. These are to be recorded on the appropriate case report form. Subjects should not take any other medications, including over-the-counter medications, herbal medications, or mega-doses of vitamins during the study without prior approval of the Investigator.

If it becomes necessary for a subject to take any other medication during the study, the specific medication(s) and indication(s) must be discussed with the Investigator. All concomitant medications taken during the course of the study must be recorded in the Subject’s medical record or source document and transcribed into the case report form.

6.2 Prohibited Medications

Subjects who require treatment during the course of the study with either an anticonvulsant (phenobarbital, phenytoin, carbamazepin or primidone) or chronic treatment with any form of heparin will be discontinued. Estrogens given as HRT are allowed at entry into the study but cannot be initiated during the study except for local low dose vaginal estrogen.

Drugs that may compromise renal function such as non-steroidal anti-inflammatory drugs should be used with caution.

7.0 STUDY ASSESSMENTS

Subjects randomized to Abaloparatide-SC/Placebo in Study BA058-05-003 will receive alendronate at a dose of 70 mg once per week for a total of 24 months.

The assessments performed at each study visit are displayed in the Schedule of Visits and Procedures in Appendix 14.1. Appendix 14.2 provides a more detailed schedule of the study procedures by study visit with a suggested order of procedure conduct. Exact procedures for centrifuging, storage, and shipping of laboratory samples will be detailed in a separate document. The actual time of each blood collection will be recorded on the appropriate source documents and in the eCRF.

Study-specific assessments are to be conducted only after the subject has provided written informed consent to participate in this study. The study assessments are described in more detail in Section 7.1 below.

7.1 Clinical Procedures/Assessments

7.1.1 Informed Consent

At the End-of-Treatment Visit (Visit 9) for Study BA058-05-003, the possibility of participating in the Extension Study will be discussed with the subjects randomized to Abaloparatide-SC/Placebo. The Informed Consent must be signed prior to undergoing any BA058-05-005 study related procedures, and may be signed at either Visit 9 or Visit 10 of Study BA058-05-003.

7.1.2 Recent Health Status

The subject’s health status will be updated from their last visit in Study BA058-05-003, as necessary. Any changes in health status should be recorded as an adverse event, as appropriate.

The physical examination from the End-of-Treatment visit (Visit 9) of Study BA058-05-003 will be the baseline for this study (Day 1).

Interim or symptom-directed physical examinations may be performed at the discretion of the Investigator, if necessary, to evaluate adverse events or clinical laboratory abnormalities.

7.1.3 Vital Signs

Blood pressure, body temperature (ºC), pulse (bpm) and respiration rate (breaths per minute) are to be measured and recorded at each study visit (Day 1, Month 3 and Month 6, Month 12, Month 18 and Month 24). Only the Day 1 blood pressure assessments need be conducted as an orthostatic measurement (See Section 7.1.5).

7.1.4 Height and Weight

Height and weight are to be measured at each study visit (Day 1, Month 3, Month 12, Month 18 and Month 24). Height is to be measured in the standing position using a medical stadiometer.

7.1.5 Orthostatic Blood Pressure and Heart Rate

The Day 1 orthostatic blood pressure measurement for Study BA058-05-005 will serve as the Visit 10 orthostatic blood pressure for Study BA058-05-003. Blood pressure (mmHg; measured in the same arm at each visit) and pulse rate (bpm) will be measured after five minutes in the supine position. Immediately following this measurement, blood pressure will be measured again after three minutes in the standing position.

7.1.6 Electrocardiogram

A twelve-lead supine electrocardiograms (ECGs) will be performed and the following ECG parameters will be recorded: rhythm, heart rate, PR interval, QRS duration and QT/QTc.

The Day 1 ECG measurement for Study BA058-05-005 will serve as the Visit 10 ECG measurement for Study BA058-05-003. An ECG will also be obtained at Month 6.

7.1.7 Clinical Laboratory Evaluations

Clinical laboratory evaluations will be performed by a central laboratory. Prior to starting the study, the Sponsor (or its designee) will provide each Investigator with copies of the appropriate laboratory certifications and normal ranges for all laboratory parameters to be performed by that laboratory.

The blood and urinalysis samples are to be obtained under fasting conditions (NPO for 8 hours; water is acceptable) in the morning of each scheduled study visits on Day 1 and Months 6, 12, 18, and 24.

All clinically significant laboratory abnormities indicating an adverse event will be followed up by repeat testing and further investigated as necessary, according to the judgment of the Investigator.

7.1.8 Clinical Chemistry and Urinalysis (Dipstick)

Clinical chemistry and dipstick urinalysis will be performed on Day 1 and at Months 6, 12, 18, and 24. Urinalysis will be performed using samples freshly voided during the clinic visit. If there are positive findings noted on the dipstick, a urine microscopic examination will be performed. The following tests will be performed:

Serum Chemistry	· Sodium
	· Potassium
	· Chloride
	· Inorganic phosphorus
	· Albumin
	· Total protein
	· Glucose
	· Blood urea nitrogen (BUN)
	· Creatinine
	· Uric acid
	· Aspartate aminotransferase (AST)
	· Alanine aminotransferase (ALT)
	· Gamma-glutamyltranspeptidase (GGT)
	· Creatine phosphokinase (CPK)
	· Alkaline phosphatase
	· Total bilirubin
	· Lactate dehydrogenase (LDH)
	· Cholesterol
	· Triglycerides
	· Total calcium
Urinalysis	· pH
	· Glucose
	· Protein
	· Ketones
	· Bilirubin
	· Blood
	· Urobilinogen

	· Specific gravity
	· Nitrite
	· Leukocytes

7.1.9 Hematology

Hematology testing will be performed on Day 1 and at Months 6, 12, 18, and 24. The following tests will be performed:

Hematology :	· Hemoglobin
	· Hematocrit
	· WBC count with differential in absolute counts
	· RBC count
	· Mean corpuscular volume (MCV)
	· Mean corpuscular hemoglobin concentration (MCHC)
	· Mean corpuscular hemoglobin (MCH)
	· Platelet count

7.1.10 Coagulation

Coagulation testing will be performed on Day 1 and at Months 6 and 24. The following tests will be performed:

	· Prothrombin time (PT)
	· Partial thromboplastin time (PTT)

7.1.11 24-Hour Urine Collection

The 24-hour urine collection is to be begun the day before the Day 1 and Month 6 visits. If a sample was not able to be collected on the day prior to the Day 1 visit (i.e., if the subject had not yet signed the ICF for study participation), a 24-hour urine sample must be collected on the day prior to the Month 3 visit. Subjects are to be instructed to begin the urine collection by discarding the first morning void (~6 a.m.) the day prior to the scheduled clinic visit and to then collect their urine for 24 hours. A final void is to be collected at the end of the 24-hour period and the urine collection transported to the clinic by the subject. The 24-hour urinalysis will be used to measure urinary calcium and urinary creatinine.

7.1.12 Bone Mineral Density

All subjects will have bone mineral density measurements (BMD) taken via DXA at Months 6, 12, 18, and 24. The End-of-Treatment (Visit 9) bone mineral density tests for Study BA058-05-003 will serve as the baseline BMD measurements for Study BA058-05-005.

DXAs will be performed on the hip (femoral neck) and spine (L1-4). The spinal DXA is to be taken in the postero-anterior (PA) projection with any subsequent spinal DXA to be taken in the same projection. Subjects who underwent wrist DXAs in Study BA058-05-003 will also have wrist DXAs performed at Months 6, 12, 18, and 24. The same side of the hip and wrist that were used in Study BA058-05-003 must be used for the DXA scan, and the same scanner should be used throughout the study, when possible.

If the independent radiologist identifies any patient who shows a continuing significant deterioration from the Day 1 assessment of Study BA058-05-005 (>7%) of BMD at spine or hip during the study, the study physician will be notified, the assessment will be repeated

and, if confirmed, the patient will be discontinued from the study. The study physician will make this determination on the basis of the centrally read DXA relative to the baseline measurement in consultation with the Sponsor Medical Monitor.

