Item 1. Business
Company Overview
TNI BioTech, Inc., (“TNI BioTech” or “the Company”) was initially incorporated in Florida on December 2, 1993 as Resorts Club International, Inc. (“Resorts Club”). It was formed to manage and market golf course properties in resort markets throughout the United States. Galliano International Ltd. (“Galliano”) was incorporated in Delaware on June 27, 1998. The Company began trading in November 1999 through the filing of a 15C-211. On November 10, 2004, Galliano merged with Resorts Club International, Inc. Resorts Club was the surviving corporation. On February 27, 2012, Resorts Club changed its name to pH Environmental Inc. (“pH Environmental”).
On April 23, 2012, pH Environmental completed a name change to TNI BioTech, Inc., and on April 24, 2012, pH Environmental executed a share exchange agreement for the acquisition of all of the outstanding shares of TNI BioTech, IP. The Company currently operates out of Orlando, Florida and Frederick, Maryland. In July 2012, the Company’s focus turned to acquiring patents that would protect and advance the development of new uses of opioid-related immune- therapies, such as low-dose naltrexone (“LDN”) and Methionine [Met
5
]-enkephalin (“MENK”). The Company’s therapies are believed to stimulate and/or regulate the immune system in such a way that they provide the potential to treat a variety of diseases. We believe our therapies may be able to correct abnormalities or deficiencies in the immune system in diseases such as HIV infection, autoimmune disease, immune disorders, or cancer; all of which can lead to disease progression and life-threatening situations when the immune system is not functioning optimally.
In October 2012, the Company formed TNI BioTech International, Ltd., a BVI company in Tortola, British Virgin Islands. TNI BioTech International was set up to allow the Company to market and sell Naltrexone in those countries outside the U.S. in which we have been able to obtain approval to sell the Company’s products.
In August 2013, the Company formed its United Kingdom subsidiary, TNI BioTech, LTD (the “Subsidiary”). TNI BioTech, LTD received approval to be considered a micro, small or medium-sized enterprise (“SME”) with the European Medicines Agency (“EMA”) on August 21, 2013. The designation provides the Subsidiary with significant discounts when holding meetings or submitting filings to the EMA. On September 19, 2013, the Subsidiary submitted a pre-submission package to the EMA regarding Crohn’s Disease. The EMA granted the Subsidiary a meeting that took place on September 27, 2013. The Subsidiary is eligible to benefit from the provisions for administrative and financial assistance for SMEs set out in Regulation (EC) No 2049/2005.
In December 2013, the Company formed a new subsidiary, Cytocom Inc., to focus on conducting LDN and MENK clinical trials in the United States. The Company expects that the manufacturing of TNI BioTech therapies and their subsequent distribution into emerging nations will continue to be operated directly through TNI BioTech. The Company has entered into consulting arrangements with Dr. Graham Burton, M.D., Ph.D., and Mr. Gary G. Gemignani, to focus on the clinical advancement of LDN and MENK through Cytocom. Dr. Burton will be responsible for leading Cytocom’s global development, clinical research and medical initiatives. Mr. Gemignani will be responsible for operational and business development activities and financial management of Cytocom.
In March 2014, the Company incorporated Airmed Biopharma Limited, an Irish corporation with an address in Dublin, Ireland, and Airmed Holdings Limited, an Irish company domiciled in Bermuda. The Irish companies were set up to benefit from incentives granted by the Irish government for the establishment of pharmaceutical companies (many of the world’s leading pharmaceutical companies have located in Ireland), and so that the Company could take advantage of Ireland's status as a member of the European Union and the European Economic Area (the “Euro Zone”). An Irish limited liability company enjoys a low corporate income tax rate of 12.5%, one of the lowest in the world. The Irish-domiciled company hopes to qualify for
tax incentives for Irish holding/headquartered companies and to benefit from the network of double tax treaties that reduce withholding taxes. TNI BioTech International will manage our international distribution, using product that is manufactured in Ireland and elsewhere.
TNI BioTech is focused on the development and commercialization of therapeutic treatments for cancer, HIV/AIDS and autoimmune diseases and immune disorders by combating these severe and fatal diseases through the stimulation and/or regulation of the body’s immune system. TNI’s growth strategy includes the near-term commercialization of its existing immunotherapies targeting cancer, Crohn’s disease and/or HIV/AIDS. Phase II dose-response studies of LDN are anticipated to begin in late 2014 to early 2015, to be followed shortly by a Phase III study.
Product Development
The drugs currently being developed by the Company include:(i) Methionine [Met
5
]-enkephalin (“MENK”), which is a small synthetic pentapeptide that is naturally produced in the body. Exogenous MENK is being manufactured and developed under the name “IRT-101”; and (ii) naltrexone, a small molecular weight chemical entity that is being developed in low doses under the name “IRT-103.” Both IRT-101 and IRT-103 bind specifically to opioid receptors which are found not only in the central nervous system but also on other cells including immune-mediating cells, cancerous cells and epithelial cells (including those in the gastrointestinal tract) where they play a role in regulation of inflammation, growth, and mucosal repair. Opioid receptors have been associated with most types of immune cells and chemokine receptors, where their interaction involves changes in cell proliferation, alteration of functions, and release of inflammatory cytokines.
The Company seeks to benefit patients with chronic and often life-threatening diseases through the stimulation and/or regulation of the body’s immune system. Using our patented immunotherapy, management believes that the Company’s products, technologies and patents will harness the power of the immune system to improve the treatment of cancer, HIV/AIDS, autoimmune diseases and disorders such as Crohn’s disease.
MENK
MENK is a potent endogenous opioid peptide that influences DNA synthesis and cell growth. MENK interacts with the opioid growth factor receptor (OGFr) which has been shown in nonclinical studies to delay the cell cycle by modulating cyclin-dependent inhibitory kinase pathways. The MENK-OGFr axis is an inhibitory pathway that plays a role in the onset and progression of autoimmune diseases, viral disease (such as HIV/AIDS) and cancer. Studies have shown that the modulation of the MENK-OGFr axis can be accomplished by the administration of exogenous MENK intravenously, or through other methods such as subcutaneous administration.. By regulating this pathway with MENK, this can have a direct impact in maintaining human health and treatment of diseases ( Zagon IS, Donahue R, McLaughlin PJ. Targeting the opioid growth factor: opioid growth factor receptor axis for treatment of human ovarian cancer.
Exp Biol Med (Maywood).
2013 May; 238(5):579-87.
McLaughlin PJ
,
Zagon IS
. The opioid growth factor-opioid growth factor receptor axis: homeostatic regulator of cell proliferation and its implications for health and disease (
Biochem Pharmacol.
2012 Sep 15; 84(6):746-55).
TNI BioTech’s first acquisition was the patents and intellectual property of Dr. Nicholas P. Plotnikoff and Professor Fengping Shan in 2012. While Dr. Plotnikoff was with Oral Roberts University, he was a member of the team that developed and patented the specific application of MENK as a treatment for cancer, HIV/AIDS, and infectious diseases.
Dr. Nicholas Plotnikoff initiated and completed Phase I and Phase II clinical studies of MENK under Investigational New Drug (“IND”) protocols filed with the Food and Drug Administration (“FDA”). In these clinical trials, MENK has been shown to reduce the symptoms of early AIDS and AIDS Related Complex (“ARC”), a condition also known as pre-AIDS which includes symptoms such as fever, diarrhea, weight loss, swollen lymph nodes and herpes. In addition to the therapeutic effects of the treatments, trial reports indicated an elevation in mood of the patients treated (Bihari, B., Plotnikoff, N., Freeman, K., Dowling, J., Duguid, C., and Altmann, E., ‘‘Methionine Enkephalin in the Treatment of ARC,’’ Seventh Int. Conf. on AIDS, Florence, Italy, 1991).
A double-blind, randomized controlled Phase II study of 46 patients was performed with ARC (Bihari B, Plotnikoff NP. Methionine Enkephalin in the Treatment of AIDS-Related Complex.
CRC Press, LLC;
Cytokines: Stress and Immunity
. 1999; 77-91) that was designed to measure the effect of a regular weekly dosing schedule of MENK at two different dose levels. The study involved randomized assignment to three arms: (i) patients on the first arm received weekly doses of 60µg/kg of MENK (low dose) for 12 weeks; (ii) patients on the second arm received a weekly infusion of 60µg/kg of MENK (low dose) for 2 weeks, followed by 10 weekly doses of MENK at 125µg/kg (high dose) and (iii) the patients on the third arm received a placebo intravenously for 12 weeks.
The MENK treatment was generally well tolerated with no significant toxicity observed. The high dose of MENK significantly increased adaptive cell immunity resulting in increased activity of the body’s immune system (e.g. increased IL-2 receptors, CD56 NK and LAK cells, CD3, CD4 and CD8 cells) and a significant reduction in the size of lymph nodes. One patient in the high dose group administered by rapid intravenous infusion experienced dizziness, diaphoresis, elevated blood pressure and decreased pulse rate. These signs and symptoms were responded to with supportive measures.
Recently, Professor Fengping Shan and Dr. Plotnikoff have published, in a number of peer-reviewed international journals, that MENK inhibited regulatory T-cells, increasing the functional activities of T cells and NK cells and, thus, is a key to improved cancer therapy. They additionally published results showing that MENK alone or in combination with Interleukin-2 (“IL -2”) or
Interferon-γ (“IFN-γ”) can enhance the production of interferon- γ or IL-2 from CD4+T cells, respectively (Shan F, Yanjie Xia, Ning Wang, Jingjuan Meng, Changlong Lu, Yiming Meng, Nicolas P. Plotnikoff. Functional modulation of the pathway between dend
ritic cells (DCs) and CD4+T cells by the neuropeptide: Methionine enkephalin (MENK).
Peptides
32. 2011; 929–937). MENK also appeared to be more potent than IL -2 or IFN-γ, alone (Hua H, Changlong Lu, Weiwei Li, Jingjuan Meng, Danan Wang, NicolasP Plotnikoff, Enhua Wang and Fengping Shan. Comparison of stimulating effect on subpopulations of lymphocytes in human peripheral blood by methionine enkephalin with IL-2 and IFN-γ.
Human Vaccines & Immunotherapeutics
8:8, 2012; 1082-1089), two widely known cytokines that have been approved by the FDA for marketing.
Research results indicate that MENK, at suitable doses, boosts the immune system through the following possible mechanisms:
|
●
|
increasing proliferation and functional activities of CD4+T-cells and CD8+T-cells which will play a role in anti-virus and anti-tumor activities;
|
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●
|
increasing maturation of dendritic cells which will initiate and intensify T-cell responses;
|
|
●
|
increasing secretion of cytokines such as IL-2, TNF, IL-12 and IFN-γ which will amplify
the T-cell response and mediate interaction among immune cells, forming a modulated and balanced immunity;
|
|
●
|
increasing functions of macrophages, resulting in enhanced cellular immunity through secreting a set of cytokines; and
|
|
●
|
increasing activity of NK cells which have the ability to kill cancer cells and virus-infected cells.
|
A team from Penn State University ("PSU"), led by Dr. Ian Zagon as the senior basic scientist and Dr. Jill Smith as the senior physician scientist, have shown that in addition to the reported immunotherapy effects of MENK, they have discovered a novel opioid receptor that is highly expressed on cancer cells and on some normal tissue cells, which selectively bind MENK and thereby has been shown to induce direct inhibition of cancer cell growth in the laboratory or in immunodeficient nude mice, and they have decided to refer to MENK as an opioid growth factor (“OGF”). Therefore, MENK has been shown to have therapeutic activity by both immune stimulating effects (binding to OGF receptors (OGFr) on immune cells to increase immune function) and direct anti-cancer inhibitory effects (binding to OGFr on cancer cells to inhibit cell growth).
Based upon published literature, the Company believes that, in oncology in particular, MENK has two possible mechanisms of actions:
|
1.
|
Immune stimulation and regulation effects; and
|
|
2.
|
Direct anti-cancer inhibitory effects.
|
Based upon data from multiple
in vivo
and
in vitro
studies conducted by Zagon
et al.
over the past 15 years, the onset and/or progression of some cancers may be related to defects in MENK and/or OGFr, which would promote or exacerbate tumorigenesis. These findings show there may be an advantage in up-regulating the peptide (e.g., MENK administration) to enhance anti-cancer activity (Zagon IS, Donahue RN, McLaughlin PJ. Opioid growth factor-opioid growth factor receptor axis is a physiological determinant of cell proliferation in diverse human cancers.
Am J Physiol Regul Integr Comp Physiol.
2009;
297: R1154–R1161). Further exploration and clinical trials are needed to confirm MENK’s mechanism of action and its ability to stop the growth of cancerous cells in human subjects with advanced cancer; however, supportive literature around the possible mechanism of actions for MENK are provided below.
MENK as an immune stimulator/regulator
While Dr. Nicholas Plotnikoff was a faculty member at Oral Roberts University, he discovered that all three of the classical opioid receptors are expressed on most subsets of immune cells, and that either
in vitro
incubation with MENK or parenteral administration of and humans, especially those with immunodeficiencies associated with cancer or HIV/AIDS, MENK
in vivo
increased the number and functional activities of T cells, including cytotoxic CD8+ T cells, and also natural killer (NK) cells (Plotnikoff NP, Faith RE, Murgo AJ, Herberman RB, Good RA. Methionine Enkephalin: A New Cytokine – Human Studies.
Clinical Immunology and Immunopathology
. February 1997; 82(2): 93-101). Following those pioneering studies, several other investigators observed that administration of MENK to mice increased CD4+ and CD+ T cells, and increased various immune functions, including cytotoxic activities of both T cells and NK cells (
Wybran J
,
Schandené L
,
Van Vooren JP
,
Vandermoten G
,
Latinne D
,
Sonnet J
,
De Bruyère M
,
Taelman H
,
Plotnikoff NP
. Immunologic properties of methionine-enkephalin, and therapeutic implications in AIDS, ARC, and cancer.
Ann N Y Acad Sci.
