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UNITED STATES  

SECURITIES AND EXCHANGE COMMISSION  

WASHINGTON, D.C. 20549

 

FORM 10-K

 

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

 

For the Fiscal Year Ended December 31, 2021

 

Commission File Number 001-36019

 

TONIX PHARMACEUTICALS HOLDING CORP. 

(Exact name of registrant as specified in its charter)

 

Nevada   26-1434750
(State or other jurisdiction of incorporation or organization)     (IRS Employer Identification No.)
     

26 Main Street, Suite 101 

Chatham, New Jersey 

  07928
(Address of principal executive office)   (Zip Code)

 

(862) 799-8599 

(Registrant’s telephone number, including area code)

 

Securities registered pursuant to Section 12(b) of the Act:

 

Title of each class       Trading Symbol   Name of each exchange on which registered
Common Stock, $0.001 par value   TNXP   The NASDAQ Stock Market LLC

 

Securities registered pursuant to Section 12(g) of the Act:  None

 

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined by Rule 405 of the Securities Act. Yes ☐    No ☒

 

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes ☐    No ☒

 

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

 

Indicate by check mark whether the registrant has submitted electronically on its corporate Web site, if any, every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§ 229.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒    No ☐

 

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

 

Large accelerated filer ☐  Accelerated filer ☐
Non-accelerated filer ☒  Smaller reporting company 
   Emerging growth company 

 

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

 

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

 

The aggregate market value of the voting common equity held by non-affiliates as of June 30, 2021, based on the closing sales price of the common stock as quoted on The NASDAQ Global Market was $384,121,940. For purposes of this computation, all officers and directors are deemed to be affiliates. Such determination should not be deemed an admission that such directors, officers, or 5 percent beneficial owners are, in fact, affiliates of the registrant.

 

As of March 14, 2022, there were 533,928,624, shares of registrant’s common stock outstanding.  

 

 

DOCUMENTS INCORPORATED BY REFERENCE

 

None.

 

 

 

 

 

TABLE OF CONTENTS

 

    PAGE
PART I    
     
Item 1. Business 3
Item 1A. Risk Factors 46
Item 1B. Unresolved Staff Comments 72
Item 2. Properties 72
Item 3. Legal Proceedings 73
Item 4. Mine Safety Disclosures 73
     
PART II    
     
Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities 73
Item 6. Reserved 73
Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations 73
Item 7A. Quantitative and Qualitative Disclosures about Market Risk 87
Item 8. Financial Statements and Supplementary Data F-1 – F-32
Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosures 88
Item 9A. Controls and Procedures 88
Item 9B. Other Information 89
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 89
     

PART III

   
     
Item 10. Directors, Executive Officers and Corporate Governance 89
Item 11. Executive Compensation 95
Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters 102
Item 13. Certain Relationships and Related Transactions, and Director Independence 104
Item 14. Principal Accounting Fees and Services 104
     
PART IV    
     
Item 15. Exhibits, Financial Statement Schedules 105
     
  Signatures 108

   

2

 

 

PART I

 

ITEM 1 - BUSINESS

 

This Annual Report on Form 10-K (including the section regarding Management’s Discussion and Analysis of Financial Condition and Results of Operations) contains forward-looking statements regarding our business, financial condition, results of operations and prospects. Words such as “expects,” “anticipates,” “intends,” “plans,” “believes,” “seeks,” “estimates” and similar expressions or variations of such words are intended to identify forward-looking statements, but are not deemed to represent an all-inclusive means of identifying forward-looking statements as denoted in this Annual Report on Form 10-K. Additionally, statements concerning future matters are forward-looking statements.