7.1.13 Serum Markers of Bone Metabolism

Blood samples to measure bone markers will be taken on Day 1 and at Months 6, 12, 18 and 24. The results of the bone markers will be reported in the same subset of subjects reported on for Study BA058-05-003.

The following markers of bone formation will be measured:

· Serum N-terminal propeptide of type I procollagen (PINP);

· Serum bone-specific alkaline phosphatase (BSAP);

· Serum osteocalcin.

The following marker of bone resorption will be measured:

· Serum C-telopeptides of type 1 collagen crosslinks (CTX).

7.1.14 Clinical and Radiologic Evaluation of Fractures

Subjects will undergo protocol directed antero-posterior and lateral radiographs of the lumbar and thoracic spines at Month 6 and Month 24. The End-of-Treatment (Visit 9) clinical and radiological evaluation of fractures for Study BA058-05-003 will serve as the baseline assessments for Study BA058-05-005. Subjects will also be clinically evaluated for non-vertebral fractures (wrist, hip, rib, etc.) that occur de novo during the Treatment Period. Documentation should be obtained on all de novo fractures that occur during the Treatment Period. This documentation should be maintained in the source documents.

All radiographs will be viewed and assessed centrally by a blinded, independent assessor (radiologist) on the basis of existing baseline and study-acquired vertebral deformity. Fractures will be assessed according to the severity scale of Genant (1993). A second blinded radiologist will confirm the assessment of the first reviewer for all subject radiographs in which an incident fracture has been identified. In the case of any disagreement, a third consensus assessment will be made to adjudicate the incident fracture.

Fractures identified during the study will not be recorded as AEs unless the subject is hospitalized, the fracture is complicated, or the Investigator considers the fracture to be unrelated to the subject’s underlying osteoporosis. All fractures (vertebral and non-vertebral) will be identified and evaluated as part of the disease assessment and will be documented in the fracture page of the case report form and source documents.

7.1.15 Abaloparatide Antibody Assessments

The occurrence of anti-drug antibodies will be assessed at the completion of the initial six months of the study. Serum samples will be drawn at Month 6. Any subject who tests positive, or has previously tested positive for antibodies will be retested at six month intervals as deemed medically necessary. Exact procedures for collection, preparation, storage, and shipping of these samples will be detailed in a separate document. The actual time and date of each blood collection will be recorded on the appropriate source document and in the eCRF.

7.1.16 Subject Diaries

A weekly diary will be completed by the subject beginning on the Day 1 visit and continuing until the last day of Month 24. This diary will capture missed doses of vitamin D, calcium and alendronate. The weekly diary will be reviewed at each study visit.

7.1.17 Activity and Diet

Subjects who qualify for enrollment in the study will have no restrictions placed on their usual level of activity or on their usual diet, unless directed by the treating physician for medically justified reasons.

8.0 ADVERSE EVENTS AND SAFETY EVALUATION

Timely, accurate, and complete reporting and analysis of safety information from clinical studies are crucial for the protection of subjects, Investigators and the Sponsor, and is mandated by Regulatory Agencies worldwide. All clinical trials sponsored by RADIUS will be conducted in accordance with Standard Operating Procedures (SOPs) that have been established to conform to regulatory requirements worldwide to ensure appropriate reporting of safety information.

8.1 Definitions, Documentation, and Reporting

8.1.1 Adverse Event Definition

An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product, which does not necessarily have a causal relationship with the treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug, whether or not it is considered to be study drug related. This includes any newly occurring event or previous condition that has increased in severity or frequency since the administration of study drug.

8.1.2 Serious Adverse Event Definition

A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of causality that:

· Results in death.

· Is life-threatening. Life-threatening means that the subject was at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction which hypothetically might have caused death had it occurred in a more severe form.

· Requires in-patient hospitalization or prolongation of existing hospitalization. Hospitalization admissions and/or surgical operations scheduled to occur during the study period, but planned prior to study entry are not considered AEs if the illness or disease existed before the subject was enrolled in the trial. Provided that the illness/disease did not deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier than planned).

· Results in persistent or significant disability/incapacity. Disability is defined as a substantial disruption of a person’s ability to conduct normal life functions.

· Is a congenital anomaly/birth defect. This includes any anomaly detected at or after birth, or any anomaly that results in fetal loss.

· Is an important medical event. An important medical event is an event that may not result in death, be life-threatening, or require hospitalization, but may be considered an SAE when, based upon appropriate medical judgment, it may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definitions for SAEs. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in in-patient hospitalization, or the development of drug dependency or drug abuse.

Clarification should be made between the terms “serious” and “severe” since they are not synonymous. The term “severe” is often used to describe the intensity (synonym: severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as a severe headache). This is not the same as “serious,” which is based on subject/event outcome or action criteria described above and are usually associated with events that pose a threat to a subject’s life or functioning. A severe adverse event does not necessarily need to be considered serious. For example, persistent nausea of several hours duration may be considered severe nausea but not an SAE. On the other hand, a stroke resulting in only a minor degree of disability may be considered mild, but would be defined as an SAE based on the above noted criteria. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.

8.2 Monitoring of Adverse Events and Period of Observation

All AEs will be monitored until they are resolved or have become chronic or stable. AEs and SAEs will be recorded on the case report forms starting from the time of subject entry from Day 1 of the study until the final study visit (Month 24). Any SAEs that occur at any time after completion of the study, which the Investigator considers to be related to study drug, must be reported to the Sponsor or its designee.

8.3 Procedures for Recording and Reporting AEs and SAEs

All adverse events spontaneously reported by the subject and/or in response to an open question from study personnel or revealed by observation, physical examination or other diagnostic procedures must be recorded in the source document and on the appropriate page of the case report form. Any clinically relevant deterioration in laboratory assessments or other clinical findings is considered an adverse event and must be recorded on the appropriate pages of the case report form. When possible, signs and symptoms indicating a common underlying pathology should be noted as one comprehensive event.

All SAEs that occur during the course of the study, as defined by the protocol, must be reported by the Investigator to the Study Safety Officer by completing and transmitting the SAE Form within one working day from the point in time when the Investigator becomes aware of the SAE. In addition, all SAEs including all deaths, which occur up to and including 30 days after administration of the last dose of study drug, must be reported to the Study Safety Officer within one working day. All SAEs and deaths must be reported whether or not considered causally related to the study drug. SAE forms will be provided to the study site. The information collected will include a minimum of the following: Subject number, a narrative description of the event, and an assessment by the Investigator as to the

intensity of the event, and relatedness to study drug. Follow-up information on the SAE may be requested by the CRO, the Study Safety Officer or the Sponsor Medical Monitor. Contact information for reporting SAEs to the Study Safety Officer is provided on the SAE form.

It is the responsibility of the Investigator to promptly notify the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of all serious adverse drug reactions involving risk to human subjects in accordance with the requirements of the IRB/IEC. An unexpected event is one that is not reported in the Investigator’s Brochure.

Planned hospital admissions or surgical procedures for an illness or disease that existed before the subject was enrolled in the trial or before study drug was given are not to be considered AEs unless they occur at a time other than the planned date.

Fractures identified during the study are not to be recorded as AEs unless the subject is hospitalized, the fracture is complicated, or the Investigator considers the fracture to be unrelated to the subject’s underlying osteoporosis. All fractures will be identified and evaluated as part of the disease assessment and will be documented in the case report forms and source documents.

For both serious and non-serious adverse events, the Investigator must determine the intensity of the event and the relationship of the event to study drug administration. Intensity for each AE will be defined according to the following criteria:

Intensity		Definition

Mild		Awareness of sign or symptom, but easily tolerated.

Moderate		Discomfort enough to cause interference with normal daily activities.

Severe		Inability to perform normal daily activities

If the intensity of an adverse event changes within a day, the maximum intensity should be recorded. If the intensity changes over a longer period of time, the changes should be recorded as separate events (having separate onset and stop dates for each intensity).

Relationship to study drug administration will be determined by the Investigator according to the following criteria:

Relationship		Definition

None		No relationship between the event and the administration of study drug. The event is related to other etiologies, such as concomitant medications or subject’s clinical state.