1987; 496:108-14). recently, Drs. Fengping Shan and Nicholas Plotnikoff have reported that MENK treatment of mice stimulates the cytotoxic activities of T cells and NK cells and reduces levels of T regulatory cells, and augments therapeutic effects in tumor-bearing immunocompetent mice.
MENK as an inhibitor of cancer cell growth
MENK has been found to exert a profound inhibition on the initiation and progression of human pancreatic cancer
in vitro
and
in vivo
(Zagon IS, Smith JP, McLaughlin PJ. Opioid Growth Factor (OFG) Inhibits Human Pancreatic Cancer Transplanted into Nude Mice.
Cancer Letters.
1997 Jan 30; 112(2):167-175. Zagon IS, Smith JP, Conter R, McLaughlin PJ. Identification and Characterization of Opioid Growth Factor Receptor in Human Pancreatic Adenocarcinoma.
International J of Molecular Med.
2000 Jan; 5(1):77-84.). This led to the discovery that MENK interacted with a novel opioid receptor (OGFr) on human cancer cells (ovarian, SCCHN, pancreatic
, colorectal and others) creating a competitive inhibition profile and subcellular location that is different from other well-known “classic” opioid receptors [mu (µ), delta (δ) and kappa (κ)]. The other “classic” opioid receptors have not been found to h
ave any impact on cell growth; thus there is specificity in the MENK-OGFr interaction which regulates cell proliferation. In an extensive number of experiments that have been conducted on human pancreatic cancer cells in tissue culture exposed to a variety of opioid-related compounds, MENK was the only compound that inhibited cell proliferation. Based upon data from multiple
in vivo
and
in vitro
studies conducted by Zagon
et al
., the onset and/or progression of some cancers may be related to defects in MENK and/or OGFr, which would promote or exacerbate tumorigenesis. These findings show there may be an advantage in up-regulating the peptide (e.g., MENK administration) to enhance anti-cancer activity.
Therefore, as opioid receptors are not only found on cancer cells, but also on most subsets of immune cells, MENK has the ability to not only inhibit cancer cell growth, but also have a direct impact on the patient’s immune system by increasing the number and functional activities of T cells and NK cells.
Zagon and McLaughlin have not recorded in any of their animal studies any side effects of MENK for non-oncological indications such as experimental autoimmune encephalomyelitis (EAE, the mouse model of multiple sclerosis) or relapse-remitting EAE (RR-EAE) with MENK being administered daily. Treatment with MENK or LDN did not exacerbate EAE and was able to halt progression of disease, reverse neurological deficits, and prevent the onset of neurological dysfunction over time (Rahn KA,
McLaughlin PJ
,
Zagon IS
. Prevention and diminished expression of experimental autoimmune encephalomyelitis by low dose naltrexone (LDN) or opioid growth factor (OGF) for an extended period: Therapeutic implications for multiple sclerosis.
LDN
Management believes clinical trials involving low-dose naltrexone (“LDN”) hold great promise for the millions of people worldwide with autoimmune diseases or disorders, central nervous system disorders or those who face cancer. Management also believes it could be the first low-cost, easy to administer therapy with minimal to no side-effects for the treatment of HIV/AIDS, autoimmune diseases and immune disorders, in particular Crohn’s disease, multiple sclerosis, and/or fibromyalgia.
Naltrexone is an orally effective opioid receptor antagonist, used as a treatment for opiate addiction. Naltrexone was originally synthesized in 1963 and patented in 1967. In 1984, the US Food and Drug Administration (FDA) approved naltrexone in a 50 mg dose as a treatment for heroin addiction. Naltrexone 50 mg film-coated tablets have been approved in Europe since at least 1989 for the treatment of opiate addiction and more recently alcohol dependency. At lower doses (approximately 4.5 mg/day), it has been gaining popularity as a treatment for signs and symptoms of autoimmune diseases and immune disorders, HIV/AIDS and cancer. Research studies by others have indicated that the short-term blockage of opioid receptors on circulating and tissue cells by LDN was followed by a substantial rebound in opioid receptor expression and increased levels of
β
-endorphin and methionine-enkephalin (Zagon IS, McLaughlin PJ. Opioid antagonist modulation of murine neuroblastoma: A profile of cell proliferation and opioid peptides and receptors.
Brain Res
. 1989; 480:16–28.)
Oral administration of LDN has been shown to transiently (approximately 4 hours) inhibit opioid receptors which in turn provides a remaining window of approximately 20 hours for the unregulated opioids and receptors to interact (
Donahue RN
,
McLaughlin PJ
,
Zagon IS
. The opioid growth factor (OGF) and low dose naltrexone (LDN) suppress human ovarian cancer progression in mice.
Gynecol Oncol.
2011 Aug; 122(2):382-8).
LDN has been shown to increase the levels of endogenous opioid activity, thereby having the ability to play a direct role in enhancing the human body’s stress resilience, improving psychiatric problems such as autism, in addition to being able to have a direct impact on the immune system and regulation of how the immune system works when faced with disease. LDN is believed to facilitate the body’s own resources to slow down or combat cancers, autoimmune diseases and HIV/AIDS; thus reducing the overall impact and load on the body (Brown N, and Panksepp J. Low-dose naltrexone for disease prevention and quality of life.
Med Hypotheses
. 2008 Mar: 72(3):293-6.).
Naltrexone was originally patented in 1967 by the specialty pharmaceutical company Endo Health Solutions Inc. At the time, it seemed unlikely that naltrexone would be developed because the experimental drug had relatively low market potential, and naltrexone’s patent protection would likely expire before the completion of clinical trials. With the assistance of DuPont, a division of Merck & Co. that acquired Endo in 1969, the US government’s National Institute on Drug Abuse (“NIDA”) advanced naltrexone through the FDA approval process, leading to approval for marketing as a treatment for heroin addiction in a 50 mg dose in 1984. Although its patent expired that same year, naltrexone gained seven additional years of marketing exclusivity for DuPont when the FDA designated it (trademarked as Trexan) an Orphan Drug. Marketing exclusivity provides a pharmaceutical company the right to sell its drug for a certain length of time free of competition from generic versions of the drug and is often granted to encourage companies to develop a use for a drug whose patent has expired or to encourage a company to develop an already approved drug for a new use. With market exclusivity, the anticipated returns on investment are higher, improving the profitability of a drug. With funding provided by the US National Institute on Alcohol Abuse and Alcoholism (“NIAAA”) and the potential to gain three additional years of post-approval market exclusivity for naltrexone, DuPont advanced naltrexone through additional clinical trials, and gained FDA approval for a 50 mg dose (trademarked as ReVia) as a treatment for alcohol abuse in 1995. As naltrexone had already been on the market for 10 years as a treatment for heroin addiction, the FDA’s confidence in its safety resulted in approval only six months after naltrexone’s regulatory application was submitted.
Naltrexone has a black box warning for liver toxicity, which was included based on liver enzyme elevations reported with daily dosing at 100 mg-300 mg. These doses were evaluated in clinical trials for obesity; however, they have not been approved for this use. Our review of the literature and adverse effect reports in naltrexone clinical trials did not demonstrate a risk for liver damage with daily dosing at 50 mg. Although the black box warning does remain, the FDA has stated that naltrexone does not appear to be a hepatotoxin at the recommended doses for the currently approved indications. Recently, naltrexone at 4 mg and 8 mg, in combination with the anti-depressant drug, bupropion at 90 mg, was evaluated as an anti-obesity drug by Orexigen Therapeutics Inc. and submitted for FDA approval in 2010. Data from studies with the drug combination (trademarked Contrave) showed potential hepatotoxicity in 1.2% of subjects treated with Contrave (n = 3,239). [Note: After the FDA requested a long-term study to demonstrate the daily recommended dose of the drug combination (two tablets each with 8 mg naltrexone plus 90 mg bupropion taken twice daily) does not raise the risk of heart attacks, Orexigen initiated a Phase III trial to evaluate Contrave in a study expected to enroll more than 9,000 subjects and is anticipated to be completed in 2017.] Other than its small potential association with liver toxicity at high doses, the most common adverse effects reported with naltrexone are non-specific gastrointestinal complaints such as diarrhea and abdominal cramping.
The following table provides a summary of clinical trials for LDN that have recently been or are being conducted by Pennsylvania State University:
|
Title
|
Indication(s)
|
Dose
|
ClinicalTrials.gov Identifier / Status
|
|
Low Dose Naltrexone for Metastatic Melanoma, Castrate Resistant Prostate Cancer and Renal Cancer
|
Metastatic Melanoma, Castrate Resistant Prostate Cancer and Renal Cancer
|
5 mg/day
|
NCT01650350 /
Currently Recruiting
(verified May 2013)
|
|
Effects of Low Dose Naltrexone in Fibromyalgia
|
Fibromyalgia
|
3-4.5 mg/day
|
NCT00568555 / Completed June 2012
(verified June 2012)
|
|
Low Dose Naltrexone in Symptomatic Inflammatory Bowel Disease
|
Inflammatory Bowel Disease
|
4.5 mg/day
|
NCT01810185 /
Not yet recruiting
(verified June 2013)
|
|
Low-Dose Naltrexone for Glioma Patients
|
Malignant Glioma
|
4.5 mg/day
|
NCT01303835 /
Active, not recruiting
(verified January 2014)
|
|
Low-Dose Naltrexone for Depression Relapse and Recurrence
|
Major Depressive Disorder
Depression, Unipolar
Recurrence
Relapse
|
1 mg/day
|
NCT01874951 /
Recruiting
(verified September 2013)
|
Significant published clinical trial evidence indicates that LDN, particularly daily dosing at 3mg - 4.5 mg, stimulates the immune system and is effective in the treatment of some immunodeficiency diseases, such as HIV/AIDS diseases, and advanced cancer as shown in the studies referenced herein. In addition, LDN has been used quite widely for treatment of a variety of autoimmune diseases and immune disorders. The first clinical trial results with LDN for immune disorders, however, were published only recently in a peer-reviewed medical journal in 2007 which evaluated LDN treatment in a pilot phase II study of 17 patients with Crohn’s disease, a form of inflammatory bowel disease that most commonly affects the ileum and the beginning of the colon. 4 Two-Thirds of patients in this study went into remission after 4.5 mg daily LDN treatment (p < 0.001), with 89% of patients overall showing some degree of response.
An open-label pilot study was conducted by Pennsylvania State University with LDN to evaluate response, safety and toxicity in adult subjects with moderate to severe, active Crohn’s disease. Patients were treated with LDN orally each evening at a dose of 4.5 mg for 3 months. A total of 17 patients were enrolled, 16 of whom completed the study. No laboratory abnormalities were noted. The most common side effect was sleep disturbances (occurred when dosing at night, at about bed-time), occurring in seven patients (41%).
A second clinical study was conducted by Pennslyvania State University as a randomized double-blind, placebo-controlled study to test the efficacy and safety of LDN for 12 weeks in adults with moderate to severe active Crohn’s disease. Forty subjects with moderate to severe active Crohn’s disease were enrolled in the study. Randomized patients received daily oral administration LDN (4.5 mg/day) or placebo. Fatigue was the only side effect reported of statistical significance, and it was greater in subjects receiving placebo.
A pilot Phase II clinical trial was conducted by Pennsylvania State University in children with moderate to severe active Crohn’s disease. Fourteen subjects were enrolled, 12 subjects were randomized and treated with a mean age of 12.3 years (range 8-17 years). Children were randomized to placebo or LDN (0.1 mg/kg or a maximum dose of 4.5 mg) orally for 8 weeks followed by open-label treatment for an additional 8 weeks of LDN at the same dose of 0.1 mg/kg or 4.5 mg. Oral LDN was well tolerated without any serious adverse events.
Adverse Events reported to date in patients with Crohn’s Disease
|
Adverse Event
|
|
Phase 1 Open-label Study in Adults
N=17
|
|
Phase 2 Randomized, double-blind, placebo-controlled study in Adults
N=40
|
|
Phase 2 Pilot study in Children
N=12 a
|
|
|
|
LDN
|
|
Placebo
|
|
LDN
|
|
Placebo
|
|
LDN
|
|
Sleep disturbance
|
|
7
|
|
5
|
|
5
|
|
2
|
|
2
|
|
Unusual dreams
|
|
1
|
|
3
|
|
2
|
|
0
|
|
2
|
|
Insomnia
|
|
5
|
|
0
|
|
0
|
|
0
|
|
0
|
|
Nausea
|
|
1
|
|
4
|
|
4
|
|
0
|
|
1
|
|
Hair thinning/ Hair loss
|
|
1
|
|
1
|
|
0
|
|
1
|
|
0
|
|
Hair growth
|
|
0
|
|
0
|
|
1
|
|
0
|
|
0
|
|
Blurred vision
|
|
1
|
|
0
|
|
0
|
|
0
|
|
0
|
|
Irritability
|
|
1
|
|
0
|
|
0
|
|
0
|
|
0
|
|
Mood swings
|
|
1
|
|
0
|
|
0
|
|
0
|
|
0
|
|
Mild disorientation
|
|
1
|
|
0
|
|
0
|
|
0
|
|
0
|
|
Twitching
|
|
0
|
|
0
|
|
0
|
|
1
|
|
1
|
|
Headaches
|
|
0
|
|
2
|
|
4
|
|
1
|
|
0
|
|
Decreased appetite/ Loss of appetite
|
|
0
|
|
0
|
|
2
|
|
1
|
|
0
|
|
Fatigue
|
|
0
|
|
3
|
|
0
|
|
1
|
|
0
|
|
Flushed ears
|
|
0
|
|
0
|
|
0
|
|
0
|
|
1
|
|
Papules, rash
|
|
0
|
|
0
|
|
0
|
|
1
|
|
0
|
|
Double vision
|
|
0
|
|
0
|
|
0
|
|
0
|
|
1
|
|
Flatulence
|
|
0
|
|
5
|
|
6
|
|
0
|
|
0
|
|
Vomiting
|
|
0
|
|
1
|
|
3
|
|
0
|
|
0
|
|
Diarrhea
|
|
0
|
|
5
|
|
7
|
|
0
|
|
0
|
|
Abdominal Pain
|
|
0
|
|
5
|
|
5
|
|
0
|
|
0
|
|
Constipation
|
|
0
|
|
0
|
|
2
|
|
0
|
|
0
|
a Fourteen (14) subjects were enrolled, 12 subjects were randomized and treated
(Smith J.
et al
., 2007; Smith J.
et al
., 2011; Smith J.
et al
., 2013).