 

Although forward-looking statements in this Annual Report on Form 10-K reflect the good faith judgment of our Management, such statements can only be based on facts and factors currently known by us. Consequently, forward-looking statements are inherently subject to risks and uncertainties and actual results and outcomes may differ materially from the results and outcomes discussed in or anticipated by the forward-looking statements. Factors that could cause or contribute to such differences in results and outcomes include, without limitation, those specifically addressed under the heading “Risks Factors” below, as well as those discussed elsewhere in this Annual Report on Form 10-K. Readers are urged not to place undue reliance on these forward-looking statements, which speak only as of the date of this Annual Report on Form 10-K. We file reports with the Securities and Exchange Commission (“SEC”). You can read and copy any materials we file or will file with the SEC, which, among other places, can be found on the SEC's website at http://www.sec.gov, as well as on our corporate website at www.tonixpharma.com).

 

We undertake no obligation to revise or update any forward-looking statements in order to reflect any event or circumstance that may arise after the date of this Annual Report on Form 10-K. Readers are urged to carefully review and consider the various disclosures made throughout the entirety of this Annual Report, which attempt to advise interested parties of the risks and factors that may affect our business, financial condition, results of operations and prospects.

 

Tonix Pharmaceuticals®, Tonmya®, Protectic™, Angstro-Technology™ and other trademarks and intellectual property of ours appearing in this report are our property. This report contains additional trade names and trademarks of other companies. We do not intend our use or display of other companies’ trade names or trademarks to imply an endorsement or sponsorship of us by such companies, or any relationship with any of these companies.

 

 Business Overview  

 

We are a clinical-stage biopharmaceutical company focused on discovering, licensing, acquiring and developing therapeutics and diagnostics to treat and prevent human disease and alleviate suffering. We are building capabilities in synthetic biology, precision medicine, protein engineering and vaccine manufacturing through internal efforts as well as through collaborations with academic institutions and contract research organizations. Our therapeutics under development include both small molecules and biologics. All of our drug, biologic and diagnostic candidates are still in development.

 

Tonix’s portfolio is primarily composed of immunology, central nervous system, or CNS, and infectious disease product candidates. Tonix’s immunology portfolio includes biologics to address organ transplant rejection, autoimmune diseases and cancer. The CNS portfolio includes small molecules and biologics to treat pain, neurologic, psychiatric and addiction conditions. Tonix’s infectious disease portfolio of product candidates includes next-generation vaccines to prevent COVID-19, an antiviral to treat COVID-19, and a potential treatment for Long COVID. The infectious disease portfolio also includes a vaccine in development to prevent smallpox and monkeypox.

 

Tonix’s lead candidate within its immunology pipeline is TNX-1500*, a humanized monoclonal antibody, or mAb, directed against CD40-ligand, or CD40L, engineered to modulate binding to Fc receptors, that is being developed as a prophylaxis against organ transplant rejection as well as to treat autoimmune conditions. In experiments at the Massachusetts General Hospital, a teaching hospital of Harvard Medical School, TNX-1500 is being studied as monotherapy or in combination with other immunosuppressive agents in heart and kidney organ transplants in non-human primates. Preliminary results from an ongoing experiment in heart transplants indicate that TNX-1500 appears to have comparable efficacy to historical experiments using the chimeric mouse/human IgG1 version (5c8H1) of the anti-CD40L mAb 5c8. First generation anti-CD40L mAb were associated with an increased risk of blood clots or thrombosis. In the non-human primate studies with TNX-1500, no evidence of thrombosis has been observed so far. We expect to start a Phase 1 study of TNX-1500 in the second half of 2022.

 

 Among the CNS candidates in development is TNX-1300* (double-mutant cocaine esterase) which is in Phase 2 for the treatment of life-threatening cocaine intoxication. TNX-1300 has been granted Breakthrough Therapy designation, or BTD, by the U.S. Food and Drug Administration, or FDA. TNX-1300 was licensed from Columbia University in 2019 after a Phase 2 study showed that it rapidly and efficiently disintegrates cocaine in the blood of volunteers who received intravenous, or i.v., cocaine. We expect to initiate a Phase 2 open-label safety study of TNX-1300 in an emergency room setting in the first half of 2022.