Unlikely		The current state of knowledge indicates that a relationship to study drug is unlikely or the temporal relationship is such that study drug would not have had any reasonable association with the observed event.

Possible		A reaction that follows a plausible temporal sequence from administration of the study drug and follows a known response pattern to the suspected study drug. The reaction might have been produced by the subject’s clinical state or other modes of therapy administered to the subject.

Probable		A reaction that follows a plausible temporal sequence from

administration of the study drug and follows a known response pattern to the suspected study drug. The reaction cannot be reasonably explained by the known characteristics of the subject’s clinical state or other modes of therapy administered to the subject.

For the purpose of safety analyses, all AEs that are classified with a relationship to study medication administration of possible or probable will be considered treatment-related events.

8.4 Rules for Suspension of the Study

As this is an extension study using approved alendronate products it is not anticipated that the study will need to be suspended, and therefore, suspension rules are not assigned. In the event that the prior study (Study BA058-05-003) is suspended, the circumstances of the Study BA058-05-003 suspension will be considered to determine if this study, Study BA058-05-005, should be suspended as well.

9.0 STATISTICAL PROCEDURES

The primary objective of this study is to evaluate data obtained following six months of treatment with alendronate, in subjects who have previously received 18 months of blinded treatment with Abaloparatide-SC/Placebo. Safety data will be obtained with clinical, laboratory and radiologic assessment. Following the initial six months of treatment in this study, subjects will then enter the long-term observational phase of this study during which the subjects will continue to receive alendronate treatment for an additional 18 months.

The specific objectives of this study are to:

· Provide additional information on safety in study subjects receiving six months of treatment with alendronate following 18 months of treatment with Abaloparatide-SC/Placebo.

· Provide information on the vertebral fracture rate of subjects receiving six months of treatment with alendronate following 18 months of treatment with Abaloparatide-SC/Placebo.

· Provide additional information on non-vertebral fractures and BMD change associated with six months of treatment with alendronate following 18 months of treatment with Abaloparatide-SC/Placebo.

· Provide additional information on BMD change and osteoporosis status associated with 24 months of treatment with alendronate after 18 months of treatment with Abaloparatide-SC/Placebo.

The analysis performed at six months will be used as a follow-up to the 18 month fracture endpoint for Study BA058-05-003. Analyses will also be performed cumulatively at Month 12, 18, and 24 (i.e., Visits 4, 5, and 6). Full details of the statistical procedures to be used will be provided in the Statistical Analysis Plan.

9.1 Sample Size

As this is an extension study, no formal sample size analysis was performed for this study. Study data will be tabulated and summarized.

9.2 Randomization, Stratification and Blinding

Osteoporosis treatment will be open label and no randomization is required.

9.3 Populations for Analysis

All analyses and data summaries will be presented for the Intent-to-Treat (ITT) or Safety Population. In addition key selected endpoints will also be analyzed for the mITT and Per Protocol Populations.

9.3.1 ITT (Safety) Population

The Safety Population is comprised of all patients who receive one or more doses of study medication.

9.3.2 Modified Intent-to-Treat Population

The Modified ITT Population includes all patients with Pretreatment and at least one post-baseline evaluable radiologic assessments.

9.3.3 Per Protocol Population

The Per-Protocol (PP) population includes subjects in the mITT population who complied with treatment and did not have any protocol violations.

A protocol violation is defined as a deviation from basic requirements of the study protocol, including inclusion and exclusion criteria, concomitant medication restrictions, or any other protocol requirements that result in a significant added risk to the study subject or has an impact on the quality of the data collected or the outcome of the study.

A protocol deviation is defined as a deviation from the protocol that does not impose added risk to the study design or the study subject. The criteria for the determination of the evaluability of subjects will be defined in the Statistical Analysis Plan.

9.4 Procedures for Handling Missing, Unused, and Spurious Data

All available data will be included in the data listings and tabulations. Where appropriate, imputations of values for missing data for primary and secondary efficacy analyses will be performed as specified in the Statistical Analysis Plan. All data recorded on the CRF will be included in the data listings that will accompany the clinical study report.

9.5 Statistical Methods

9.5.1 Statistical Considerations

Statistical analysis will focus on safety, fracture incidence, including vertebral fracture and BMD change following six months of alendronate treatment in subjects who have previously received 18 months of blinded treatment with Abaloparatide-SC/Placebo. Additional

analyses will also be cumulatively at Month 12, 18, and 24 (i.e., Visit 4, 5, and 6). Full details of these analyses will be provided in the Statistical Analysis Plan.

The efficacy and safety analyses performed at six months will be used as a follow-up to the 18 month fracture endpoint for Study BA058-05-003. Subjects will be analyzed based upon the randomization assignment in the BA058-05-003 study.

9.5.2 Baseline Comparisons

Baseline characteristics, medical history, physical examination, vital signs and ECG, will be summarized using standard descriptive statistics.

9.5.3 Fractures and BMD Analysis

All specified endpoints will be summarized by treatment group and study period using standard descriptive statistics (n, mean, SD, median, minimum, maximum, or n and %, as appropriate). The fracture incidence and BMD results from the additional six months of treatment with alendronate will be analyzed based on the treatment arm they were randomized to in the BA058-05-003 study. These analyses will be conducted on all subjects with baseline and post-baseline data. The analysis performed at six months will be used a follow-up to the 18 month fracture endpoint for Study BA058-05-003.

Vertebral fractures based on radiologic assessments will also be analyzed at Month 24. Additional analyses for the other endpoints will also be performed cumulatively at Month 12, 18, and 24 (i.e., Visits 4, 5, and 6). Full details of these analyses will be provided in the Statistical Analysis Plan.

9.5.4 Safety Analysis

· Incidence and severity of AEs;

· Pathological changes in hematology, chemistry and urinalysis data based on normal ranges supplied by the clinical laboratory, if applicable;

Safety assessments for changes in physical examination, vital signs, ECG, and laboratory tests will be descriptively summarized by treatment and study periods. The results of anti-BA058 testing will be summarized. Concomitant medication classes will be categorized using World Health Organization (WHO) drug dictionary and summarized by number and percent of subjects using each class by treatment group. All treatment emergent adverse events (TEAEs) will be coded for system organ class (SOC) and preferred term (PT) using MedDRA and the number (%) of subjects experiencing each AE (SOC/PT) will be summarized by treatment, relationship to treatment, and severity. All serious adverse events (SAE) will be listed and the number (%) of subjects with an SAE presented by treatment group.

Similar safety analyses will be conducted cumulatively at Months 12, 18, and 24 (i.e., Visits 4, 5, and 6). Full details of these analyses will be provided in the Statistical Analysis Plan.

9.5.5 Procedures for Reporting Deviations to Original Statistical Analysis Plan

All deviations from the original statistical analysis plan will be provided in the final clinical

study report.

9.6 Data Oversight

9.6.1 Central Review of Radiographs and DXA Scans

All radiographs will be viewed and assessed by a blinded, independent assessor (radiologist) on the basis of existing baseline and study-acquired vertebral deformity, and fractures will be assessed according to the method of Genant. A second blinded radiologist will review the assessment of the first reviewer for all subject radiographs in which an incident fracture has been identified. In the case of any disagreement, a third consensus assessment will be made to adjudicate the incident fracture. All study DXA scans will also be evaluated centrally by a blinded independent reviewer. The primary objective of the independent review is to provide objective data to determine the treatment benefit as demonstrated on the pertinent radiologic and clinical data associated with this study.

10.0 ADMINISTRATIVE REQUIREMENTS

10.1 Good Clinical Practice

This study will be conducted in accordance with the International Conference on Harmonization (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirements. The Investigator will be thoroughly familiar with the appropriate use of the study medication as described in the protocol and the Investigator’s Brochure. Essential clinical documents will be maintained to demonstrate the validity of the study and the integrity of the data collected. The Investigator/institution should establish master files at the beginning of the study which will be maintained and updated during the study and retained thereafter according to the appropriate regulations.