Pennsylvania State University researchers have also demonstrated in a mouse model of Crohn’s disease (chemically induced colitis with dextran sodium sulfate) that opioid receptor blockade by LDN resulted in less weight loss, lower disease activity index scores and less histological evidence of inflammation when compared to controls. Furthermore, the researchers demonstrated that tissue inflammatory cytokine mRNA was reversed to baseline levels in the colons of mice treated with LDN.
Management believes in LDN’s potential treatment effects for Crohn’s disease, as the treatments currently available for Crohn’s disease do not control the disease well and there are major side effects associated with virtually all of the currently used drugs. In addition, most of these drugs are very expensive. Management believes that LDN provides an attractive alternative. Three published clinical trials in patients with moderate to severe disease, two in adults and one in children, have shown significant disease and quality of life improvement by 12-weeks. LDN was able to reverse the inflammatory activity, promote mucosal healing, and significantly decrease histologic inflammation when compared to placebo-treated controls (Smith J.
et
al,
2011; Smith J.
et
a
l,
2013). Based on these results, the Company has placed a very high priority on implementing a Phase II dose response study by late 2014 to early 2015. By using the 505(b)(2) pathway, confirmation of efficacy in our Phase III study is expected to result in approval by the FDA.
With its increasing recognition in children and adolescents, Crohn’s disease has become one of the most significant chronic diseases that affect young people. Pediatric Crohn’s disease affects approximately 80,000 patients in the United States, and thus has led to orphan drug designation with the FDA. In addition to the common GI symptoms due to inflammation in the small and/or large intestine, children often experience growth failure, malnutrition, pubertal delay, bone demineralization, and psychological issues. Crohn’s tends to be both severe and extensive in the pediatric population with a relatively high proportion of pediatric Crohn’s patients having involvement of their small intestine, proximal to the ileum.
The 505(b)(2) Regulatory Pathway
Traditionally, pharmaceutical drugs had to be approved by the FDA under the standard 505(b)(1) regulatory pathway, which could take as long as 15 years. Now, drugs approved under 505(b)(2) may rely in part on data from existing reference drugs meaning they can be developed and achieve FDA approval in as little as 30 months with only a fraction of the number of required clinical trials and at a much lower cost.
Developing LDN using the 505(b)(2) regulatory pathway decreases the amount of development time and cost in order to obtain FDA approval. As naltrexone is an FDA-approved product for alcohol or opiate dependence, prescriptions are currently being filled for naltrexone in 50 mg doses by hundreds of local pharmacies and mail-order pharmacies around the United States.
The FDA’s 505(b)(2) pathway for approving drugs opens the door for the Company to gain FDA approval of LDN (which is used at doses of approximately 1/10
th
the approved dose) for new diseases. A 505(b)(2) drug application for LDN will contain full reports of clinical investigations to support the safety and effectiveness in the new indication(s); however, at least some of the information required for approval will come from studies not conducted by or for the applicant, and for which the applicant has not obtained a right of reference or use, as many of these drugs are now off-patent. With the opportunity to use previous findings of safety, the Company intends to use the 505(b)(2) pathway to study and gain approval for LDN in other diseases, with Crohn’s disease slated as its first therapeutic indication.
As there is a sufficient database of information around the safety of this product, and the reference listed drug (NDA 018932 REVIA) is being used, the FDA agreed that a 505(b)(2) application would be an acceptable approach at this time.
Intellectual Property
The Company has been developing active forms of immunotherapies through the acquisition of patents, Investigational New Drug (“IND”) Applications, clinical data and all proprietary technical information, know-how, procedures, protocols, methods, prototypes, designs, data and reports which are not readily available to others through public means, and which were owned, generated or developed through experiments or testing by Dr. Plotnikoff, Professor Shan, Dr. Bernard Bihari, Dr. Ian S. Zagon, Dr. Jill Smith, Dr. Patricia J. McLaughlin and Moshe Rogosnitzky.
The Company’s management believes that to be successful, it was imperative to not only acquire all of the intellectual property and patents but also the scientist(s) behind their development. To date, the Company has been able to acquire many of the patents and intellectual property it was seeking, and has also been able to team up with some of the leaders in the field of immunology, experts such as the late Dr. Ronald Herberman (1940-2013), Dr. Angus Dalgleish and Dr. Joseph Fortunak.
Dr. Plotnikoff is the inventor behind a number of patents granted for cancer treatments and an adjunct to patents for autoimmune diseases including: European Patent United Kingdom, Germany, France, Ireland EP 1401471 BI Methods for inducing sustained immune response; Russian Patent Russian Federation patent number 2313364; The Patent Office of the People’s Republic of China, Application No.: 200810165784.8 China Patent CN1015113407 A The Patent Office of the People’s Republic of China ISSN: 1006-2858 CN 21-1349/R; Patent Agencies Government of India Patent, Application number 1627/KOLNP/2003 number 220265 an Enkephalin Peptide Composition; and the US Patent Pending, US Patent Application 10/146.999 e (the “Plotnikoff Patents”). The Patent Cooperation Treaty (“PCT”) enables a U.S. applicant to file a single application, known as “an international application,” in a standardized format in English in the U.S. Receiving Office (the U.S. Patent and Trademark Office) that is acknowledged as a regular national or regional filing in any state or region that is party to the PCT.
The Company entered into a Sale of Technology Agreement with Dr. Nicholas P. Plotnikoff on March 4, 2012, wherein Dr. Plotnikoff agreed to transfer and assign all of his rights, title and interest in the Plotnikoff Patents to the Company. The Company received all the production formulations and technology designs from Dr. Plotnikoff necessary for the manufacturing, formulation, production and protocols of the MENK treatment of cancer and HIV/AIDS. As consideration for entering into the Sale of Technology Agreement, Dr. Plotnikoff received 8,000,000 shares of common stock, a royalty of a single-digit percentage on all sales of MENK and was granted the position of Non-Executive Chairman of the Board of Directors.
In addition to the above patents, TNI also signed an exclusive licensing agreement for all of the intellectual property developed at Pennsylvania State University by Dr. Ian S. Zagon, Dr. Patricia J. McLaughlin and Dr. Jill P. Smith for the treatment of cancer. The patents cover methods and formulations related to the treatment and prevention of cancers. More specifically, the present inventions describe the use of drugs that interact with opioid receptors (naltrexone, naloxone and the pentapeptide MENK) to inhibit and arrest the growth of cancer. Such efficacy has been discovered to be partially due to the functional manipulation of the zeta opioid receptor through exogenous and endogenous MENK. This receptor has been determined to be present in a variety of cancers, including pancreatic, ovarian, liver, head and neck, and colon cancer. US Patent Numbers 6,737,397, CA 2,557,504,
US 20010046968
,
US 6737397
,
US 6136780
,
US 20080015211
,
US 20070053838
,
US 8003630
,
US 20110123437
,
US 7807368
,
US 7576180
,
US 7517649
,
US 20080146512
,
US 7122651
,
US 20060073565
,
US 20050191241
, Patent No 8,003,630.
TNI also acquired the licensing rights to the patent portfolio and intellectual property developed by Dr. Bernard Bihari relating to treatments with drugs that interact with opioid receptors such as LDN and MENK for a variety of diseases and conditions including malignant lymphoma, chronic lymphocyctic leukemia, Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma, chronic herpes virus infections, and chronic infections due to the Epstein-Barr virus and a treatment method for humans infected with HTLV-III (AIDS) virus including patients clinically diagnosed as suffering from HIV/AIDS and those suffering from HIV/AIDS-related complex (“ARC”). The licensed rights include all reissues or modifications, reexaminations, or other related U.S. patent filings directed to the same subject matter and the use of
U.S. Patent Number 6,586,443
,
U.S. Patent Number 6,384,044
,
U.S. Patent Number 6,288,074
,
U.S. Patent Number 5,356,900
,
U.S. Patent Number 5,013,739
,
U.S. Patent Number 4,888,346
.
Once the Company acquired the above patents, it was then able to sign a licensing agreement to acquire the exclusive patent rights for the intellectual property of Dr. Jill Smith and LDN Research Group, LLC, whose members include Dr. Ian S. Zagon, Dr. Patricia J. McLaughlin and Moshe Rogosnitzky. The patents cover methods and formulations for the treatment of the inflammatory and ulcerative diseases of the bowel, using naltrexone in low doses as an opioid antagonist. Endogenous opioids and opioid antagonists at low doses have been shown to play a role in stimulating and rebalancing the immune system and the healing and repair of tissues. US Patent No. 6,136,780, Patent No. US 7879870. The Company then negotiated with Dr. Jill Smith to arrange the transfer of the Orphan Drug Designation for the use of naltrexone for the treatment of pediatric Crohn’s disease with the FDA. Dr. Smith has since transferred the IND to TNI BioTech, and the FDA has acknowledged that the Company is now the sponsor for this IND.
The Company acquired these patents and intellectual property because management believes clinical trials involving LDN hold great promise for the millions of people worldwide with autoimmune diseases or disorders, central nervous system disorders or those who face cancer. Management also believes it could be the first low-cost, easy to administer therapy with minimal to no side-effects for the treatment of HIV/AIDS, autoimmune diseases and immune disorders, in particular Crohn’s disease, multiple sclerosis, and/or fibromyalgia.
The Company is in discussion with a number patent holders regarding additional patents surrounding LDN and MENK. The Company has also recently obtained a license from Professor Shan for the exclusive rights to patents that were filed and approved in China.
Patents Overview:
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Patent:
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Title:
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Expiration:
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License:
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Product or Use:
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U.S. Patent Number 6,586,443
(Related to US 5,356,900, 5,013,739 and 4,888,346 – all expired)
(No related foreign patents)
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|
Multiple sclerosis in a human patient is treated by the administration preferably via a pharmacologically effective route of an essentially pure opiate receptor antagonist.
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January 3, 2019
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Exclusive License from Jacqueline Young.
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IRT-103 (LDN)
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U.S. Patent Number 6,384,044
(No related foreign patents)
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Cancer of the prostate in human male patients even at an advanced state with metastasis to other organs is preferably treated by administration.
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November 8, 2019
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Exclusive License from Jacqueline Young.
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IRT-103 (LDN)
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U.S. Patent Number 6,288,074
(No related foreign patents)
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Lymphoproliferative syndrome, including such diseases as malignant lymphoma, chronic lymphocytic leukemia, Hodgkin's lymphoma, and non-Hodgkin's lymphoma, are treated in human patients via administration.
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November 15, 2019
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Exclusive License from Jacqueline Young.
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IRT-103 (LDN)
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US Patent Number 6,136,780
(Related to US 6,737,397)
(No related foreign applications)
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Control of cancer growth through the interaction of [Met5] - Enkephalin and the zeta (s) receptor.
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May 17, 2021
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Exclusive License: Penn State University.
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IRT-101 (MENK)
and IRT-103 (LDN)
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US Patent No. 6,737,397
(Related to US 6,136,780)
(No related foreign applications)
|
|
Control of cancer growth through the interaction of [Met5]-Enkephalin and the zeta receptor.
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May 17, 2021
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Exclusive license: Penn State University.
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IRT-101 (MENK)
and IRT-103 (LDN)
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US Patent No. 7,879,870
(US PgPub 2008/0015211)
(No related foreign patents)
|
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Treatment of inflammatory and ulcerative diseases of the bowel with opioid antagonists.
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February 1, 2028
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License with Dr. Jill Smith and LDN Research Group, LLC.
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IRT-103 (LDN)
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Israeli Patent mentioned in license
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Treatment of inflammatory and ulcerative diseases of the bowel with opioid antagonists.
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Pending
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License with Dr. Jill Smith and LDN Research Group, LLC.
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Treatment of Crohn’s disease
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US Application Number: 11/061,932
(Claims Priority to US60/548,021)
Canadian Application Number: 2,557,504 (Pending)
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Combinatorial therapies for the treatment of neoplasias using the opioid growth factor receptor.
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Pending application
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Exclusive license: Penn State University.
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IRT-101 (MENK)
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US Patent No. 8,003,630 (Application Number: 11/510,682)
(US PgPub 2007/0053838)
(Claims Priority to US60/548,021)
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Combinatorial therapies for the treatment of neoplasias using the opioid growth factor receptor.
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May 22, 2028
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Exclusive license: Penn State University.
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IRT-101 (MENK)
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US PgPub 2013/0084242 A1
(Application Number: 13/660,129)
(Claims Priority to US60/548,021)
Patent Cooperation Treaty (PCT) application:
PCT/US2010/030967
(Claims priority to US61/173,351)
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Combinatorial therapies for the treatment of neoplasias using the opioid growth factor receptor.
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Pending
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Exclusive license: Penn State University.
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IRT-101 (MENK)
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US 7,807,368
(US PgPub 2008-0146512 A1)
(No related foreign applications)
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Cyclin-dependent kinase inhibitors as targets for opioid growth factor treatment.
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October 4, 2027
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Exclusive license: Penn State University.
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IRT-101 (MENK)
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US 7,576,180
(Claims priority to US60/106,879)
(There is a related PCT application PCT/US1999/025802, claiming priority to the US60/106,879, but no National Phase applications were filed)
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Opioid growth factor receptors.
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August 17, 2026
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Exclusive license: Penn State University.
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IRT-101 (MENK)
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US 7,122,651
(No related foreign applications)
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Novel nucleic acid molecules encoding opioid growth factor receptors.
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October 17, 2023
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Exclusive license: Penn State University.
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Treatment of cancer
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US 7,517,649
(US PgPub 20060073565)
(No related foreign applications)
|
|
Methods of detecting opioid growth factor receptor (OGFr) in tissue.
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April 13, 2026
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Exclusive license: Penn State University.