 

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Our latest stage CNS product candidate is TNX-102 SL*, a proprietary sublingual tablet formulation of CBP, designed for bedtime administration. TNX-102 SL has active INDs for fibromyalgia, or FM, posttraumatic stress disorder, or PTSD, agitation in Alzheimer’s disease, or AAD, and alcohol use disorder, or AUD. We also intend to develop TNX-102 SL as a treatment for Long COVID, which is also known as post-acute sequelae of COVID-19, or PASC.

 

TNX-102 SL is in mid-Phase 3 development for the management of FM, a pain disorder characterized by chronic widespread pain, non-restorative sleep, fatigue and impaired cognition. In December 2020, we reported positive results from the Phase 3 RELIEF study of TNX-102 SL 5.6 mg for the management of FM. In July 2021, we reported pre-planned interim analysis results from a second Phase 3 study, RALLY. Based on the recommendation from the independent data monitoring committee that the RALLY trial was unlikely to demonstrate a statistically significant improvement in the primary endpoint, we stopped enrollment of new participants but allowed those participants who were already enrolled to complete the study. We expect to report topline data from the completed study in the first quarter of 2022. We expect to analyze the RALLY results to improve the design of subsequent Phase 3 studies. In addition, we plan to employ pharmacogenomic techniques to compare the RALLY and RELIEF study populations, which may provide a path to precision medicine-based companion diagnostics for TNX-102 SL in FM. We intend to start a new Phase 3 study of TNX-102 SL in FM in the first half of 2022.

 

TNX-102 SL is also being developed as a potential treatment for Long COVID. We met with the FDA in the third quarter of 2021 to seek agreement on the design of a Phase 2 potential pivotal study and the overall clinical development plan to qualify TNX-102 SL as an indicated treatment for Long COVID. We intend to focus our clinical development on the subgroup of Long COVID patients whose symptoms overlap with FM, particularly with respect to widespread pain. We received the official minutes from this meeting in the third quarter of 2021 and intend to initiate a Phase 2 study in the first half of 2022.

 

For TNX-102 SL in PTSD, we completed the Phase 3 RECOVERY trial and reported topline results in the fourth quarter of 2020 in which TNX-102 SL did not meet the primary efficacy endpoint. PTSD is a serious psychiatric condition that develops in response to experiencing a traumatic event. We subsequently completed a meeting with the FDA to discuss potential new endpoints for the indication of treatment of PTSD, and we expect to begin enrolling a Phase 2 study of TNX-102 SL in police in Kenya in the first half of 2022. The AAD program is Phase 2 ready with an active IND and FDA Fast Track designation. AAD, which includes emotional lability, restlessness, irritability, and aggression, is one of the most distressing and debilitating of the behavioral complications of Alzheimer’s disease. Tonix does not have any near-term plans to start a Phase 2 study in AAD. The AUD program is also Phase 2 ready with an active IND. AUD is a chronic relapsing brain disease characterized by compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using alcohol. Tonix does not have any near-term plans to start a Phase 2 study in AUD.

 

TNX-1900* (intranasal potentiated oxytocin) is in development for prophylaxis of chronic migraine and for the treatment of craniofacial pain, insulin resistance and related conditions as well binge eating disorder, or BED. TNX-1900 was acquired from Trigemina, Inc. and licensed from Stanford University in 2020. The potentiated formulation includes magnesium, which has been shown in animals to potentiate binding of oxytocin to the oxytocin receptor in the trigeminal ganglion. We received IND clearance from the FDA in the fourth quarter of 2021 and intend to initiate a Phase 2 study in migraine in the second half of 2022. Tonix also licensed technology to use TNX-1900 for the treatment of insulin resistance from the University of Geneva. TNX-1900 will be studied as a potential treatment for BED in an investigator-initiated Phase 2 clinical trial. The Phase 2 clinical trial is expected to start in the second half of 2022. In March 2022, we announced an agreement with Massachusetts General Hospital, a teaching hospital of Harvard Medical School, to conduct this study. Tonix does not own an IND for BED.