10.2 Ethical Considerations

The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki. The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will review all appropriate study documentation in order to safeguard the rights, safety and well-being of the subjects. The study can only be conducted at study sites where IRB/IEC approval has been obtained. The protocol, informed consent form, Investigator’s Brochure, advertisements (if applicable), and all other forms of information given to subjects will be provided to the IRB/IEC by the Investigator. In addition, reports on the progress of the study will be submitted to the IRB/IEC by the Investigator at the appropriate intervals.

10.3 Subject Information and Informed Consent

Each subject (or a legally authorized representative) must give written informed consent prior to any new study-specific procedures being conducted. It is the responsibility of the Investigator to ensure written informed consent is obtained from each subject participating in this study after an explanation of the objectives, methods, discomforts and potential risks of the study has been provided. The Investigator (or study personnel) must also explain to each subject that he/she is free to refuse participation in the study or to withdraw from it at any time. Each subject will also be told that his/her records may be examined by competent authorities and authorized persons but that personal information will be treated as strictly confidential and will not be publicly available.

The informed consent form must be in accordance with the Declaration of Helsinki, ICH and GCP guidelines, and be approved by the Sponsor and the IRB/IEC. State or local laws may require additional information. Each subject (or his/her legally authorized representative) must sign and be given a copy of the informed consent form. Each subject’s signed informed consent form must be maintained by the Investigator and be readily available for review by the Sponsor (or its designee) or the Regulatory Authorities.

10.4 Protocol Compliance

The Investigator will conduct this study in compliance with the protocol provided by the Sponsor and given approval/favorable opinion by the IRB/IEC and the appropriate Regulatory Authority(ies). Changes to the protocol will not be made without agreement of the Sponsor Medical Monitor. All changes to the protocol will require IRB/IEC approval prior to implementation, except when necessary to eliminate an immediate hazard to study subjects or when the change involves only logistical or administrative aspects of the study (e.g., change in Sponsor Medical Monitor or telephone number). The IRB/IEC may provide, if applicable regulations permit, expedited review and approval/favorable opinion for minor changes in ongoing studies. The Sponsor will submit all protocol changes to the appropriate Regulatory Authority in accordance with the governing regulations.

In situations requiring a departure from the protocol, the Investigator or other physician in attendance will contact the Sponsor Medical Monitor by telephone, e-mail or fax. If possible, this contact will be made before implementing any departure from the protocol. In all cases, contact with the Sponsor Medical Monitor must be made as soon as possible in order to review the situation and agree on an appropriate course of action. The case report form and source document will describe any departure from the protocol and the circumstances requiring it.

10.5 Case Report Form Completion

eCRFs will be developed to collect information obtained during this study. It is the Investigator’s responsibility to ensure that the e-CRFs are completed for each subject enrolled in this study and for the accuracy, completeness, legibility and timeliness of the data reported in each e-CRF. Data for subjects who are screened but not enrolled into the study because they do not meet study criteria or do not complete all screening procedures, should be recorded in the e-CRF.

eCRFs will be completed and any corrections of data will be made according to procedures provided by the Sponsor (or designee).

10.6 Source Documents

Source documents are defined as original documents, data and records. This may include hospital records, clinical and office charts, laboratory data/information, work sheets, subjects’ diaries or evaluation checklists, pharmacy dispensing and other records, recorded data from automated instruments, microfiches, photographic negatives, microfilm or magnetic media, ECG printouts, and/or x-rays.

The Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data documents.

10.7 Study Monitoring

The Sponsor (or its designee) will ensure that the study is monitored in accordance with ICH-GCP Guidelines. Monitoring is the act of overseeing the progress of a clinical trial and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures, Good Clinical Practice, and the applicable regulatory requirements and that the study data are accurate, complete and verifiable from source data. All study documentation and other source data will be made available to the Sponsor (or its designee), the IRB and to Regulatory Authorities for inspection upon request.

10.8 On-Site Audits

Representatives of the IRB or the Sponsor (or designee) may visit the study site to carry out an audit of the study in compliance with regulatory guidelines and company policy. Such audits will require access to all study records including source documents, CRFs, and other study documents. Direct access to these study records must be guaranteed by the Investigator, who must provide support for these activities at all times.

Similar auditing procedures may also be conducted by agents of any Regulatory Authority reviewing the results of this study. The Investigator/institution should immediately notify the Sponsor if they have been contacted by a Regulatory Authority concerning an upcoming inspection.

10.9 Drug Accountability

Accountability for the study medication at the study site is the responsibility of the Investigator. Drug accountability will be performed only on alendronate, calcium and vitamin D. The Investigator will ensure that the study medication is used only in accordance with this protocol. Where allowed, the Investigator may choose to assign some of the study medication accountability responsibilities to qualified study personnel.

Study medication accountability records indicating the delivery date to the study site, inventory at the study site and dispensing/use will be maintained. These records will adequately document that the study medications were dispensed and returned as specified in the protocol. Accountability records will include dates, quantities, and subject numbers. The Sponsor (or its designee) will review study medication accountability records at the study site on an ongoing basis during the study. All used and unused study medication must be inventoried, accounted for, and approved by the Sponsor (or its designee) prior to destruction. If the site is not capable of study drug disposal/destruction, the Sponsor will arrange for an alternative method. Records of disposal must be maintained with the study records.

10.10 Record Retention

The Investigator will maintain all study records according to ICH/GCP and applicable regulatory requirements. Essential documents must be retained for two years after the final marketing approval in an ICH region or at least two years have elapsed since the discontinuation of clinical development of the study medication. It is the responsibility of the Sponsor to inform the Investigator of when these documents can be destroyed. In addition, all subject medical records and other source documentation will be kept for the maximum time permitted by the hospital, institution or medical practice.

The Investigator/institution will take measures to prevent accidental or premature destruction of these documents. If the responsible Investigator retires, relocates, or for other reasons withdraws from the responsibility of keeping the study records, custody must be transferred to a person who will accept the responsibility. The Sponsor must be notified in writing of the name and address of the new custodian.

10.11 Study Termination

This study may be terminated at any time by the Sponsor if there is sufficient reasonable cause. Circumstances that may warrant termination include, but are not limited to:

· Determination of unexpected, significant, or unacceptable risk to subjects.

· Failure of enrollment

· Administrative reasons

· Plans to modify, suspend or discontinue the development of the study drug.

In addition, individual study sites may be terminated from study participation for reasons including, but not limited to the following:

· Failure to enter subjects at an acceptable rate.

· Insufficient adherence to protocol requirements.

· Incomplete and/or non-evaluable data.

In all cases, the terminating parties will provide written notification documenting the reason for study termination to all the relevant parties.

Should the study or an individual site be prematurely closed, all study materials (completed, partially completed, and blank CRFs, study drug, etc.) must be returned to the Sponsor (or its designee).

10.12 Liability and Insurance

The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its legal liability for injuries caused to participating persons and arising out of this research performed strictly in accordance with the scientific protocol as well as with applicable law and professional standards.

11.0 USE OF INFORMATION AND PUBLICATION OF STUDY FINDINGS

11.1 Use of Information

All information regarding BA058 supplied by the Sponsor (or its designee) to the Investigator is privileged and confidential information. The Investigator agrees to use this information to accomplish the study and will not use it for other purposes without prior consent from the Sponsor.

The information developed during the conduct of this clinical study is also considered confidential and will be used by the Sponsor in connection with the development of BA058. This information may be disclosed as deemed necessary by the Sponsor to other clinical Investigators, other pharmaceutical companies, and to Regulatory Authorities. To allow for the use of the information derived from this study and to ensure complete and thorough

analysis, the Investigator is obligated to provide the Sponsor (or its designee) with complete study results and all data developed in this study and to allow direct access to source data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory inspection.

11.2 Publication

Results of this study may not be published prior to the completion of this study and completion of the formal clinical study report and other required regulatory reports and documents.