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IRT-101 (MENK)
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CN 200910011030
(No related US applications)
|
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Shan Fengping, Nikola Polonikov, Lu Changlong: Application of naloxone and composition thereof in preparing drug for treating cancer. Shan Fengping: August 26, 2009.
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August 23, 2026
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Exclusive license: Nicholas Plotnikoff and Fengping Shan.
|
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IRT-101 (MENK)
and IRT-103 (LDN)
|
|
CN 200710051586
(No related US applications)
|
|
Huang Jianyin, Zhang Ding, Shan Fengping, Luo Zhinong: Application of methionine enkephalin in preparing human or animal vaccination. Huang Jianyin: August, 20 2008.
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|
August 20, 2025
|
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Exclusive license: Nicholas Plotnikoff and Fengping Shan.
|
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IRT-101 (MENK)
|
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CN 200710158742
(No related US applications)
|
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Shan Fengping, Lv Changlong, Nikola Polonikov, Huang Jianyin: Application of compounds Methionine Enkephalin for preparing medicine for curing blood medulla hematopoietic system cancer. Dan Fengping: May 14, 2008.
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May 13, 2025
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Exclusive license: Nicholas Plotnikoff and Fengping Shan.
|
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IRT-101 (MENK)
|
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CN 200610046249
(No related US applications)
|
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Shan Fengping, Lv Changlong, Huang Jianyin, Zhang Ding, Luo Zhinong: Aerosol containing Met-Enkephalin. Shan Fengping: November 15, 2006.
|
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November 14, 2023
|
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Exclusive license: Nicholas Plotnikoff and Fengping Shan.
|
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IRT-101 (MENK)
|
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CN 200310120896
(No related US applications)
|
|
Shan Fengping, Li Li: Integrated health food for regulating human body immune balance. Liaoning Academy of Microorganism Sciences: July 6, 2005.
|
|
July 5, 2022
|
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Exclusive license: Nicholas Plotnikoff and Fengping Shan.
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Oncology treatments
and cancer treatment
|
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WO 2007/067753
(PCT/US2006/046925
|
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Huang John, Chang Ding, Lo Shi-Lung, Shan Fengping: Methods of reducing side effects in cancer therapy. Penta Biotech: June 14, 2007.
|
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Pending
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Exclusive license: Fengping Shan.
|
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IRT-101 (MENK)
|
|
CN 200510019964
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Huang Jianyin, Zhang Ding, Luo Zhinong, Shan Fengping: Use of Methionine Enkephalin in preparation of medicine for reducing toxic side effects of chemical or radioactive therapy. Huang Jianyin: August 9, 2006.
|
|
August 8, 2023
|
|
Exclusive license: Fengping Shan.
|
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IRT-101 (MENK)
|
|
US PgPub 2003/0148942 A1
(Application Number: 10/146,999)
Our Docket #6463-0101PUS1
(Claims Priority to US60/291,237)
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Methods for inducing sustained immune response.
|
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May 16, 2022
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Assigned and licensed: Nicholas Plotnikoff.
|
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IRT-101 (MENK)
|
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Russian Application 2003136161/14
(Claims Priority to US60/291,237)
|
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Methods for inducing sustained immune response.
|
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May 16, 2022
|
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Assigned and licensed: Nicholas Plotnikoff.
|
|
IRT-101 (MENK)
|
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PCT application PCT/US2002/018529
(Claims priority to the US60/291,237)
|
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Methods for inducing sustained immune response.
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May 16, 2022
|
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Assigned and licensed: Nicholas Plotnikoff.
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IRT-101 (MENK)
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National Phase entries filed off the PCT/US2002/018529
China 02814327.2
(Pending)
EP App 2002746503 Granted: November 29, 2006
India Patent No. 220265 (App 01627/KOLNP/2003)
Japan App Withdrawn
|
|
Methods for inducing sustained immune response.
|
|
May 16, 2022
|
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Assigned and licensed: Nicholas Plotnikoff.
|
|
IRT-101 (MENK)
|
|
China Patent 200810229085
|
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The invention belongs to the technical field of treating tumors by immunization therapy. In particular, a method for treating intestinal cancer and pancreatic cancer cells by Methionine Enkephalin under conditions of in-vivo injection and in-vitro cell culture so as to achieve the treating aim.
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March 21, 2026
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Licensed: Fengping Shan.
|
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IRT-101 (MENK)
|
Overview of Immunotherapy
The role of the immune system in counteracting the development of cancer was initially supported by individual clinical case reports, when it was observed that cancer occurs more frequently in individuals with compromised immune systems. In groundbreaking work in the late 1800s, it was noted that some cancer patients suffering from bacterial infections had regression in their tumors. In trying to fight off the bacterial infection, the patients’ immune systems had become highly activated, thus affording some resistance to the tumor. Since then there have been hundreds of clinical trials conducted to evaluate numerous candidates and decades of research by countless scientists. In April 2010, Provenge became the first cancer immunotherapy to acquire FDA approval.
Immunotherapy History
More than 100 years after researchers first explored the potential to harness the body’s immune system to fight cancer, many of the field’s leading doctors believe the concept will finally prove itself on a large scale within the next two years. A number of large companies now work on immunotherapy drugs for the treatment of cancer and, if proven successful, could gain a significant share of the global market for oncology drugs. IMS Health estimates the oncology drug market will reach $75 Billion by 2015 (The Global Use of Medicines: Outlook Through 2015, IMS Institute for Healthcare Informatics (2011), available at http://www.imshealth.com/deployedfiles/ims/Global/Content/Insights/IMS%20Institute%20for%20Healthcare%20Informatics/Global_Use_of_Medicines_Report.pdf). Scores of new immunotherapy vaccines and other immune system modifiers are being tested against a variety of cancers. The new understanding of how immunotherapies work may demand a revised definition of clinical success.
Antigen Presentation
Antigen presentation is a process in the body’s immune system by which antigen-presenting cells (“APCs”), such as macrophages, B-lymphocytes, dendritic cells and other types of cells, process and present antigens on their surfaces to effector cells in the immune system and enable their recognition, inducing two major types of defense (i.e., adaptive and innate) against the target protein. The adaptive response is thought to be “specific” and is composed of highly specialized, systemic T and B cells and processes that eliminate or prevent disease, whereas the innate response is active spontaneously, is “non-specific,” and reacts against foreign cells immediately. There are several types of cells involved in the innate immune response, especially natural killer (“NK”) cells and dendritic cells which are present in tissues in contact with the external environment and have garnered the most research interest as antigen presenting cells. Tumor cells display a number of proteins on the cell surface that signal to the immune system that these cells are not normal, healthy cells. As a result, cancer patients often have specific anti-tumor antibodies and T-cells circulating in their blood, demonstrating that the immune system detected the tumor cells and mounted a specific response.
In many cases, the immune system response fails due to strategies that tumor cells use to evade immune detection. These strategies range from methods designed to hide tumor cells, to active incapacitation of immune cells by tumor-produced agents that lower the immune system’s responses. Based on the types of antigens and method of their presentation used, the following immunotherapy strategies have been evaluated:
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●
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Active Immunotherapy by which drugs or vaccines stimulate the body’s own defenses to fight disease;
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●
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Adoptive Immunotherapy which uses immune system components (e.g., antibodies, cytokines, or immune cells) created outside the body and then administered to patients; and
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Non-Specific Immunotherapies which stimulate the body’s immune system in general ways, including activity against cancer cells or virus-infected cells.
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While extending life is the gold standard, most cancer drug trials have been deemed successful when tumors shrink or when a treatment can demonstrate a delay in tumor growth or in worsening of the disease, known as progression-free survival (“PFS”). New approaches based on more recent knowledge of the immune system include activating a variety of cells to go after tumors and modifying mechanisms that keep either the immune system in check or turn it loose.
Immunotherapy presents a number of potential advantages over approved cancer treatments. The traditional tools for treating cancer have been around for years, including radiation, which has been used since the 1800s; surgery; and chemotherapy, which evolved from the original use of mustard gas after World War I. All of these treatments are based on destroying the cancer cells either by damaging their DNA, selective toxicity or removing them. All of these therapies have a high number of side effects. The goal of immunotherapy is to treat the disease by harnessing the immune system to eliminate or control chronic, life-threatening diseases avoiding the necessity for these traditional treatments.
The immune system is quite diverse and includes major biological functions: (1) immune defense, which works against infectious organisms such as bacteria, viruses, fungi, and parasites; (2) immune homeostasis which works to remove senescent cells and debris; and (3) immune surveillance to clear mutated cells or cancer cells. Researchers discovered that the principal cells in the immune system that attacked viruses and tumors were macrophages, dendritic cells, T-cells, NK cells, NKT cells and gamma/delta T-cells. These cells originate in bone marrow and perform functions in peripheral blood, skin, respiratory and intestinal tracts, and immune organs. The most important participant in the immune response is a class of white blood cells known as lymphocytes. These cells develop in the bone marrow and are released into general circulation. There are different subpopulations of T-Cells including: Helper T-Cells (Th) (CD4+), cytotoxic T-cells (CTL)(CD8+) and CD4+/CD25+T cells (T regulatory cells), and NK cells.
One of the most significant medical advances in the past 30 years has been the discovery of the hormones of the immune system, known as “cytokines.” Cytokines are small proteins or polypeptides produced by certain body cells that interact with other cells of the immune system in order to regulate the body’s response to disease or other disorder. The most famous of these are the interleukins (“IL”) and the interferons (“IFN”), such as IL-2 and IFN-gamma. Another major group includes the enkephalins, such as MENK and endorphins. Clinically, these cytokines have been found to be useful in stimulating the immune system in treating viral infections such as AIDS and hepatitis as well as in a number of different types of cancer. The resulting balance of systems protects the individual from harmful extremes of uncontrolled activity. Diseases such as those caused by viral infections (especially HIV), bacterial infections and cancer tend to result in deficiencies of the immune system response. Thus, it is critical to restore the body’s immunity to its effective level and to restore system balance.
Our Company’s Immunotherapy
Management believes one of the most significant medical advances in the past 20 years has been the discovery of the hormones of the immune system, known as “cytokines.” MENK is a member of the body of hormones known as cytokines, which are produced by the immune system. MENK plays an essential role in influencing all components of the immune system.
Two of the most important compounds being researched by the Company are LDN and MENK. Both LDN and MENK are proven immune-stimulating drugs. They boost the immune system by increasing the T and NK cells in the body, thereby activating the body’s own natural defenses against cancer, autoimmune diseases, immune disorders and infections. As previously mentioned, Dr. Plotnikoff and Professor Shan have published articles proving that MENK plays a very important role in immune stimulation. Dr. Plotnikoff and Professor Shan have been able to show that MENK has more advantages in boosting the human immune system than either IFN (interferon) or IL-2 (interleukin-2). MENK inhibits Treg cells while interferon or interleukin-2 does not. This is a unique discovery by the Company that supports the company’s strategy to combat cancer with its patented technologies and therapies.
The most important participant in the immune response is a class of white blood cells known as lymphocytes. These cells develop in the bone marrow and are released into general circulation. The lymphocytes (or white blood cells) traveling through the thymus are transformed into T-lymphocytes (or T-Cells) by a hormone known as thymosin. Others, known as B-lymphocytes (or B-Cells), mature in other regions of the body. B-Cells produce specific substances called antibodies that bind to and destroy antigens.
Researchers discovered that the principal cells in the immune system that attack viruses and tumors are T-cells and NK cells. These cells originate in certain body tissues such as the bone marrow and are activated by hormones known as cytokines, which include enkephalins. Several of these are recognized as stress hormones that stimulate the immune system to fight off infections and cancer.
Thus, the immune system acts as a defensive system against infectious organisms such as bacteria, viruses, fungi and parasites and, importantly, tumor cells. The immune system includes many different defense cells such as macrophages, T-cells, NK cells, B-cells and neutrophils. These cells and their produced cytokines communicate with all of the cells in the immune system.
Our Immunotherapy Products
IRT-101 is an active immunotherapy systemic administration of MENK that works by stimulating and/or regulating a patient’s immune system against infectious diseases, autoimmune diseases, immune disorders and tumor cells. This is accomplished by increasing the number of T-cells and NK cells, NKT and gamma/delta T-cells that destroy infective organisms and tumor cells, while simultaneously inhibiting T regulatory cells.
IRT-103 is an active immunotherapy by administration of LDN which works by the short-term blockage of opioid receptors on circulating and tissue cells followed by a substantial rebound in opioid receptor expression and increased levels of
β
-endorphin and methionine-enkephalin.
Management considers any condition that results in altered-immune response a target for investigation. However, the Company will most likely pursue additional investigations for LDN and MENK as valuable candidates in the treatment of the following:
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Autoimmune diseases or immune disorders such as Crohn’s disease and multiple sclerosis;
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As an adjunct to antivirals in the treatment of HIV/AIDS; and
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●
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In cancer patients undergoing chemotherapy, radiation treatments or surgery.
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In clinical trials there is evidence that LDN and MENK stimulate the immune system and are effective in the treatment of some immune-suppressed diseases. The treatment modality to date has been demonstrated to be effective while avoiding certain deleterious effects on the body, as is often the case with traditional treatments.
Cancer
In clinical trials with MENK, and off-label use of LDN around the world, both products are being used to fight cancer. MENK treatment has been shown in clinical trials to have a substantial degree of efficacy against a wide variety of cancers in patients, with only mild side effects.
Patients with Kaposi’s sarcoma (9 patients), lung cancer (12 patients), melanoma (3 patients), hypernephroma (1 patient), or pancreatic cancer (1 patient) were treated with MENK for 1 week to 12 months at doses of 10
µg
/kg three times per week up to 80
µg
/kg 3 times per week. After 1-2 weeks increases in T cell subsets (CD3, CD4, CD8, and CD2 positive cells) were observed. An increase also occurred in IL-2 receptor expression. NK cell activity was measured in 14 patients and an increased NK activity was present in 12/14 patients. No toxicity attributable to treatment with MENK was observed in any patient.