 

TNX-2900* is another intranasal oxytocin-based therapeutic in development for the treatment of Prader-Willi syndrome, or PWS. The technology for TNX-2900 was licensed from Inserm, the French National Institute of Health and Medical Research. PWS, an orphan condition, is a rare genetic disorder of failure to thrive in infancy, associated with uncontrolled appetite beginning in childhood with complications of obesity and diabetes. We have sponsored a research program at the Inserm to study oxytocin on suckling behavior in mice that have been engineered to express one of the Prader-Willi genes. TNX-2900 has been granted Orphan-Drug Designation for the treatment of PWS.

 

TNX-601 CR* (tianeptine oxalate and naloxone controlled-release tablets) is a CNS product candidate in development as a treatment for major depressive disorder, or depression, for PTSD, and for neurocognitive dysfunction associated with corticosteroid use. We completed a Phase 1 trial for formulation development outside of the U.S. Based on official minutes from a pre-IND meeting with the FDA, we expect to initiate a pharmacokinetic study in the third quarter of 2022, and a Phase 2 study in the first quarter of 2023.

 

Tonix’s infectious disease portfolio includes vaccines based on Tonix’s recombinant pox vaccine, or “RPV” technology platform. RPV vaccines are believed to protect against negative outcomes of infectious diseases by eliciting T cell responses in addition to antibody responses. TNX-801* is an RPV live horsepox virus vaccine for percutaneous administration in the pre-IND stage of development to protect against smallpox and monkeypox. TNX-801 vaccinated non-human primates were protected from monkeypox in studies reported in the first quarter of 2020. 

 

TNX-1800* is a live virus vaccine that expresses the SARS-CoV-2 spike protein from the ancestral Wuhan strain, which has shown encouraging results in non-human primates. Because the subsequent omicron variant has out-competed the ancestral Wuhan strain, we are now planning new vaccine versions, TNX-1840* and TNX-1850*, that are designed to express spike protein from the omicron variant and from the BA.2 variant, respectively. The COVID-19 vaccines that are approved for use, or have emergency use authorization, or EUA, in the U.S. have provided significant health benefits to the vaccinated population; however, they are showing limitations in the durability of protection conferred and, in their ability, to block forward transmission. Live virus vaccines that protect against other viral diseases by eliciting T cell responses have shown durability of protection that lasts years to decades and some live virus vaccines have significantly inhibited forward transmission. With respect to TNX-1800 vaccination, we reported positive efficacy data from animal challenge studies using live SARS-CoV-2 in the first quarter of 2021. In this study, TNX-1800 vaccinated, SARS-CoV-2 challenged animals had undetectable SARS-CoV-2 in the upper airways, which we believe relates to potential inhibition of forward transmission of this respiratory pathogen.

 

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TNX-3500* (sangivamycin) is an antiviral inhibitor of SARS-CoV-2 which has demonstrated broad-spectrum activity in laboratory-based assays against the coronaviruses SARS-CoV-2 and MERS-CoV. Tonix licensed this technology from OyaGen, Inc. and intends to develop it as a treatment for COVID-19 and potentially other viral diseases. The active ingredient of TNX-3500 has been studied for safety in humans in prior studies with cancer patients at the U.S. National Cancer Institute but has not been approved for marketing in any jurisdiction. Tonix intends to conduct further animal studies in preparation for filing an IND.

 

TNX-3600* refers to a series of fully human mAbs generated by a human-human hybridomas from COVID-19 convalescent volunteers. Tonix is collaborating with Columbia University to produce these fully human mAbs to SARS-CoV-2 spike proteins from variants such as delta and omicron and to other viral targets. The initial focus is to develop COVID-19 therapeutic mAbs. Tonix plans to seek indications similar to current EUA therapeutic mAbs for treating individuals with mild-to-moderate COVID-19 who are at high risk for progression to severe disease. TNX-3600 mAbs may also be used in combination therapy with other COVID-19 therapeutic mAbs. Combination therapies with other anti-SARS-CoV-2 mAbs may reduce the emergence of resistant viral strains. Given the unpredictable trajectory of the SARS-CoV-2 virus and new variants, we seek to contribute to a broad set of mAbs from a variety of patients, that can be scaled up quickly and potentially combined with other mAbs. We envision the future of mAb therapy for COVID-19 to be cocktails of mAbs with specificity to variants of concern.  TNX-3600 is in the preclinical stage of development. Tonix intends to study inhibition of SARS-CoV-2 variants in tissue culture and initiate animal studies in the first half of 2022.