It is anticipated that the results of this study will be presented at scientific meetings and/or published in a peer reviewed scientific or medical journal. A Publications Committee composed of Investigators participating in the study and representatives from the Sponsor as appropriate will be formed to oversee the publication of the study results, which will reflect the experience of all participating study centers.

Subsequently, individual Investigators may publish results from the study in compliance with their agreement with the Sponsor. A pre-publication manuscript must be provided to the Sponsor at least 30 days prior to the submission of the manuscript to a publisher. Similarly, the Sponsor will provide any company prepared manuscript to the Investigators for review at least 30 days prior to submission to a publisher.

The Investigator shall comply with the policy of the Sponsor regarding confidential or proprietary information in any such paper and agrees to withhold publication of same for an additional 60 days in order to permit the Sponsor to obtain patent or other proprietary rights protection, if the Sponsor deems it necessary.

12.0 INVESTIGATOR AGREEMENT

To be completed by the Investigator

I have read Protocol BA058-05-005: “An Extension Study to Evaluate 24 Months of Standard-of-Care Osteoporosis Management Following Completion of 18 Months of BA058 or Placebo Treatment in Protocol BA058-05-003”.

I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for Good Clinical Practice and applicable regulatory requirements and to inform all who assist me in the conduct of this study of their responsibilities and obligations.

The signature below constitutes my agreement to the contents of this protocol.


Signature of Principal Investigator				Date


Principal Investigator (print)


Signature of Sponsor’s Medical Officer (where applicable)



Alan Harris, MD				Date

13.0 REFERENCES

Balena R, Toolan BC, Shea M, Markatos A, Myers ER, Lee SC, Opas EE, Seedor JG, Klein H, Frankenfield D, Quartuccio H, Fiovanti C, Clair J, Brown E, Hayes WC, Rodan GA. The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates. J Clin Invest 1993; 92:2577-2586.

Balena R, Markatos A, Seedor JG, Gentile M, Stark C, Peter CP, Rodan GA. Long-term safety of the aminobisphosphonate alendronate in adult dogs. II Histomorphometric analysis of the L5 vertebrae. J Pharmacol Exp Ther 1996; 276(1):277-83.

Black DM, Bilezikian JP, Ensrud KE, Greenspan SL, Palermo L, Hue T, Lang TF, McGowan JA, Rosen CJ. One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med 2005; 353(6):555-565.

Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonito RP, Rodriguez-Portales JA, Downs RW, Grupta J, Santora AC, Liberman UA, Alendronate Phase III Osteoporosis Treatment Study Group. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Eng J Med 2004 ; 350(12):1189-99.

Devogelaer JP, Broll H, Correa-Rotter R, Coming DC, De Deuxchaisnes CN, Geusens P, Hosking D, Jaeger P, Kaufman JM, Leite M, Leon J, Liberman U, Menkes CJ, Meunier PJ, Reid I, Rodriguez J, Romanowicz A, Seeman E, Vermeulen A, Hirsch LJ, Lombardi A, Plezia K, Santora AC, Yates AJ, Yuan W. Oral alendronate induces progressive increases in bone mass of the spine, hip and total body over 3 years in postmenopausal women with osteoporosis. Bone 1996; 18(2):141-50.

EMEA. Guideline on the evaluation of medicinal products in the treatment of primary osteoporosis. 2007.

FDA. Guidelines for preclinical and clinical evaluation of agents used in the prevention or treatment of postmenopausal osteoporosis. 1994.

FDA. Draft guidance: Development of parathyroid hormone for the prevention and treatment of osteoporosis. 2000.

Fosamax® Prescribing Information. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; 2012.

Genant HK, Wu CY, van KC, and Nevitt MC. Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 1993; 8:1137-1148.

Guidance for Industry. E6 Good Clinical Practice: Consolidated Guidance. U.S.Department of Health and Human Services, Food and Drug Administration. April 1996.

Gullberg B, Johnell O, Kanis JA. World-wide projections for hip fracture. Osteoporos Int 1997; 7:407-413.

Lefage M-H, Balena R, Battle MA, Shea M, Seedor JG, Klein H, Hayes WC, Rodan GA. Comparison of alendronate and sodium fluoride effects on cencellous and cortical bone in minipigs. J Clin Invest 1995; 95:2127-2133.

Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs Jr. RW, Dequeker J, Favus M, Seeman E, Recker RR, Capizzi T, Santora AC, Lombardi A, Shah RV, Hirsch LJ, Karpe DB. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995; 333(22):1437-43.

Reginster JY, Burlet N. Osteoporosis: still increasing prevalence. Bone 2006; 38(Suppl 1):S4-9.

Rittmaster RS, Bolognese M, Ettinger MP, Hanley DA, Hodsman AB, Kendler DL, Rosen CJ. Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab 2000; 85(6):2129-34.

Rizzoli R, Bonjour JP, and Ferrari SL. Osteoporosis, genetics and hormones. J Mol Endocrinol 2001; 26:79-94.

Tucci JR, Tonino RP, Emkey RD, Peverly CA, Kher U, Santora AC 2 nd . Effect of three years of oral alendroneate treatment in postmenopausal women with osteoporosis. Am J Med 1996; 101(5):488-501.

WHO Scientific Group on the assessment of osteoporosis at primary health care level. World Health Organization Summary Meeting Report 2007.

World Medical Association Declaration of Helsinki. The World Medical Association, Inc. 2008.

14.0 APPENDICES

14.1 Schedule of Visits and Procedures

Visit

Procedure

Study Day/Month:

Visit 10 003/
Visit 1(1) 005

Month 3

Month 6

Month 12

Month 18

Month 24

Day

180

360

540

720

Visit Window (Days)

N/A

± 5

± 14

Informed consent

Review of entrance criteria

Recent health status

Vital signs, weight and height measurements(2)

Electrocardiogram

Urinalysis (dipstick) (3)

Chemistry blood collection(4)

Hematology blood collection(5)

Coagulation blood collection(5)

PTH(1-84)

25-hydroxy vitamin D level

1,25-dihydroxy vitamin D level

Serum markers of bone metabolism(5)

BA058 antibody levels

24-hour urine collection (for calcium:creatinine and creatinine clearance)(6)

X(7)

Clinical and radiologic (spine, lumbar and thoracic vertebrae) fracture assessments

Clinical assessment of de novo fractures(8)

Bone mineral density of hip and spine by DXA(9)

Bone mineral density of wrist by DXA(10)

Calcium and vitamin D supplements

Daily

Alendronate administration (if applicable)

Dosing as per prescribing information

Study medication resupply (if applicable)

Subject diary review(11)

Document adverse events and concomitant medications

Daily

(1)The procedures for the Follow-up visit (Visit 10) for Study BA058-05-003 will serve as the procedures performed at Day 1 (for Study BA058-05-005). The consent form will need to be signed if it was not signed during the End-of-Treatment Visit (Visit 9) of Study BA058-05-003.

(2) Vital signs (blood pressure, pulse rate, body temperature, and respiration rate) are to be recorded at each study visit. Only the blood pressure assessment on Day 1 (Visit 10) needs to be orthostatic. Height is to be measured at each visit in the standing position using a medical stadiometer. Weight is to be measured at each visit. Orthostatic blood pressure is to be measured initially after 5 minutes in the supine position and then again after standing for three minutes.

(3) All routine urinalysis will be performed on a sample freshly voided during the clinic visit.

(4) These blood samples are to be obtained under fasting conditions (N.P.O. for 8 hours; water is acceptable) in the morning of each scheduled study visit.

(5) Includes blood samples for PINP, bone-specific alkaline phosphatase, serum osteocalcin and CTX.

(6) Twenty-four hour urine collection will be used for urinary calcium and urinary creatinine measurements. Subjects will discard the 1 st void and begin a 24-hour urine collection the day prior to the clinic visit.

(7) A 24-hour urine collection will be collected at Month 3 only if a sample was not collected for the Day 1 (Visit 10).

(8) Documentation should be obtained on all de novo fractures that occur during the Treatment Period. This documentation should be maintained in the source documents.