Two case studies have been reported in an infant and a 20-month old child who were treated with MENK. The infant was diagnosed with hepatoblastoma and was treated with one course of neoadjuvant chemotherapy at approximately 1 week of age. Due to significant complications from the chemotherapy (neutropenic fever, pneumonia and sepsis), the patient’s parents declined further chemotherapy, and the infant was treated with surgical resection and MENK/low dose naltrexone (LDN). She is currently close to 10 years disease–free survival (Rogosnitzky M,
et al.,
2013). The 20-month-old child was diagnosed with hepatoblastoma. Due to existing comorbidities (including autosomal recessive polycystic kidney disease and hypertension), and biopsy results that indicated the tumor might be insensitive to chemotherapy, the parents elected not to proceed with neoadjuvant chemotherapy. The patient was treated with surgical resection and MENK/LDN, and is currently at more than 5 years disease-free survival (Rogosnitzky M,
et al.,
2013).
Multiple clinical trials have been performed by Dr. Jill Smith and her colleagues at the Pennsylvania State University (PSU) School of Medicine in Hershey, PA. A total of five advance cancer studies have been conducted with MENK via i.v. infusion or s.c. injection. Three studies were conducted in patients with advanced pancreatic cancer, one study in patients with hepatocellular carcinoma, and one study in patients with advanced head and neck cancer. Across the five studies, MENK therapy has been observed to be safe with limited toxicity when given to adults with advanced cancer.. The patients with pancreatic cancer had failed prior chemotherapy regimens and were either treated with MENK or were entered into a hospice program. Clinical benefits were experienced by 53% of MENK-treated patients, whereas historical controls with similarly advanced disease had only 23.8% and 4.8% for gemcitabine and 5-fluorouracil (5-FU), respectively. Of the MENK-treated patients surviving more than eight weeks, 62% showed either a decrease or stabilization in tumor size by computed tomography. The median survival time for the MENK-treated patients was three times that of the untreated hospice patients (65.5 versus 21 days, p < 0.001). No adverse effects on hematologic or chemistry parameters were noted, and quality of life surveys suggested improvement with MENK (Smith JP, Conter RL, Bingaman SI, Harvey HA, Mauger DT, Ahmad M, Demers LM, Stanley WB, McLaughlin J, Zagon IS. Treatment of advanced pancreatic cancer with opioid growth factor: Phase I. Anti-Cancer Drugs. 2004; 15:203–209. Smith JP, Bingaman SI, Mauger DT, Harvey HA, Demers LM, Zagon IS. Opioid Growth Factor improves clinical benefit and survival in patients with advanced pancreatic cancer. Open Access Journal of Clinical Trials. 2010; 2 37–48).
The use of MENK therapy at earlier stages of disease or in combination with chemotherapeutic agents may further improve the outcome of this very aggressive malignancy.
HIV/AIDS
Early stage clinical trials in AIDS patients have been completed and results from these trials show great promise.
A single blind nine-month randomized clinical trial and a single prospective cohort study were conducted in Mali to evaluate the impact of LDN on asymptomatic HIV+ adults. Results of the nine-month study showed an improvement in CD4 count in the treatment groups that was significantly greater than the control group at 6 months (p = 0.041) and marginally at 9 months (p = 0.067) (Traore AK, Thiero O, Dao S, Kounde FF, Faye O, Cisse M, McCandless JB, Zimmerman JM, Coulibaly K, Diarra A, et al. Impact of low dose naltrexone (LDN) on antiretroviral therapy (ART) treated HIV+ adults in Mali: A single blind randomized clinical trial.
J. AID HIV Res
. 2011; 3(10):189-198). Results of the single prospective cohort study showed 71% of subjects (71%) that completed the study did not show any indication of clinical AIDS symptoms, side effects or a loss of CD4 count that would warrant initiation of ART medication (Traore AK, Thiero O, Dao S, Kounde FF, Faye O, Cisse M, McCandless JB, Zimmerman JM, Coulibaly K, Diarra A, et al. Single cohort study of the effect of low dose naltrexone on the evolution of immunological, virological and clinical state of HIV+ adults in Mali.
J. AID HIV Res
. 2011; 3(10):180-188).
A 12-week, placebo-controlled trial of LDN was conducted from 1985-1986 in 38 patients with AIDS by Dr. Bihari and his colleagues. Patients who participated in this trial showed a significant difference in the incidence of opportunistic infections with 5 out of 16 patients (31%) on placebo developing opportunistic infections in comparison to 0 of the 22 patients in the LDN group. Other difference between placebo and LDN treated patients included: lymphocyte mitogen responses declined on placebo and not on LDN; pathologically elevated levels of acid-labile alpha interferon declined significantly in the patients on LDN and not in those patients on placebo (Bihari B. Low Dose Naltrexone in the Treatment of HIV Infection.
www.lowdosenaltrexon.org
. September 1996.
http://www.lowdosenaltrexone.org/ldn_hiv_1996.htm
).
After the conclusion of the above clinical trial Dr. Bihari began to use LDN in his own medical practice. Of 158 patients in his practice that were evaluated, only 10 (6%) were on antivirals. Patients of Dr. Bihari who had taken the drug regularly as prescribed showed no drop in CD4 cells. The average CD4 number in these patients before starting LDN was 358, and the average 18 months later increased to 368. There were 55 patients who had not taken the drug, or had taken it only sporadically (non-compliant) and these patients showed a drop of CD4 cells from an average of 297 to 176 in 18 months. This represented a drop in CD4 of approximately 80 per year, which corresponds to the average drop observed in patients with HIV receiving no treatment. The stabilization of CD4 cells in patients who were administered LDN was also accompanied by disease stabilization. The 55 patients who were non-compliant experienced 25 opportunistic infections, in comparison to the 103 compliant patients who only experienced 8. Survival between the two groups was also significantly different, 13 deaths occurred in the 55 non-compliant patients compared to only one death in the compliant group of 103. At the time of this referenced article (1996), patients in Dr. Bihari’s practice had been on LDN for 7 to 8 years, with no disease progression, no drop in CD4 levels and no evidence of resistance to the beneficial effects of LDN. None of the patients experienced side effects while on LDN.
Dr. Bihari also examined CD4 changes in 19 patients who were on the combination treatment regimen of 3TC (Epivir), AZT and LDN. The rise in CD4 counts at 6 months in Dr. Bihari’s patients was compared with the rise in CD4 counts reported by an investigator working for Glaxo (New England Journal of Medicine, December 21, 1995, Vol. 333, number 25, pg. 1662). In both groups none of the patients had taken AZT previously; however Dr. Bihari’s patients simultaneously were treated with LDN, which the Glaxo group did not receive. The patients on LDN had an average baseline CD4 count of 88 while the Glaxo group had an average baseline value of 352. The Glaxo patients experienced an average rise in CD4 of 40 at 6 months; or an increase of 11.3%. The LDN patients experienced an average rise of 106 CD4's at 6 months, representing a 128% increase. Of the 19 LDN patients, each patient experienced an increase of at least 30%. In 18 of the 19 LDN patients, a significant increase in energy, appetite and mood was observed. In those LDN patients who were severely underweight, weight gains of 10 to 50 pounds were observed in the first two months of treatment.
Crohn’s Disease
Crohn’s disease is an inflammatory bowel disease (“IBD”) marked by chronic inflammation potentially involving any location of the gastrointestinal tract (“GI”) causing abdominal pain, diarrhea, GI bleeding, and weight loss. Crohn’s disease can be both painful and debilitating, and sometimes may lead to life-threatening complications. Current therapies for the condition reduce the inflammation but can be expensive and may incur rare but serious side effects, including infections and lymphoma. Prior research has suggested that endorphins and enkephalins may play a role in the development or continuation of inflammation.
References are as follows (conducted by Penn State University Hershey Medical Center (“PSU”)):
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1.
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Smith JP, Bingaman SI, Ruggiero F, Mauger DT, Mukherjee A, McGovern CO, Zagon IS. Therapy with the Opioid Antagonist Naltrexone Promotes Mucosal Healing in Active Crohn’s Disease: A Randomized Placebo-Controlled Trial. Dig Dis Sci . 2011 July; 56(7): 2088-2097.
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2.
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Smith JP, Field D, Bingaman SI, Evans R, Mauger DT. Safety and Tolerability of Low-dose Naltrexone Therapy in Children With Moderate to Severe Crohn’s Disease A Pilot Study. J Clin Gastroenterol . 2013 Apr; 47(4):339-45.
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3.
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Smith JP, Stock H, Bingaman SI, Mauger DT, Rogosnitzky M, Zagon IS. Low-Dose Naltrexone Therapy Improves Active Crohn’s Disease. Am J Gastroenterol . 2007; 102:820-828.
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To date the comparator used in the clinical trials has been stable doses of standard of care in combination with LDN or with placebo. However, patients enrolled in these trials had significantly elevated CDAI (Crohn’s Disease Activity Index) and PCDAI (Pediatric Crohn’s Disease Activity Index) scores upon enrollment despite maintenance standard of care drugs and other concomitant medications. CDAI is an index utilized to determine an adult patient’s progress, or lack of progress with their disease state and PCDAI is the corresponding pediatric index. The CDAI and PCDAI are utilized to provide a common scoring method of disease state across multiple sites. This scoring method takes into account symptoms such as abdominal pain and frequency of liquid or very soft stools. In addition to the CDAI or PCDAI, the Simple Endoscopic Score for Crohn’s Disease (SES-CD) will be utilized to determine endoscopic disease state and changes in endoscopic activity pre- and post-treatment.
LDN has been shown to be effective to date as is detailed in the publications below:
Randomized, Double-Blind, Placebo-Controlled Study in Adults (Smith
et al
., 2011)
Results: 88% of those treated with naltrexone had at least a 70-point decline in CDAI scores compared to 40% of placebo-treated patients (p = 0.009). After 12 weeks, 78% of subjects treated with naltrexone exhibited an endoscopic response as indicated by a 5-point decline in the Crohn’s disease endoscopy index severity score (CDEIS) from baseline compared to a 28% response in placebo-treated controls (p = 0.008), and 33% achieved remission with a CDEIS score <6, whereas only 8% of those on placebo showed the same change. Fatigue was the only side effect reported that was significantly greater in subjects receiving placebo.
Randomized, Double-Blind, Placebo-Controlled Study in Children (Smith
et al
., 2013)
Results: When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported.
Regulatory Status
The Company holds the following Investigation New Drug (IND) Applications:
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IND #
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Indication
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Product Name
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Status
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34,442
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HIV/AIDS
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MENK
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Inactive
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67,442
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Crohn’s Disease
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Naltrexone HCL
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Active
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50,987
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Pancreatic Cancer
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MENK/OGF
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Active
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Clinical trials under the INDs are anticipated to be conducted in the United States with the potential for global Phase III studies.
IRT-101
: The Company had an End-of-Phase 1 Meeting with the FDA in August 2013 to discuss its development plan and protocol designs. Based on the guidance from the FDA, the Company plans to initiate a Phase II dose response/dose-confirmation study in patients with advanced cancer. Possible indications include MENK as an adjuvant therapy for the treatment of advanced ovarian cancer, advanced hepatocellular cancer or , advanced head and neck cancer.
IRT-103
: A Type C meeting was held with the FDA on June 26, 2013. Based on the guidance from the FDA, the Company plans to initiate a Phase II dose-response/dose-confirmation study in patients with active Crohn’s disease. Possible indications include Multiple Sclerosis, Crohn’s disease, fibromyalgia or HIV (in combination with antivirals in asymptomatic HIV patients).
IRT-103 is currently our lead candidate.
An End-of-Phase 1 meeting occurs with the FDA after completion of Phase 1 studies, where guidance is sought prior to moving into Phase 2 clinical trials. This type of meeting is also considered a Type B meeting. Type B meetings are typically scheduled to occur within 60 days of FDA receipt of the official written meeting request.
A Type C meeting is any meeting requested with the FDA that does not fall into the category of a Type A or Type B meeting. Type C meetings are typically scheduled to occur within 75 days of FDA receipt of the official written meeting request.
A Type A meeting is a meeting needed to help an otherwise stalled product development program proceed.
Type B meetings are: (i) pre-investigational new drug application (pre-IND) meetings (ii) certain End-of-Phase 1 meetings (iii) End-of-Phase 2 meetings and (iv) pre-new drug application (NDA)/biologics license application (BLA) meetings.
The FDA review staff participates in meetings with sponsors and applications who seek guidance relating to the development and review of INDs and drug or biological product marketing applications. These meetings are often at critical points in the regulatory process and are helpful for applicants to help them continue to make progress toward FDA approval.
Business Strategy
The Company’s short-term business strategy focuses on several key areas described below, all of which are being undertaken simultaneously.
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Commencing by the end of the second quarter of 2014, the distribution of IRT 103 LDN to support the large scale treatment in emerging nations, initially in Africa and Central/South America as an immune-stimulating therapy for HIV/AIDS, cancer, autoimmune disease and immune disorders;
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Commencing by the end of the second quarter of 2014, the distribution of IRT-103 LDN marketed under the name Lodonal™ through various distribution agreements;
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Outsourcing of the manufacturing of IRT-103 LDN to Laboratorios Ramos in Managua, Nicaragua to provide LDN in capsule, tablet and/or cream form, throughout Africa and expanding to other developing nations. Work on the outsourcing commenced in the last quarter of 2013. Laboratorios Ramos has already produced LDN, and the Company will commence shipments when all regulatory approvals have been received in Africa for the importation of LDN; and
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A cooperative venture with the Hubei Qianjiang Pharmaceutical Company (“Qianjiang”), to be in operation by the end of 2014, pursuant to which Qianjiang will provide the funding required for the clinical trials of the Company’s products in China in exchange for the Company providing exclusive licensing rights in China. The Company will also receive 6% of the gross revenue from sales of those products in China.
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To further the business strategy, the Company has entered into relationships with a number of groups to promote the sale of its products outside the U.S., focusing initially on countries in Africa and Central/South America. They include: the Brewer Group; GB Oncology & Imaging Group, LLC; American Hospitals and Resorts Limited (“AHAR”), an advanced surgical and medical facility, as well as a number of U.S. doctors that own and operate clinics in the U.S. and Nigeria.