 

Tonix also is collaborating with Columbia University to better understand immune responses to SARS-CoV-2 in healthy individuals who have recovered from COVID-19, which is expected to provide a foundation for tailoring therapeutics to appropriate individuals using precision medicine.

 

TNX-3700* is a COVID-19 mRNA vaccine candidate employing a zinc nanoparticle (ZNP) formulation. In collaboration with Kansas State University, Tonix is developing this ZNP technology as a potential replacement for the lipid nanoparticle (LNP) technology used in current mRNA vaccines. ZNP technology potentially allows for improved stability which facilitates shipping and storage and addresses the limitations in current mRNA vaccines which require ultra-cold storage and shipping. This current requirement limits the use of mRNA vaccines in less developed countries. We plan to seek initial indications as a booster, similar to the current FDA approved mRNA vaccines. Tonix intends to conduct research with Kansas State University on ZNP SARS-CoV-2 spike based vaccines in tissue culture and animals in the first half of 2022.

 

TNX-2100* is an in vivo diagnostic skin test we are developing to measure SARS-CoV-2 exposure and T cell immunity. T cell immunity is more durable than antibody immunity since serum antibodies wane between six months and one year after vaccination. TNX-2100 is a potential test to measure delayed-type hypersensitivity (DTH) response to SARS-CoV-2. The DTH response for other pathogens, notably tuberculosis, can serve as an in vivo measure of functional T cell immunity. TNX-2100 is comprised of GMP peptides designed to mimic SARS-CoV-2 proteins and stimulate SARS-CoV-2 specific T cells. We initiated a first-in-human, dose-finding clinical study in the first quarter of 2022 and expect study results in the first half of 2022.

 

Our immunology pipeline also includes TNX-1700*. TNX-1700 is a recombinant modified form of Trefoil Family Factor 2, or rTFF2, that was licensed from Columbia University in 2019. TNX-1700 is a biologic being developed to treat gastric and colorectal cancers by an immune-oncology mechanism and is in the preclinical stage of development.

 

Our biodefense pipeline includes TNX-701*, an undisclosed small molecule technology being developed to prevent deleterious effects of radiation exposure which has the potential to be used as a medical countermeasure to improve biodefense. TNX-701 is in the preclinical stage of development.

 

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Finally, our CNS pipeline includes TNX-1600*, an inhibitor of the reuptake of neurotransmitters serotonin, norepinephrine and dopamine, or a triple reuptake inhibitor. TNX-1600 was licensed from Wayne State University in 2019 and is being developed as a treatment for PTSD, depression and attention-deficit/hyperactivity disorder, or ADHD. TNX-1600 is in the preclinical stage of development.

 