(9) Each DXA for a given subject should be performed on the same machine, and if available, preferably by the same technician

(10) Each DXA for a given subject should be performed on the same machine, and if available, preferably by the same technician. Only subjects who had wrist DXA assessments in Study BA058-05-003 will have wrist DXAs performed.

(11) The subjects will maintain a diary throughout the study to record missed doses of medication (including supplements) on a weekly basis; the diaries are to be reviewed with the subject at each study visit.

14.2 Suggested Schedule of Events and Procedures by Study Visit

The purpose of this guide is to provide more detailed instructions for the study procedures listed in Appendix 14.1. This guide presents the procedures in a suggested sequence of performance at each study visit. Further information may be found within the protocol and in other study reference manuals (e.g., ECG, clinical laboratory sample processing).

Of note:

· Blood and urinalysis samples are to be obtained under fasting conditions (NPO. for 8 hours; water is acceptable) in the morning of Day 1 and Months 6, 12, 18, and 24.

· DXA Scans: Always use the same study-validated machine; preferably the same technician.

· The 24-hour urine collection will be started at home the day before the clinic visit where the collection is required. Subjects will be instructed to discard the first morning void and begin the collection at least 24 hours before their clinic visit the following day. They will collect all urine for 24 hours with a final void before coming to the clinic. Routine urinalyses are to be performed using samples freshly voided during the clinic visit. Subjects should receive a reminder to initiate their 24-hour urine 2 days before their scheduled visit.

· Alendronate for Europe, Hong Kong and the US will be sourced centrally; alendronate for South America will be sourced locally by the medical center and reimbursed by the Sponsor.

· Subjects will be instructed to take the calcium and vitamin D supplements daily (in the evening with or without food or as otherwise instructed by the Investigator) until discharge from the study. This is required until the end of Month 24.

Definitions of Common Procedures:

The terms used in the by-visit schedule that follows are further defined below.

Recent health status (document any changes from last visit)

· Question subject regarding any new health issues

· Question subject regarding any new adverse events

· Question subject regarding any new concomitant medications

· Question subject regarding any new issues related to ability to continue with study

Pulse, respiration and temperature:

· Pulse rate (beats/minute) taken after approximately five minutes in the supine position.

· Respiration rate (breaths/minute).

· Body temperature (°C).

Weight and height measurements:

· Weight (kg).

· Height (cm) standing measurements are to be performed using the same medical stadiometer and standardized procedures each time.

Orthostatic blood pressure:

· Orthostatic blood pressure (mmHg) (measured in same arm each time/each visit) is measured after five minutes in the supine position followed by a measurement taken after 3 minutes in the standing position. Only the blood pressure assessment on Day 1 (Visit 10) needs to be orthostatic.

ECG

· Twelve-lead supine electrocardiogram

· Print hard copy for reading by qualified study personnel

· More than one ECG may be performed per time-point.

24 hour urine collection

· Subject to discard first morning void (suggest 6 a.m.) on day before clinic visit

· Subject to collect urine for approximately 24 hours

· Subject to collect final void at end of collection and bring collection to clinic.

· Process for calcium and creatinine

Urinalysis

· Obtain under fasting conditions (NPO. except water for 8 hours)

· Routine urinalysis is to be performed using a sample freshly voided during the clinic visit (microscopic examination if positive dipstick).

Review study medication administration procedures with subject

· Alendronate should be taken daily, preferably at the same time each morning/day of the week

Scheduling and instructions for next clinic visit

· Schedule visit

· Remind subject of any fasting requirements

· Provide urine collection instructions and materials as necessary

· Remind subjects to complete the diaries until the end of the study

Vitamin D and calcium supplements

· Vitamin D and calcium supplements are required throughout the study. Only those supplements supplied as part of study medication may be used and are to be used at the daily recommended dose (see Section 5.1.2) .

· Supplements should be taken in the evening, with or without food as instructed by the Investigator.

· At each study visit, assess the subject’s supply and resupply as necessary.

· Drug usage reconciliation is to be performed when a new supply is provided.

Visit 10 for Study BA058-05-003

Day 1 Visit for Study BA058-05-005

Day 1

VISIT

ACTIVITIES

Day 1

Day 1 Visit for Study BA058-05-005

Visit 10 for Study BA058-05-003

Written informed consent must be obtained

Recent health status

· Document any changes since End-of-Treatment visit (Visit 9) from Study BA058-05-003

Study staff will receive your prior days 24-hour urine sample (if a 24-hour urine sample was not collected prior to Day 1, the subject must begin a 24-hour urine sample on the day prior to the Month 3 visit

Subject diary review

· Review study medication diary (calcium and vitamin D)/dispense new diary if necessary

· Record deviations in dosing or any AEs in source documents and CRFs

· Collect diaries and enter data into CRF

Vital signs, weight and height measurement

Orthostatic blood pressure

ECG

Blood collection: fasting conditions (NPO except water for 8 hours)

· Chemistry

· Hematology

· Coagulation (PT and PTT)

· Serum markers of bone metabolism, where applicable

· PINP

· bone-specific alkaline phosphatase

· serum osteocalcin

· serum CTX

· Urinalysis (Dipstick)

Study medication

· Dispense three month supply of alendronate

· Assess subject’s supply of calcium and vitamin D supplements; resupply as necessary

· Instruct subject to take daily until they are discharged from the study

Scheduling and instructions for next clinic visit

· Remind subject to take study medication as instructed

· 24-hour urine collection: If subjects did not provide a 24-hour urine sample for Visit 1, dispense urine collection container and instruct subjects to perform 24-hour urine collection beginning the morning 24 hours prior to their next scheduled visit (Month 3)

· Remind subject to record study medication use

Month 3 Visit for Study BA058-05-005

Day 90 (±5 days)

VISIT

Activities

Month 3

Recent health status

· Document any changes since previous visit

Study staff will receive the prior days 24 hour urine sample, if applicable

Vital signs, height and weight measurement

Subject diary review

· Review study medication diary/dispense new diary if necessary

· Record deviations in dosing or any AEs in source documents and CRFs.

· Collect diaries and enter data into CRF

Study medication

· Dispense three month supply of alendronate

· Assess subject’s supply of calcium and vitamin D supplements; resupply as necessary, instruct subject to take daily until they are discharged from the study

Scheduling and instructions for next clinic visit

· 24-hour urine collection: Dispense urine collection container and instruct subjects to perform 24-hour urine collection beginning the morning 24 hours prior to their next scheduled visit (Month 6)

· Remind subject to take study medication as instructed

· Remind subject to record study medication use

Month 6 Visit for Study BA058-05-005

Day 180 (±14 Days)

VISIT

Activities

Month 6

Physical Examination

Recent Health Status

· Document any changes from last visit

Collect 24 hour urine sample from subject

Study staff will receive your prior days 24-hour urine sample

· Review diary of study medication

· Collect diary and enter data into CRF, record dosing deviations or any AEs in source documents and CRFs

Vital signs, weight and height measurement

ECG

Blood collection: fasting conditions (NPO except water for 8 hours)

· Chemistry

· Hematology

· Coagulation (PT and PTT)

· Serum markers of bone metabolism, where applicable

· PINP

· bone-specific alkaline phosphatase

· serum osteocalcin

· serum CTX

· BA058 antibody levels

· Urinalysis (Dipstick)

Clinical and radiologic fracture evaluations

· Obtain antero-posterior and lateral radiographs of the lumbar and thoracic vertebrae

· Document any non-vertebral fractures

Bone mineral density

· Perform DXA of spine (L1-L4), hip (femoral neck), and wrist (distal 1/3 radius), where applicable.

Study Medication

· Dispense six month supply of alendronate

· Assess subject’s supply of calcium and vitamin D supplements, resupply as necessary

Scheduling and instructions for next clinic visit

· Remind subject to take study medication as instructed

· Remind subject to record study medication use

Month 12 Visit for Study BA058-05-005

Day 360 (±5 days)

VISIT

Activities

Month 12

Recent health status

· Document any changes since previous visit

Vital signs, height and weight measurement

Blood collection: fasting conditions (NPO except water for 8 hours)

· Chemistry

· Hematology

· Serum markers of bone metabolism, where applicable

· PINP

· bone-specific alkaline phosphatase

· serum osteocalcin

· serum CTX

· Urinalysis (Dipstick)

Bone mineral density

· Perform DXA of spine (L1-L4), hip (femoral neck), and wrist (distal 1/3 radius), where applicable.