The Brewer Group, Inc. is an international business advisory firm engaged in the business of identifying and capitalizing on opportunities with international governments, non-government organizations and professional athletes. The CEO of The Brewer Group is also the founder and Executive Director of The Jack Brewer Foundation. The Jack Brewer Foundation seeks to provide the Company with medical equipment where it is needed. Under the Engagement Agreement for Corporate Advisory Services dated effective February 5, 2013, the Brewer Group agreed to evaluate the Company’s options for expansion and growth into certain international markets, including Africa and, upon request, markets in Haiti, the Dominican Republic and/or Panama. Pursuant to the Engagement Agreement, the Brewer Group agreed to endorse the Company publicly and assist the Company in securing strategic partnership deals to enhance brand and market awareness. The initial term of the Engagement Agreement was 12 months, with an option for either party to terminate upon 30 calendar days with written notice to the other party. The agreement has been extended through February 2015. The Company issued the Brewer Group 500,000 shares of its common stock in accordance with the Engagement Agreement.
GB Oncology and Imaging Group LTD. (“GBOIG”), a subsidiary of GB Energie LLC, is a Washington D.C.-based business managed by Dr. Gloria B. Herndon, a director of the Company. Dr. Herndon is committed to sourcing sustainable solutions in the field of health care in Africa, and has been involved since the 1990s on health-care related issues in Africa. The Company and GBOIG are working with the ministries of health in African countries to provide better access to and public awareness of the prevention, diagnosis and treatment of cancer and chronic infectious diseases. The Company plans to work with onsite clinics to complete patient assessments at little or no cost and prescribe treatments used to stimulate the immune system of the patients with various chronic diseases, especially HIV/AIDS and/or cancer.
In September 2012, the Company announced an agreement to open an outpatient's clinic at Queen Elizabeth Central Hospital in Malawi for the treatment of cancer and infectious diseases with GBOIG. Once the facility is operational, AHAR has agreed to assist in the operation of the clinic in Malawi and the implementation of the Company’s therapies. The contract with the Republic of Malawi calls for delivery of 25,000 pills a day, increasing to 500,000 pills a day within 24 months. The Company is still awaiting final approvals to import the drugs. The Company expects to commence operations in Malawi before the end of 2014.
In October 2013, the Company announced the signing of an exclusive distribution agreement with AHAR Pharma, a Nigerian company, to market Lodonal™™, in Nigeria for the treatment of autoimmune diseases and cancer. Dr. Richard Afonja formed AHAR Pharma in 2013 for the sole purpose of marketing TNI BioTech therapies. Dr. Afonja is a Hematologist/Oncologist and the Founder and CEO of a number of medical operations in both the United States and Nigeria for the treatment of cancer and blood disorders. AHAR Pharma intends to distribute Lodonal™ through a local distributor network, an Internet client base and directly to hospitals, pharmacists and doctors in Nigeria. The Company expects to implement the agreement in 2014, and expects to treat up to 500,000 patients per day within a year of implementation.
In October 2012, the Company entered a Strategic Framework Agreement (“Strategic Framework Agreement”) with Hubei Qianjiang Pharmaceutical Company (“the China Partner”). The agreement calls for the parties to co-develop new cancer drugs based the Company’s patents and licenses involving Methionine Enkephalin, which
when approved will be marketed in China under the brand name IRT-101 and IRT-102.The Company signed a Supplementary Agreement in March 2014 (together with the Strategic Framework Agreement, the “China Agreements”), obligating the Company to provide to the China Partner with the Company’s research materials, data and trial results to date so that the China Partner can begin conducting basic studies and clinical trials in China. Under the China Agreements, the China Partner will fund the subsequent studies in China.
Management believes the pharmaceutical industry is eager to acquire advanced clinical-phase and approved products. However, despite the strong demand for advanced clinical-phase products, nearly 4,000 known compounds have had their development suspended in Phase II or earlier. Many of these are promising therapeutic drug candidates, but their development was discontinued because of strategic or financial constraints rather than for clinical reasons.
The Company is focused on our lead therapies designed for the treatment of cancer, HIV/AIDS, Crohn’s disease, fibromyalgia and MS. Management believes the pharmaceutical industry is eager to acquire advanced clinical-phase and approved products. However, despite the strong demand for advanced clinical-phase products, nearly 4,000 known compounds have had their development suspended in phase II or earlier. Many of these are promising therapeutic drug candidates, but their development was discontinued because of strategic or financial constraints rather than for clinical reasons.
Therefore, management believes there are clear market opportunities with a significant amount of unmet needs and a robust potential for partnering activities.
Distribution and Production
The Company has entered into a contract for the supervision and inspection of manufacturing processes with ViPharma. The supervision and manufacturing agreement provides ViPharma with exclusive rights to supervise and inspect all manufacturing processes of IRT-103 low-dose naltrexone (“LDN”) in Latin America. The initial term of the agreement is ten years commencing in September 2013, with automatic five-year renewal terms provided neither party is in breach. The agreement may be terminated by (i) mutual agreement, (ii) in the event of a breach after a 45 day cure period or (iii) by either party upon provision of written notice at least 90 days before the end of the agreement, provided however that if TNI terminates the contract without cause it will be required to pay ViPharma a $10 million penalty.
The Company executed a manufacturing agreement with Laboratorios Ramos, a current good manufacturing practice (“cGMP”) facility for IRT-103 LDN effective August 16, 2013. Under the agreement, Laboratorios Ramos will produce LDN tablets, capsules and/or cream in accordance with the technical specifications provided by TNI, current good manufacturing practices and the practices of Nicaragua and of any other regulatory body of the countries where the products will be exported. Laboratorios Ramos has obtained all permits and licenses necessary to carry out the manufacturing of LDN.
The manufacturing agreement has a five-year term, renewable by a signed agreement by the parties at least 60 days before the expiration of the agreement. The agreement may be terminated earlier through mutual agreement or upon expiration of a 30-day cure period following notice from the non-breaching party to the breaching party of a material failure of the obligations under the agreement. Additionally, TNI may terminate the agreement upon at least 30 days written notice if Laboratorios Ramos does not act in strict accordance with the technical specifications provided by TNI and with current good manufacturing practices or those of any regulatory body of the importing countries. The Company will pay Laboratorios Ramos a low single digit cent amount per tablet or capsule and a low double-digit cent amount per each cream produced.
In October 2013, the Company announced the signing of a distribution agreement with AHAR Pharma, a Nigerian company, to market Lodonal™, in Nigeria for the treatment of autoimmune diseases and cancer. The agreement gives AHAR Pharma exclusive rights to sell to customers in the private sector, and non-exclusive rights to sell to customers in the public sector, AHAR Pharma intends to distribute Lodonal™ through a local distributor network, an Internet client base and directly to hospitals, pharmacists and doctors in Nigeria. Under the agreement, the Company is obligated to provide delivery of an initial supply of between 0.5 million and 1.0 million doses of Lodonal™ product per day to cover AHAR Pharma’s purchase commitments in 2015.
Raw Materials and Principal Suppliers
The Company has decided to enter into third party manufacturing agreements; accordingly, we rely on third parties for clinical production of our products and product candidates.
The active pharmaceutical ingredient (“API”) for initiating clinical trials in the United States has been and will continue to be sourced from a cGMP established vendor that has filed or will file a Type II Drug Master File in the United States. Prior to sourcing, a quality due diligence/vendor qualification will be completed that will include, but is not limited to, a review of the vendor’s inspection and compliance history with the FDA and, as relevant, the vendor’s inspection and compliance history with other regulatory bodies (i.e. EMA).
The Company expects that the Finished Pharmaceutical Product (“FPP”) for initiating the proposed clinical trials will be prepared by a U.S. vendor with extensive cGMP experience, a strong record of compliance with FDA regulations as evidenced by a site Quality Audit, and an extensive history of manufacturing products administered to humans in the U.S.
American Peptide Company is the Company’s supplier of the API in MENK. S.A.L.A.R.S SpA supplies the API in LDN.
Competition
The pharmaceutical industry is characterized by rapidly evolving technology and intense competition. A large number of companies of all sizes, including major pharmaceutical companies and specialized biotechnology companies, engage in activities similar to ours. Many of our competitors have substantially greater financial and other resources available to them. In addition, colleges, universities, governmental agencies and other public and private research organizations continue to conduct research and are becoming more active in seeking patent protection and licensing arrangements to collect royalties for use of technologies that they have developed. Some of our competitors’ current or future products and technologies may be in direct competition with ours. We also must compete with these institutions in recruiting highly qualified personnel.
Established pharmaceutical companies that currently sell or are developing drugs in our markets of interest include, for example; Abbott Laboratories, Amgen, AstraZeneca, Biogen Idec, Bayer, Elan, Johnson & Johnson, Merck, Merck Serono, Takeda, Novartis, Pfizer, Reata, Sanofi-Aventis and Teva. Many or all of these established competitors are also involved in research and drug development regarding various OGF receptors. Pharmaceutical and biotechnology companies which are known to be involved in immuno therapy research and related drug development include Pfizer, Bristol-Myers Squibb, Merck, Takeda, Sanofi-Aventis, Incyte, and UCB Pharma, among others.
Coronado BioScience and ChemoCntryx are two companies that are focused on immune therapies for autoimmune diseases and cancer including Crohn’s Disease, Multiple Sclerosis and inflammatory diseases. Coronado is a biopharmaceutical company focused on novel immunotherapy biologic agents for autoimmune diseases and cancer. Coronado’s two principal pharmaceutical product candidates are initially targeted for clinical development for inflammatory bowel disease, multiple sclerosis and acute myeloid leukemia. ChemoCentryx is a biopharmaceutical company focused exclusively on discovering, developing and commercializing orally-administered therapeutics to treat autoimmune diseases, inflammatory disorders and cancer.
There are also comparable companies focused on advancing drugs for various diseases using the FDA’s 505(b)(2) pathway including Akorn Inc., Chelsea Therapeutics Inc., MAP Pharmaceuticals Inc., Pain Therapeutics Inc., Rexahn Pharmaceuticals Inc., Santarus Inc., Ventrus Biosciences Inc., and XenoPort Inc.
The current lack of safe, effective, low cost oral treatments for autoimmune diseases such as multiple sclerosis and Crohn’s disease provides an attractive opportunity for our product. Treatment of cancer is an unmet medical need in developing countries, and the need for a safe, effective, low-cost oral treatment provides an opportunity for our Company. Clinical results with LDN trials support further evaluation of our products in the treatment of Crohn’s disease.
Customers
The Company had no sales to customers in 2013 or 2012. The Company obtained a Certificate of Pharmaceutical Products on November 27, 2013 for the Republic of Nigeria, Republic of Equatorial Guinea, Republic of Malawi and Republic of Gabon. The certificate was issued by the Director, Pharmacy Division, Minister of Health. The Company anticipates that sales will begin in these countries by July, 2014.
The Company has made final applications for the importation of Lodonal™ into the Republic of Nigeria, Republic of Equatorial Guinea, and Republic of Malawi and has received approval for the importation of Lodonal™ into Republic of Equatorial Guinea. We are awaiting final approvals in the Republic of Nigeria and Republic of Malawi, which we expect before the end of the second quarter of 2014. The Company is also working with its distributor to apply for import permits in Republic of Niger, Republic of Burkina Faso and Republic of Senegal The application process takes between four and twelve months, depending upon the regulatory authority.
The Company, with approval from the Minister of Health in Nicaragua and countries that approve and register the product inclusive of the Certificate of Pharmaceutical Products issued for that jurisdiction, will look to open distribution channels in Central and South America in the second and third quarters of 2014.
Government Regulations
United States
The research, testing, manufacturing, labeling, approval, selling, import, export, marketing and distribution of drug products are subject to extensive regulation by the United States Food and Drug Administration (“FDA”) and other regulatory authorities in the United States and other countries with regulations differing from country to country. Neither we nor our collaboration partners are permitted to market our drug candidates in the United States until we receive approval of a New Drug Application (“NDA”) from the FDA. Neither we nor our collaboration partners have submitted an application for or received marketing approval for any of our drug candidates. Obtaining approval of an NDA can be a lengthy, expensive and uncertain process.
Prior to receiving approval to commercialize any of our drug candidates in the United States or abroad, we and our collaboration partners must demonstrate with substantial evidence from well controlled clinical trials, and to the satisfaction of the FDA and other regulatory authorities abroad, that such drug candidates are safe and effective for their intended uses. Results from preclinical studies and clinical trials can be interpreted in different ways. Regulatory approval of an NDA or NDA supplement is not guaranteed, and the approval process is expensive and may take several years.
Before a drug can be tested in people, the sponsor (in this case the Company) performs laboratory and animal tests to discover how the drug works and whether it's likely to be safe and effective in humans. As LDN and MENK have previously been used in clinical trials, this phase of development was not required by the Company to initiate clinical trials under its applications.
Next, a series of tests in people (i.e. clinical trials) is begun to determine whether the drug is safe when used to treat a disease and whether it provides a real health benefit. The clinical phase typically starts at Phase 1 and progresses to Phase 3. The Company will have an abbreviated list of clinical trials that need to be conducted due to published literature on previously conducted studies, as well as utilizing the approval of naltrexone previously at 50 mg by the US FDA.
Upon completion of the clinical trials, the Company will send the FDA and/or the European Medicines Agency (the “EMA”) the evidence from these tests to prove the drug is safe and effective for its intended use (New Drug Application (NDA) in the US or Marketing Authorisation Application in the EU). The regulatory bodies will review these data and determine if the sponsor has approval to market the product at the specified dose(s) and formulation(s) for the specified indication(s) (
http://www.fda
.
gov/Drugs/DevelopmentApprovalProcess/default.htm).