Relating to our COVID-19 and other infectious disease development programs, we are developing the resources necessary to enable internal research, development and manufacturing capabilities necessary to meet the goal of producing new vaccine candidates within 100 days of recognition and new diagnostics within weeks of obtaining sequence information. As articulated in the American Pandemic Preparedness Plan, or AP3, released by the U.S. Office of Science and Technology Policy, this 100-day goal for vaccines is a key component of preparedness for future pandemics. We intend to establish the infrastructure necessary to support the pandemic preparedness goals established in the AP3, specifically with respect to our RPV vaccine and skin test platforms and potentially to other vaccine, diagnostic and therapeutic platforms. This infrastructure consists of (i) our infectious disease R&D Center, or “RDC”, (ii) our Advanced Development Center, or ADC, and (iii) our Commercial Manufacturing Center, or CMC. We acquired the infectious disease RDC in Frederick, Maryland consisting of two buildings totaling approximately 48,000 square feet. The acquisition closed in October 2021 and was operational at closing, but as of December 31, 2021, the facility was not ready for its intended use. It is our intention to have the facility ready for use in the first half of 2022. The RDC facility will focus on our development of vaccines and antiviral drugs against SARS-CoV-2, its variants, and other infectious diseases. The RDC facility is currently biosafety level 2 (BSL-2), but we intend to upgrade components to BSL-3. We are in the process of a substantial renovation of the ADC located in the New Bedford business park in Dartmouth, Massachusetts. This facility is intended to accelerate development and clinical scale manufacturing of live-virus vaccines to support Phase 1 and Phase 2 clinical trials. It is currently under construction and will be an approximately 45,000 square foot BSL-2 facility once completed. It is expected to be partially operational in the first half of 2022. We also plan to build the CMC in Hamilton, Montana, where we purchased approximately 44 acres of land. The CMC will focus on developing and manufacturing commercial scale live-virus vaccines and is also intended to be BSL-2. Site enabling work is expected to be initiated for the CMC in 2022.  Together, we expect these facilities may qualify the RPV vaccine and skin test platforms for programs that are designed to carry out the goals of AP3.

 

  *All of Tonix’s product candidates are investigational new drugs or biologics and have not been approved for any indication.

 

We are led by a management team with significant industry experience in drug development. We complement our management team with a network of scientific, clinical, and regulatory advisors that includes recognized experts in their respective fields.

 

Corporate Information

 

We were incorporated on November 16, 2007 under the laws of the State of Nevada as Tamandare Explorations Inc. On October 11, 2011, we changed our name to Tonix Pharmaceuticals Holding Corp. Our common stock is listed on The NASDAQ Capital Market under the symbol “TNXP”. Our principal executive offices are located at 26 Main Street, Suite 101, Chatham, New Jersey 07928, and our telephone number is (862) 799-8599. Our website addresses are www.tonixpharma.com, www.tonix.com, and www.krele.com

 

Our Strategy

 

Our objective is to develop and commercialize our product candidates. The principal components of our strategy are to: 

 

Pursue CNS, infectious disease and immunology indications with high unmet medical need and significant commercial potential. Within the therapeutic areas that Tonix is focusing, we are pursuing multiple indications that are underserved with limited, effective treatment options. One of our latest stage product candidates, TNX-102 SL for the management of FM, affects between 6-12 million adults in the U.S. and fewer than half of those treated for FM receive relief from the three FDA-approved drugs. We are also pursuing a treatment for Long COVID using TNX-102 SL, a condition for which there is no currently approved therapy. Our broader development strategy is to leverage the patented formulation to explore the clinical potential of TNX-102 SL in multiple other pain, psychiatric, and addiction conditions, including PTSD, Agitation in Alzheimer’s and Alcohol Use Disorder (AUD), all of which are underserved by currently approved medications or have no approved treatment thus representing large unmet medical needs. Within CNS, Tonix is also developing TNX-1300, a treatment for cocaine intoxication, one of the leading causes of overdose deaths and for which there is no currently approved drug. Within infectious diseases, we are currently focusing on the development of TNX-1840 and TNX-1850 for protection against COVID-19. While there are FDA-approved COVID-19 vaccines which use mRNA technology, we believe that there are limitations to these vaccines relating to durability of protection and their relative inability to block forward transmission. We believe that the live virus technology intended to be employed in TNX-1840 and TNX-1850 has the potential to solve these problems and serve as a booster or initial vaccine to the U.S. population. Finally, with TNX-1500, we are pursuing a treatment to prevent organ transplant rejection as well as autoimmune conditions. TNX-1500 is a third generation humanized mAb targeting the CD40L that has the potential to deliver efficacy without compromising safety, based on modulated binding to Fc receptors. At this time, no mAb against CD40L has been licensed anywhere in the world.