Clinical fracture assessmentSubject diary review

· Review study medication diary/dispense new diary if necessary

· Record deviations in dosing or any AEs in source documents and CRFs.

· Collect diaries and enter data into CRF

Study medication

· Dispense six month supply of alendronate

· Assess subject’s supply of calcium and vitamin D supplements; resupply as necessary, instruct subject to take daily until they are discharged from the study

Scheduling and instructions for next clinic visit

· Remind subject to take study medication as instructed

· Remind subject to record study medication use

Month 18 Visit for Study BA058-05-005

Day 540 (±5 days)

VISIT

Activities

Month 18

Recent health status

· Document any changes since previous visit

Vital signs, height and weight measurement

Blood collection: fasting conditions (NPO except water for 8 hours)

· Chemistry

· Hematology

· Serum markers of bone metabolism, where applicable

· PINP

· bone-specific alkaline phosphatase

· serum osteocalcin

· serum CTX

· Urinalysis (Dipstick)

Bone mineral density

· Perform DXA of spine (L1-L4), hip (femoral neck), and wrist (distal 1/3 radius), where applicable.

Clinical fracture assessmentSubject diary review

· Review study medication diary/dispense new diary if necessary

· Record deviations in dosing or any AEs in source documents and CRFs.

· Collect diaries and enter data into CRF

Study medication

· Dispense six month supply of alendronate

· Assess subject’s supply of calcium and vitamin D supplements; resupply as necessary, instruct subject to take daily until they are discharged from the study

Scheduling and instructions for next clinic visit

· Remind subject to take study medication as instructed

· Remind subject to record study medication use

Month 24 Visit for Study BA058-05-005

Day 720 (±5 days)

VISIT

Activities

Month 24

Recent health status

· Document any changes since previous visit

Vital signs, height and weight measurement

Subject diary review

· Review study medication diary

· Record deviations in dosing or any AEs in source documents and CRFs.

· Collect diaries and enter data into CRF

Blood collection: fasting conditions (NPO except water for 8 hours)

· Chemistry

· Hematology

· Coagulation (PT and PTT)

· Serum markers of bone metabolism, where applicable

· PINP

· bone-specific alkaline phosphatase

· serum osteocalcin

· serum CTX

· Urinalysis (Dipstick)

Clinical and radiologic fracture evaluations

· Obtain antero-posterior and lateral radiographs of the lumbar and thoracic vertebrae

· Document any non-vertebral fractures

Bone mineral density

· Perform DXA of spine (L1-L4), hip (femoral neck), and wrist (distal 1/3 radius), where applicable.

Study medication

· Collect unused study medication

Discharge subject from study

· Subject is terminated from the study unless adverse events require further follow through

Discuss continuing treatment options

· Subjects will receive standard-of-care management according to their physician

14.3 Eastern Cooperative Oncology Group (ECOG) Common Toxicity Criteria

Category Toxicity (units)	Grade 0	Grade 1	Grade 2	Grade 3	Grade 4
Haematology
WBC (x10 9 /L)	4	3.0 - 3.9	2.0 - 2.9	1.0 - 1.9	< 1.0
Platelets (x10 9 /L)	WNL	75.0 - normal	50.0 - 74.9	25.0 - 49.9	< 25.0
Haemoglobin (g/L); (mmol/L)	WNL	100.0 – normal; 6.2 - normal	80.0 - 99.0; 5.0 – 6.1	65.0 - 79.0 4.0 – 4.9	< 65.0 < 4.0
Granulocytes/ Bands (x10 9 /L)	2	1.5 - 1.9	1.0 - 1.4	0.5 - 0.9	< 0.5
Lymphocytes (x10 9 /L)	2	1.5 - 1.9	1.0 - 1.4	0.5 - 0.9	< 0.5
Haemorrhage	none	mild, no transfusion	gross, 1 - 2 units transfusion per episode	gross, 3 - 4 units transfusion per episode	massive, > 4 units transfusion per episode
Coagulation
Fibrinogen	WNL	0.99 - 0.75 x N	0.74 - 0.50 x N	0.49 - 0.25 x N	< 0.25 x N
Prothrombin time(quick)	WNL	1.01 - 1.25 x N	1.26 - 1.50 x N	1.51 - 2.00 x N	> 2.00 x N
Partial thromboplastin time	WNL	1.01 - 1.66 x N	1.67 - 2.33 x N	2.34 - 3.00 x N	> 3.00 x N
Metabolic
Hyperglycaemia (mmol/L)	< 6.4	6.4 – 8.9	9.0 – 13.9	14.0 – 27.8	> 27.8 or ketoacidosis
Hypoglycaemia (mmol/L)	> 3.6	3.6 – 3.1	3.0 – 2.3	2.2 – 1.7	< 1.7
Amylase	WNL	< 1.5 x N	1.5 - 2.0 x N	2.1 - 5.0 N	> 5.0 x N
Hypercalcaemia (mmol/L)	< 2.65	2.65 - 2.88	2.89 - 3.13	3.14 - 3.36	> 3.37
Hypocalcaemia (mmol/L)	> 2.10	2.10 - 1.94	1.93 - 1.74	1.73 - 1.52	< 1.51
Hypomagnesaemia (mmol/L)	> 0.58	0.58 - 0.48	0.47 - 0.36	0.35 - 0.24	< 0.23
Gastrointestinal
Nausea	none	able to eat reasonable intake	intake significantly decreased but can eat	no significant intake	—
Vomiting	none	1 episode in 24 hrs	2 - 5 episodes in 24 hrs	6 - 10 episodes in 24 hrs	> 10 episodes in 24 hrs or requiring parenteral support
Diarrhoea	none	increase of 2 - 3 stools/day over pre-Rx	increase of 4 – 6 stools/day, or nocturnal stools, or moderate cramping	increase of 7 - 9 stools/day, or incontinence, or severe cramping	increase of > 10 stools/day or grossly bloody diarrhoea, or need for parenteral support
Stomatitis	none	painless ulcers, erythema, or mild soreness	painful erythema, oedema, or ulcers but can eat solids	painful erythema, oedema, or ulcers and cannot eat solids	requires parenteral or enteral support for alimentation
Liver
Bilirubin (N = 17 µmol/L)	WNL	—	< 1.5 x N	1.5 - 3.0 x N	> 3.0 x N

Category Toxicity (units)	Grade 0	Grade 1	Grade 2	Grade 3	Grade 4
Transaminase (SGOT, SGPT)	WNL	2.5 x N	2.6 - 5.0 x N	5.1 - 20.0 x N	> 20.0 x N
Alkaline phosphatase or 5-nucleotidase	WNL	< 2.5 x N	2.6 - 5.0 x N	5.1 - 20.0 x N	> 20.0 x N
Liver- clinical	No change from baseline	—	—	precoma	hepatic coma
Kidney, bladder
Creatinine	WNL	< 1.5 x N	1.5 - 3.0 x N	3.1 - 6.0 x N	> 6.0 x N
Proteinuria	No change	1 (+) or < 0.3 g% or 3 g/L	2 - 3 (+) or 0.3-1.0 g% or 3-10 g/L	4 (+) or > 1.0 g% or > 10g/L	nephrotic syndrome
Haematuria	Negative	microscopic only	gross, no clots no Rx needed	gross and clots bladder irrigation	requires transfusion or cystectomy
Weight gain/ loss	< 5.0 %	5.0 - 9.9 %	10.0 - 19.9 %	20.00%	—
Pulmonary
Pulmonary	none or no change	asymptomatic, with abnormality in PFTs	dyspnoea on significant exertion	dyspnoea at normal level of activity	dyspnoea at rest
Cardiac
Cardiac arrhythmias	none	asymptomatic, transient, requiring no therapy	recurrent or persistent, no therapy required	requires treatment	requires monitoring; or hypotension, or ventricular tachycardia or fibrillation
Cardiac function	none	asymptomatic, decline of resting ejection fraction by less than 20 % of baseline value	asymptomatic, decline of resting ejection fraction by more than 20 % of baseline value	mild CHF, responsive to therapy	severe or refractory CHF
Cardiac ischaemia	none	non-specific T- wave flattening	asymptomatic, ST and T wave changes suggesting ischaemia	angina without evidence of infraction	acute myocardial infarction
Cardiac- pericardial	none	asymptomatic effusion, no intervention required	pericarditis (rub, chest pain, ECG changes)	symptomatic effusion; drainage required	tamponade; drainage urgently required
Hypertension	none or no change	asymptomatic, transient increase by greater than 20 mmHg (D) or to > 150/100 if previously WNL. No treatment required.	recurrent or persistent increase by greater than 20 mmHG (D) or to > 150/100 if previously WNL. No treatment required.	requires therapy	hypertensive crisis
Hypotension	none or no change	changes requiring no therapy (including transient orthostatic hypotension)	requires fluid replacement or other therapy but not hospitalisation	requires therapy and hospitalisation; resolves within 48 hrs of stopping the agent	requires therapy and hospitalisation for > 48 hrs after stopping the agent