Once regulatory approval has been granted, the approved product and its manufacturer are subject to continual review by the FDA and/or non-U.S. regulatory authorities. Any regulatory approval that we or our collaboration partners receive for our drug candidates may be subject to limitations on the indicated uses for which the product may be marketed or contain requirements for potentially costly post-marketing follow-up studies to monitor the safety and efficacy of the product. In addition, if the FDA and/or non-U.S. regulatory authorities approve any of our drug candidates, we will be subject to extensive and ongoing regulatory requirements by the FDA and other regulatory authorities with regard to the labeling, packaging, adverse event reporting, storage, advertising, promotion and recordkeeping for our products. In addition, manufacturers of our drug products are required to comply with current cGMP regulations which include requirements related to quality control and quality assurance, as well as the corresponding maintenance of records and documentation. Further, regulatory authorities must approve these manufacturing facilities before they can be used to manufacture our drug products, and these facilities are subject to continual review and periodic inspections by the FDA and other regulatory authorities for compliance with cGMP regulations.
European Union
We intend to seek distribution and marketing partners for IRT-101 (MENK) and IRT-103 (LDN) in the European Union ("EU"). To market our future products in the European Economic Area (“EEA”) (which is comprised of the 27 member states of the EU plus Norway, Iceland and Liechtenstein) and many other foreign jurisdictions, we must obtain separate regulatory approvals. More concretely, in the EEA, medicinal products can only be commercialized after obtaining a Marketing Authorization (“MA”).
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The Community MA is issued by the European Commission through the Centralized Procedure, based on the opinion of the Committee for Medicinal Products for Human Use of the EMA, and is valid throughout the entire territory of the EEA. The Centralized Procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products, and medicinal products indicated for the treatment of AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and viral diseases. The Centralized Procedure is optional for products containing a new active substance not yet authorized in the EEA, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the EU.
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National MAs, which are issued by the competent authorities of the member states of the EEA and only cover their respective territory, are available for products not falling within the mandatory scope of the Centralized Procedure. Where a product has already been authorized for marketing in a member state of the EEA, this National MA can be recognized in another member state through the Mutual Recognition Procedure. If the product has not received a National MA in any member state at the time of application, it can be approved simultaneously in various member states through the Decentralized Procedure.
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Under the procedures described above, before granting the MA, the EMA or the competent authorities of the member states of the EEA make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.
Our IND is being conducted per 21 Code of Federal Regulations Title 21, Part 312. In addition, we follow ICH guidelines, including good clinical practices (ICH E6) and current good manufacturing practice (ICH Q7) throughout the development process. After completion of Phase III clinical trials, the Company will file our NDA for LDN (IRT-103) as a 505(b)(2) application. IRT-103 products will follow the 505(b)(2) pathway relying on the Reference Listed Drug (RLD) REVIA to support the safety of the product. Efficacy will be submitted by the Company directly to the LDN NDA. IRT-101 products will follow the traditional approval pathway as a RLD is not available for MENK. However, published literature will support this program.
Nigeria
The National Agency for Food and Drug Administration and Control ("NAFDAC") is the equivalent in Nigeria of the US FDA. It undertakes registration of food, drugs, medical devices, cosmetics, agrochemicals and other similar products in Nigeria. At the end of the process, a registration number is given to the product and a registration certificate is issued to the applicant. Applicants are required to follow the process as stated below:
Steps in NAFDAC Registration:
Step 1 - Documentation
The documents required include Power Of Attorney, Certificate of Manufacture and Free Sale or Certificate of Pharmaceutical Product, Comprehensive Certificate of Product Analysis, Certificate of Business Incorporation, Certificate of Registration of Brand Name/ Trademark, Completed Application Form, Application Letter for Import Permit.
Step 2 – Import Permit
The import permit authorizes the applicant to import samples for registration.
Step 3 – Product Vetting
The products to be registered are submitted for vetting with the following documents: letter of invitation to inspect the factory, copy of the permit to import samples and receipt of payment for the permit, certificate of analysis and three well labeled vetting samples.
Step 4 – Laboratory Analysis
The products are submitted for analysis once they have been successfully vetted, accompanied by proof of receipt of vetting samples and the payment of the necessary charges.
Step 5 – Product Approval
The product with all the documents passes through a series of approval meetings at the end of which a NAFDAC Registration number is assigned to it.
Product registration by NAFDAC in Nigeria ensures that genuine importers are issued NAFDAC Registration numbers for their products which in turn enhances consumer confidence.
Many of the African countries do not have a local FDA equivalent organization or agency. TNI BioTech plans to use the NAFDAC Registration as the guideline for submission in Africa for countries that do not have their own application and approval procedures.
Malawi
No formal governmental agency is in place in Malawi to govern the application of a new drug. Malawi is a member of the Southern Africa Development Community (“SADC”). The SADC has been making efforts to synchronize the regulation of medication in the SADC countries. The SADC published Guidelines for Submitting Application for Registration of a Medicine are available at: http://www.ich.org/fileadmin/Public_Web_Site/ABOUT_ICH/Organisation/SADC/Guideline_for_Medicine_Registration.pdf .
The guidelines require filing an application prior to approval of registration. However, these guidelines are preliminary. The Regional Indicative Strategic Development Plan (“RISDP”) is a comprehensive development and implementation framework guiding the Regional Integration agenda of the SADC over a period of fifteen years (2005-2020). It is designed to provide clear strategic direction with respect to SADC programs, projects and activities in line with the SADC Common Agenda and strategic priorities, as enshrined in the SADC Treaty of 1992.
8. http://www.sadc.int/about-sadc/overview/strategic-pl/regional-indicative-strategic-development-plan/
Equatorial Guinea
Equatorial Guinea does not have procedures for the official approval of traditional medical practices or remedies. Accordingly, the Company was requested to make a presentation to the Health Sector and Minister on the use of naltrexone in the treatment of certain indications. After due discussion, the Government approved the following:
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1.
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Drug use naltrexone (4.5 mg) in the treatment of diseases requiring immune system stimulating cancer, HIV infection, multiple sclerosis, etc., as demonstrated by the Company, at a cost of $1/day or 450 x F.CFA/day.
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Management – laboratory for quality control and to analyze drugs imported in to Equatorial Guinea.
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The implementation of local production of quality essential medicines.
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China
In terms of the Company’s cooperative venture with its China Partner, the Partner is required to obtain all approvals and permits required for the importation and sale of the Company’s products in China.
China’s drug registration process is administered by the China Food and Drug Administration (“CFDA”) (formerly known as China State Food and Drug Administration or “SFDA”). The process includes two applications, before and after a clinical trial.
The first step is to submit an application to the CFDA for a Clinical Trial Application (“CTA”). The CFDA will conduct a preliminary review of the submission package and then transfer the dossier to the Center for Drug Evaluation (“CDE”). Reviewers with background in pharmaceuticals, pharmacology and clinical study will run a technical review, while local sample testing will also be conducted in parallel. Few CTAs pass through the CDE review in one round. However, most applications will receive supplement notice(s) in writing to request additional information for further assessment. In such case, CDE will allow a 4-month period for the applicant to gather and submit additional requested information to CDE. This entire CTA step usually takes at least 125 working days. A CTA is similar to an IND in the United States.
The second step in drug registration is Production Application (or Imported Drug License Application), which involves submitting a clinical report and other relevant files to obtain an imported drug license. The process itself is basically the same as the CTA step. This second step will take approximately 145 days. A Product Application is similar to an NDA.
Nicaragua
Laboratorios Ramos in Managua, Nicaragua has been issued approval from the Minster of Health to manufacture Naltrexone for the Company under the trademark name Lodonal™. The certificate of free sale allows Naltrexone to be exported from the Managua facility to other jurisdictions where the Company is approved to market and sell Naltrexone in satisfaction of the import requirements of such jurisdictions. The free sale certificate is not a license for export, which is issued separately for a specific product in both the country of export as well as the country of import.
Research and Development
We continue to build our research and development ("R&D") organization and capabilities focusing primarily on new uses for the opioid-related immuno-therapies, such as LDN and MENK. These therapies stimulate the immune system in such a way that provides the potential to treat a variety of diseases that have abnormalities in the immune system.
Our R&D priorities include development of MENK IRT-101, a small synthetic pentapeptide that is naturally occurring in the body, and LDN IRT-103, an opioid receptor antagonist. Our pipeline provides two therapies with an extremely wide range of indications that can be pursued. Both molecules have the ability to stimulate and/or regulate the immune system in order to treat a variety of autoimmune diseases including multiple sclerosis, immune disorders such as Crohn’s disease, cancer, and viral infections such as HIV/AIDS.
Our R&D is overseen and managed internally, working with individuals, universities, and Contract Research Organizations ("CROs") in order to utilize patents that we have licensed or acquired since our inception. We continue to seek to expand our pipeline by reviewing other compounds, technologies or capabilities. We also seek out promising compounds and innovative technologies developed by third parties to incorporate into our discovery and development processes or projects.
Drug discovery and development is time-consuming, expensive and unpredictable. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), out of 5,000-10,000 screened compounds, only 250 enter preclinical testing, five enter human clinical trials and one is approved by the FDA. The process from early discovery or design to development to regulatory approval can take more than 10 years. Drug candidates can fail at any stage of the process, and candidates may not receive regulatory approval even after many years of research.
As of December 31, 2013 we had two compounds (IRT-101 and IRT-103) in research and development. We currently have two active development programs on both compounds, one in oncology and one in Crohn’s disease; which we are expecting to move into Phase II clinical trials.
The following table provides information about significant regulatory actions by, and filings pending with the FDA and regulatory authorities in the EU, as well as additional indications and new drug candidates in late-stage development.
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NEW DRUG CANDIDATES IN LATE-STAGE DEVELOPMENT
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CANDIDATE
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INDICATION
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REGULATORY ACTIONS
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IRT-101
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Pancreatic Cancer
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End-of-Phase 1 Meeting with FDA Complete 3Q 2013
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IRT-103
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Crohn’s Disease
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Type C Meeting with FDA Complete 2Q 2013
Scientific Advice with EMA Complete 1Q 2014
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The Company has incurred, and expects to continue incurring, substantial research, development and other costs in connection with compound partnering agreements. In 2013, the Company incurred cash expenses of $2,325,137 for research and development. The Company estimates it will spend approximately $15,000,000 in cash for research and development costs in the by the end of 2015.
Employees
As of December 31, 2013, the Company had 12 full time employees and 3 part time employees.
Available Information
Our Current Reports on Form 8-K, and Quarterly Reports are electronically filed with or furnished to the Securities and Exchange Commission (SEC), and all such reports and amendments to such reports have been and will be made available, free of charge, through our website (http://www.tnibiotech.com) as soon as reasonably practicable after such submission to the SEC. Such reports will remain available on our website for at least 12 months. The contents of our website are not incorporated by reference into this Annual Report on Form 10-K. The public may read and copy any materials filed by us with the SEC at the SEC's Public Reference Room at 100 F Street, NW, Washington, D.C. 20549.
Item 1A. Risk Factors
You should carefully consider the following factors and other information in this Annual Report and our other SEC filings before making a decision to invest in our common stock. Additional risks and uncertainties that we are unaware of may become important factors that affect us. If any of the following events occur, our business, financial conditions and operating results may be materially and adversely affected. In that event, the trading price of our common stock may decline, and you could lose all or part of your investment.
Risks Related to our Business
We have a limited operating history and are expected to incur significant operating losses during the early stage of our corporate development.
We have a limited operating history. Our
historical financial information consists only of an audits of our financial results at and for the years ended December 31, 2013, 2012 and 2011. There is limited historical financial information upon which to base an evaluation of our performance. We are an emerging company, and thus our prospects must be considered in light of the uncertainties, risks, expenses, and difficulties frequently encountered by companies in their early stages of operation, particularly in the pharmaceutical industry.
Since inception, we have invested a significant portion of our time and financial resources in the acquisition and development of our most advanced drug candidate, LDN. We have generated cumulative losses of approximately $283 million since inception, and we expect to continue to incur losses until IRT-103 (LDN) is approved by the FDA and foreign regulatory authorities. Even if regulatory approval is obtained, there is a risk that we will not be able to generate material sales of IRT-103 (LDN),
which would cause us to continue to incur losses.
We may never generate revenue, are not profitable and may never become profitable.
We expect to incur substantial losses and negative operating cash flow for the foreseeable future, and we may never achieve or maintain profitability. Even if we are able to launch IRT-103 (LDN) we expect to incur substantial losses for the foreseeable future and may never become profitable.
We do not anticipate that we will generate revenue from the sale of our products for the foreseeable future. In addition, if approved, we expect to incur significant costs to commercialize our drug candidates and our drugs may never gain market acceptance. If our drug candidates fail to demonstrate safety and efficacy in clinical trials, do not gain regulatory approval, or do not achieve market acceptance, we may never become profitable. Even if we achieve profitability in the future, we may not be able to sustain profitability in subsequent periods. If we are unable to achieve and sustain profitability, the market value of our common stock will likely decline. Because of the numerous risks and uncertainties associated with developing pharmaceutical products, we are unable to predict the extent of any future losses or whether we will become profitable.
We will see losses from our clinical trials for the foreseeable future, and if we fail at one or more of our clinical trials, it could affect the value of the Company’s stock.
We rely on financings to fund and conduct the current clinical trials needed for NDA submission with respect to IRT-103 (LDN). Any of the following events or factors could have a material adverse effect on our ability to generate revenue from the commercialization of IRT-103 (LDN):
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The Company may be unable to successfully complete the clinical development of IRT-103 (LDN);
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The Company must comply with any possible additional requests and recommendations from the United States Food and Drug Administration (“FDA”), including additional clinical trials;
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The Company may not obtain all necessary approvals from the FDA and similar foreign regulatory agencies;
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The Company may not commit sufficient resources to the development, regulatory approval, marketing and distribution of IRT-103 (LDN);
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IRT-103 (LDN) must be manufactured in compliance with requirements of the FDA and similar foreign regulatory agencies and in commercial quantities sufficient to meet market demand;
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IRT-103 (LDN) may not achieve market acceptance by physicians, patients and third party payers;
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IRT-103 (LDN) may not successfully compete against alternative products and therapies; and
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The Company or any other pharmaceutical organization may independently develop products that compete with IRT-103 (LDN).