Category Toxicity (units)	Grade 0	Grade 1	Grade 2	Grade 3	Grade 4
Neurologic
Neuro: sensory	none or no change	mild paraesthesias; loss of deep tendon reflexes	mild or moderate objective sensory loss moderate paraesthesias	severe objective sensory loss or paraesthesias that interfere with function	—
Neuro: motor	none or no change	subjective weakness; no objective findings	mild objective weakness without significant impairment of function	objective weakness with impairment of function	paralysis
Neuro: cortical	none	mild somnolence or agitation	moderate somnolence or agitation	severe somnolence, (>50 % waking hours), agitation, confusion, disorientation or hallucinations	coma, seizures, toxic psychosis
Neuro: cerebellar	none	slight incoordination, dysdiadochokinesia	intention tremor, dysmetria, slurred speech, nystagmus	locomotor ataxia	cerebellar necrosis
Neuro: mood	no change	mild anxiety or depression	moderate anxiety or depression	severe anxiety or depression	suicidal ideation
Neuro: headache	none	mild	moderate or severe but transient	unrelenting and severe	—
Neuro: constipation	none or no change	mild	moderate	severe	ileus > 96 hrs
Neuro: hearing	none or no change	asymptomatic, hearing loss on audiometry only	tinnitus	hearing loss interfering with function but correctable with hearing aid	deafness not correctable
Neuro: vision	none or no change	—	—	symptomatic subtotal loss of vision	blindness
Pain
Pain	none	mild	moderate	severe	reg. narcotics
Skin
Skin	none or no change	scattered macular or papular eruption or erythema that is asymptomatic	scattered macular or papular eruption or erythema with pruritus or other associated symptoms	generalised symptomatic macular, papular or vesicular eruption	exfoliative dermatitis or ulcerating dermatitis
Alopecia
Alopecia	no loss	mild hair loss	pronounced or total hair loss	—	—

Category Toxicity (units)	Grade 0	Grade 1	Grade 2	Grade 3	Grade 4
Allergy
Allergy	none	transient rash, drug fever < 38°C (<100.4°F)	urticaria, drug fever 38°C (100.4°F), mild bronchospasm	serum sickness, bronchospasm requiring parenteral medication	anaphylaxis
Local
Local	none	pain	pain and swelling with inflammation or phlebitis	ulceration	plastic surgery indicated
Fever of unknown origin
Fever of unknown origin	none	37.1 - 38.0°C 98.7°- 100.4°F	38.1 - 40.0° C 100.5 - 104°F	> 40.0°C (> 104°F) for less than 24hrs	> 40.0°C (> 104°F) for more than 24 hrs or accompanied by hypotension
Infection
Infection	none	mild	moderate	severe	life-threatening
Additional events
Asthenia	analogous to Karnofsky index (WHO grading)
Chills	analogous to fever
Peripheral oedema	analogous to weight gain
Anorexia	analogous to weight loss

Exhibit 31.1

CERTIFICATIONS

I, Robert E. Ward, certify that:

1. I have reviewed this Quarterly Report on Form 10-Q of Radius Health, Inc.;

2. Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered by this report;

3. Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects the financial condition, results of operations and cash flows of the registrant as of, and for, the periods presented in this report;

4. The registrant’s other certifying officer(s) and I are responsible for establishing and maintaining disclosure controls and procedures (as defined in Exchange Act Rules 13a-15(e) and 15d-15(e)) and internal control over financial reporting (as defined in Exchange Act Rules 13a-15(f) and 15d-15(f)) for the registrant and have:

a. Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our supervision, to ensure that material information relating to the registrant, including its consolidated subsidiaries, is made known to us by others within those entities, particularly during the period in which this report is being prepared;

b. Designed such internal control over financial reporting, or caused such internal control over financial reporting to be designed under our supervision, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles;

c. Evaluated the effectiveness of the registrant’s disclosure controls and procedures and presented in this report our conclusions about the effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and

d. Disclosed in this report any change in the registrant’s internal control over financial reporting that occurred during the registrant’s most recent fiscal quarter (the registrant’s fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably likely to materially affect, the registrant’s internal control over financial reporting; and

5. The registrant’s other certifying officer(s) and I have disclosed, based on our most recent evaluation of internal control over financial reporting, to the registrant’s auditors and the audit committee of the registrant’s Board of Directors (or persons performing the equivalent functions):

a. All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are reasonably likely to adversely affect the registrant’s ability to record, process, summarize and report financial information; and

b. Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant’s internal control over financial reporting.

Date: May 6, 2015

	/s/ Robert E. Ward
	Robert E. Ward
	President and Chief Executive Officer

Exhibit 31.2

CERTIFICATIONS

I, B. Nicholas Harvey, certify that:

1. I have reviewed this Quarterly Report on Form 10-Q of Radius Health, Inc.;

b. Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant’s internal control over financial reporting.

Date: May 6, 2015

	/s/ B. Nicholas Harvey
	B. Nicholas Harvey
	Chief Financial Officer

Exhibit 32.1

CERTIFICATION OF CHIEF EXECUTIVE OFFICER AND

CHIEF FINANCIAL OFFICER PURSUANT TO

18 U.S.C. SECTION 1350, AS ADOPTED PURSUANT TO

SECTION 906 OF THE SARBANES-OXLEY ACT OF 2002

Each of Robert E. Ward and B. Nicholas Harvey hereby certifies, pursuant to 18 U.S.C. Section 1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002, in his capacity as President and Chief Executive Officer (principal executive officer) and Chief Financial Officer (principal financial officer), respectively, of Radius Health, Inc. (the “Company”), that, to his knowledge, the Quarterly Report of the Company on Form 10-Q for the period ended March 31, 2015 as filed with the Securities and Exchange Commission (the “Report”) fully complies with the requirements of Section 13(a) or 15(d) of the Securities Exchange Act of 1934 and that the information contained in the Report fairly presents, in all material respects, the financial condition and results of operations of the Company.

Date: May 6, 2015	By:	/s/ Robert E. Ward
		Robert E. Ward
		*President and Chief Executive Officer*

Date: May 6, 2015	By:	/s/ B. Nicholas Harvey
		B. Nicholas Harvey
		*Chief Financial Officer*

This written statement is being furnished to the Securities and Exchange Commission as an exhibit to the Report, and “accompanies” such Report to which it relates, is not deemed filed with the Securities and Exchange Commission and is not to be incorporated by reference into any filing of the Company under the Securities Act of 1933, as amended, or the Securities Exchange Act of 1934, as amended (whether made before or after the date of the Report to which it relates), notwithstanding any general incorporation language contained in such filing. A signed original of this statement has been provided to the Company and will be retained by the Company and furnished to the Securities and Exchange Commission or its staff upon request.