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To obtain approval from the FDA of a New Drug Application (“NDA”), for IRT-103 (LDN), The Company will need to demonstrate through evidence of adequate and well-controlled clinical trials that IRT-103 (LDN) is safe and effective for each proposed indication. However, IRT-103 (LDN) may not be approved even though it achieved its specified endpoints in the current and/or future pivotal Phase III clinical trials intended to support an NDA, which may be conducted by The Company. The FDA may disagree with the trial design and the interpretation of data from clinical trials, may ask the Company to conduct additional costly and time consuming clinical trials in order to obtain marketing approval or approval to enter into an advanced phase of development, or may change the requirements for approval even after it has reviewed and commented on the design for our clinical trials. The FDA may also approve IRT-103 (LDN) for fewer or more limited indications than The Company may request, or may grant approval contingent on the performance of costly post-approval clinical trials. In addition, the FDA may not approve the labeling claims that we believe are necessary or desirable for the successful commercialization of IRT-103 (LDN).
The Company anticipates it will spend in excess of $15,000,000 on IRT-103 (LDN) clinical trials in 2014 and 2015.
The development of new drugs is a highly risky undertaking which involves a lengthy process, and therefore our drug discovery and development activities may not result in products that are approved by the applicable regulatory authorities on the time schedule we have planned, or at all.
Our drug candidates are in early stages of drug discovery or clinical trials and are prone to the risks of failure inherent in drug development. As of the date of this Form 10-K, both of our current drug candidates, IRT-101 (MENK) and IRT-103 (LDN) have been tested on human beings. We will need to conduct additional clinical trials before we can demonstrate that our drug candidates are safe and effective to the satisfaction of the FDA and other regulatory authorities. Clinical trials are expensive and uncertain processes that can take multiple years to complete. We cannot assure you that our ongoing clinical trials or any future clinical trial of any of our other drug candidates, will be completed on schedule, or at all, or whether our planned clinical trials will start in a timely manner. The commencement of our planned clinical trials could be substantially delayed or prevented by a number of factors, including:
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delays or failures in obtaining sufficient quantities of the API and/or drug product;
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delays or failures in reaching an agreement on acceptable clinical trial agreement terms or clinical trial protocols with prospective sites and with the FDA or other foreign regulatory bodies;
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delays or failures in obtaining Institutional Review Board (“IRB”) or Ethics Committee (“EC”) approvals to conduct a clinical trial at a prospective site;
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the need to successfully complete, on a timely basis, preclinical safety pharmacology studies (for IRT-101 (MENK));
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the limited number of, and competition for, suitable sites to conduct the clinical trials;
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the limited number of, and competition for, suitable patients for enrollment in the clinical trials; and
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delays or failures in obtaining regulatory approval to commence a clinical trial.
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The completion of our clinical trials could also be substantially delayed or prevented by a number of factors, including:
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slower than expected rates of patient recruitment and enrollment;
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failure of patients to complete the clinical trials;
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failure of our third party vendors to timely or adequately perform their contractual obligations relating to the clinical trials;
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inability or unwillingness of patients or medical investigators to follow our clinical trial protocols;
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inability to monitor patients adequately during or after treatment;
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termination of the clinical trials by one or more clinical trial sites;
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unforeseen safety issues;
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lack of efficacy demonstrated during clinical trial results;
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lack of adequate funding to continue the clinical trials;
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the need for unexpected discussions with the FDA or other foreign regulatory agencies regarding the scope or design of our clinical trials or the need to conduct additional trials;
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unforeseen delays by the FDA or other foreign regulatory agencies after submission of our results;
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an unfavorable FDA inspection of our contract manufacturers of APIs or drug products; and/or
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inspection of the clinical trial operations or trial sites by the FDA or other regulatory authorities resulting in the imposition of a clinical hold.
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Any failure or significant delay in completing clinical trials for our drug candidates will harm the commercial prospects for our drug candidates and adversely affect our financial results.
Additionally, changes in regulatory requirements and guidance may occur and we may need to amend clinical trial protocols to reflect these changes. Amendments may require us to resubmit our clinical trial protocols to IRBs or ECs for reexamination, which may impact the costs, timing or successful completion of a clinical trial. If we experience delays in completion of a clinical trial, or if we terminate any of our clinical trials, the commercial prospects for our drug candidates may be harmed and our ability to generate product revenues will be delayed. In addition, many of the factors that cause, or lead to, a delay in the commencement or completion of clinical trials may also ultimately lead to the denial of regulatory approval of a drug candidate.
If we are required to suspend or discontinue clinical trials due to side effects or other safety risks, or if we are required to conduct studies on the long-term effects associated with the use of our drug candidates, our efforts to commercialize our products could be delayed or halted.
Our clinical trials may be suspended or terminated at any time for a number of safety-related reasons. For example, administering any drug candidate to humans may produce undesirable side effects. We may voluntarily suspend or terminate our clinical trials if at any time we believe that our drug candidates present an unacceptable safety risk to the clinical trial patients. In addition, IRBs, ECs or regulatory agencies may order the temporary discontinuation or termination of our clinical trials at any time if they believe that the clinical trials are not being conducted in accordance with applicable regulatory requirements, including if they present an unacceptable safety risk to patients. The existence of undesirable side effects resulting from our drug candidates could cause us or regulatory authorities, such as the FDA, to interrupt, delay or halt clinical trials of our drug candidates and could result in the FDA or other regulatory agencies denying further development or approval of our drug candidates for any or all targeted indications.
Further, cytokine receptors and opiate growth factor receptors are a novel class of targets. As a result, we may experience unforeseen adverse side effects with our existing and future drug candidates, including IRT-101 (MENK) and IRT-103 (LDN). As of the date of this annual report, although we have not observed significant harmful side effects in prior studies of LDN or MENK, later trials could reveal such side effects. The pharmacokinetic profile and results of preclinical studies may not be indicative of results in any clinical trial.
We have not conducted studies on the long-term effects associated with the use of our drug candidates. Studies of long-term effects and chronic dosing (approximately 1 year of dosing); will be required for regulatory approval and may delay introduction of our therapies or our other drug candidates into the market. Additional studies could also be required at any time after regulatory approval of any of our drug candidates. Some or all of our drug candidates may prove to be unsafe for human use.
Even if our drug candidates do obtain regulatory approval they may never achieve market acceptance or commercial success.
Even if we obtain FDA or other regulatory approval, our drug candidates may not achieve market acceptance among physicians, patients and/or third party payers or they may be used only in applications more restricted than we anticipate, and ultimately, may not be commercially successful. Our treatments, if successfully developed, will compete with a number of traditional products manufactured and marketed by major pharmaceutical and biotechnology companies. Our treatments may also compete with new products currently under development by such companies and others. Physicians will prescribe a product only if they determine, based on experience, clinical data, side effect profiles and other factors, that it is beneficial as compared to other products currently available and in use. Physicians also will prescribe a product based on their traditional preferences. Market acceptance of our drug candidates for which we receive approval depend on a number of factors, including:
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the efficacy and safety of our drug candidates as demonstrated in clinical trials;
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the clinical indications for which the drug is approved;
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acceptance by physicians, major operators of clinics and patients of the drug as a safe and effective treatment;
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the potential and perceived advantages of our drug candidates over alternative treatments;
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the safety of drug candidates seen in a broader patient group, including its use outside the approved indications;
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the cost of treatment in relation to alternative treatments;
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the availability of adequate reimbursement and pricing by third parties and government authorities;
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relative convenience and ease of administration;
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the prevalence and severity of adverse side effects; and
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the effectiveness of our sales and marketing efforts.
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If our drug candidates that obtain regulatory approval fail to achieve market acceptance or commercial success, the Company’s financial results will be adversely affected.
The commercial success of IRT-103 depends, in part, on our ability to develop and market the drug in North America, and if we fail in these initiatives, our ability to generate future revenue in the United States could be significantly reduced.
If we successfully complete the clinical development program in the U.S. for our lead independent drug candidate, IRT-103 (LDN), we plan to retain commercial rights to IRT-103 as we have exclusive licensing rights. Any of the following events or factors could have a material adverse effect on our ability to generate revenue in the U.S. from the commercialization of IRT-103:
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we may be unable to successfully complete the clinical development of IRT-103;
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our lack of experience in commercializing and marketing drug products;
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we may not have or be able to obtain sufficient financial resources to develop and commercialize IRT-103;
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we may not be able to identify a suitable co-development partner;
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we, or any of our future partners, may fail to fulfill our responsibilities in a timely manner or fail to commit sufficient resources to the development, regulatory approval, and commercialization efforts related to IRT-103;
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we, or any of our future partners, must comply with additional requests and recommendations from the FDA, including additional clinical trials;
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we, or any of our future partners, may not obtain all necessary approvals from the FDA and similar foreign regulatory agencies;
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IRT-103 must be manufactured in compliance with requirements of the FDA and similar foreign regulatory agencies and in commercial quantities sufficient to meet market demand;
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IRT-103 may not achieve market acceptance by physicians, patients and third party payers;
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IRT-103 may not compete successfully against alternative products and therapies; and
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we, or any pharmaceutical company, may independently develop products that compete with IRT-103.
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Changes in pharmaceutical and biotechnology industry trends could adversely affect The Company’s operating results.
Industry trends, economic and political factors that affect pharmaceutical, biotechnology, medical device companies and academic/government entities sponsoring clinical research directly affect The Company’s business. For example, many companies in such industries and government organizations have been hiring companies (like The Company) to conduct large development projects. The Company’s operations, financial condition and growth rate could be materially and adversely affected if these industries reduce outsourcing of such projects. In the past, mergers, product withdrawals, liability lawsuits and other factors in the pharmaceutical industry have slowed decision making by pharmaceutical companies and correlating government bodies significantly delaying and/or halting drug development projects. Continuation or increases in such trends could have an adverse effect on The Company’s business. Additionally, numerous government agencies have undertaken efforts to control growing healthcare costs through legislation, regulation and voluntary agreements with medical care providers and pharmaceutical companies. If future regulatory cost-containment efforts limit potential profits derived from new drugs, The Company’s clients may reduce their drug discovery and development spending. A reduction in drug discovery and development spending could have a material adverse effect on the Company’s results and operations creating a significant reduction of The Company’s revenue.
We currently rely on third parties to conduct all our clinical trials. If these third parties do not successfully carry out their contractual duties or meet expected deadlines, we may be unable to obtain regulatory approval for or commercialize any of our drug candidates.
We currently do not have the ability to independently conduct clinical trials. We rely on medical institutions, clinical investigators, contract laboratories, collaborative partners and other third parties, such as CROs, to conduct clinical trials on our drug candidates. The third parties with which we contract for execution of our clinical trials play a significant role in the conduct of these trials and the subsequent collection and analysis of data. These third parties are not our employees, and except for contractual duties and obligations, we have limited ability to control the amount or timing of resources that they devote to our programs. In particular, we rely on outside sources and our own revenue to fund and conduct the current pivotal Phase III trials with respect to IRT-103 (LDN). Although we rely on these third parties to conduct our clinical trials, we remain responsible for ensuring that each of our preclinical studies and clinical trials is conducted in accordance with its investigational plan and protocol. Moreover, the FDA and foreign regulatory authorities require us to comply with regulations and standards, commonly referred to as current Good Clinical Practices (“cGCPs”) for conducting, monitoring, recording and reporting the results of clinical trials to ensure that the data and results are scientifically credible and accurate and that the trial subjects are adequately informed of the potential risks of participating in clinical trials.
In addition, the execution of preclinical studies and clinical trials, and the subsequent compilation and analysis of the data produced, requires coordination among various parties. In order for these functions to be carried out effectively and efficiently, it is imperative that these parties communicate and coordinate with one another. Moreover, these third parties may also have relationships with other commercial entities, some of which may compete with us. In most cases, these third parties may terminate their agreements upon a material breach by us that is not cured within 30 days by providing us with 30 days’ prior written notice. Many of these agreements may also be terminated by such third parties under certain other circumstances, including our insolvency or our failure to comply with applicable laws. In general, these agreements require such third parties to reasonably cooperate with us at our expense for an orderly winding down of services of such third parties under the agreements. If the third parties conducting our clinical trials do not perform their contractual duties or obligations, experience work stoppages, do not meet expected deadlines, terminate their agreements with us or need to be replaced, or if the quality or accuracy of the clinical data they obtain is compromised due to their failure to adhere to our clinical trial protocols or cGCPs, or for any other reason, we may need to enter into new arrangements with alternative third parties, which could be costly, and our clinical trials may be extended, delayed or terminated or may need to be repeated, and we may not be able to obtain regulatory approval for or commercialize the drug candidate being tested in such trials.
If any of our drug candidates receive marketing approval, and the Company or others later identify undesirable side effects caused by the drug candidate, our ability to market and derive revenue from the drugs could be compromised.
If the Company or others identify undesirable side effects caused by one of our drug candidates, any of the following adverse events could occur:
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regulatory authorities may withdraw approval of the drug or seize the drug;
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we may be required to recall the drug or change the way the drug is administered;
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additional restrictions may be imposed on the marketing or the manufacturing processes of the particular drug;
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we may be subject to fines, injunctions or the imposition of civil or criminal penalties;
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regulatory authorities may require the addition of labeling statements, such as a “black box” warning or a contraindication;
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we may be required to create a medication guide outlining the risks of such side effects for distribution to patients;
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we could be sued and held liable for harm caused to patients;
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the drug may become less competitive; and
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our reputation may suffer.
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Any of these could result in the loss of significant revenues, which would materially and adversely affect our results of operations and business.
We may need additional financing and may be unable to raise capital on acceptable terms, or at all, when needed, which could force us to delay, reduce or eliminate our research and development programs and other operations or commercialization efforts.
We are advancing multiple drug candidates through discovery and development and will require substantial funds to conduct development, including preclinical studies and clinical trials, of our drug candidates. Commercialization of any drug candidate will also require substantial expenditures. To further the development and commercialization efforts of our drug candidates, we may need additional financing to hire additional employees to co-promote drug candidates or to commercialize drug candidates that may not be covered by our current collaboration agreements.