 

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Maximize the commercial potential of our lead product candidates. We plan to commercialize each of our lead product candidates, including our latest stage candidate, TNX-102 SL, either on our own or through collaboration with partners. We believe our lead candidates can be marketed to U.S. physicians either by an internal sales force that we would build or by a contract sales organization, which we would engage. An alternative strategy would be to enter into partnership agreements with drug companies that already have significant marketing capabilities in the same, or similar, therapeutic areas. If we determine that such a strategy would be more favorable than developing our own sales capabilities, we would seek to enter into collaborations with pharmaceutical or biotechnology companies for commercialization.

 

Pursue a broad intellectual property strategy to protect our product candidates. We are pursuing a broad patent strategy for our product candidates, and we endeavor to generate new patent applications as supported by our innovations and conceptions as well as to advance their prosecution. In the case of TNX-102 SL, we own patents and patent applications protecting its composition-of-matter, certain methods of its use, its formulation, and its pharmacokinetic properties. In the case of TNX-801, TNX-1800, TNX-1840 and TNX-1850, we own patent applications protecting their composition-of-matter and certain methods of use. We also own patents through in-licensing transactions for TNX-1900, TNX-1700, TNX-2900 and TNX-1300. We own patents outright for TNX-601 CR and have filed patent applications for TNX-2100, TNX-3500, TNX-3700 and TNX-1500. We plan to opportunistically apply for new patents to protect our product candidates.

 

Pursue additional indications and commercial opportunities for our product candidates. We will seek to maximize the value of our other product candidates by pursuing other indications and commercial opportunities for such candidates. For example, we own rights related to the development and commercialization of TNX-102 SL for generalized anxiety disorder, depression, and fatigue related to disordered sleep. For TNX-1900, we own the rights to develop this for craniofacial pain, episodic migraine, acute migraine and insulin resistance, in addition to chronic migraine. For TNX-601 CR, we own the rights to develop this for PTSD and neurocognitive disorder from corticosteroid use, in addition to major depressive disorder. Finally, our live virus platform using our RPV technology may be developed for future pandemics, infectious diseases generally and oncology, in addition to COVID-19.

 

Disease and Market Overview

 

Our product candidates address disorders that are not well served by currently available therapies or have no approved treatment which represent large potential commercial market opportunities. Background information on the disorders and related commercial markets that may be addressed by our product candidates in or nearing the clinical-stage is set forth below.

 

Immunology

 

Organ Transplant Rejection

 

Organ transplant rejection occurs when the immune system of the organ recipient attacks the new organ as if it was an infection or tumor. Often transplantation is the last resort for most end-stage organ failure patients, affecting either kidneys, liver, heart, lungs, and/or pancreas. Genetic disparity between organ donor and recipient is often at the root of the rejection. Mismatched or not closely matched organs triggers an immune reaction that leads to rejection. Overcoming this difficulty is paramount to a patient’s survival as organ donations are in limited supply. 

Gastric and Colorectal cancers

 

 Gastric or stomach cancer is a disease in which malignant cancer cells line the inner lumen of the stomach. Development of this form of cancer is often influenced by age, diet and other stomach disease. This type of cancer begins to form in the mucosa, the surface of the lumen that is in direct contact with the contents of the stomach, and spreads through the outer layers of the stomach as the tumor grows.

 

Currently, per the National Cancer Institute, the 5-year relative survival for stomach cancer is 32.4%. The lifetime risk of developing stomach cancer is higher in men (about 1 in 96) than in women (about 1 in 152).2 In 2018, there were an estimated 120,301 people living with stomach cancer in the United States.

 

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Colorectal cancer includes cancers in the colon and the rectum, organs that are crucial to absorption of water by the body and the elimination of food-waste. Most colorectal cancers start as a growth or polyp on the inner lining of the colon or rectum. Some types of polyps can change into cancer over time (usually many years), but not all polyps become cancer. Adenomatous polyps are the ones that turn malignant with time. Similar to gastric cancer, the malignancy begins in the mucosal layer and spreads outwards.

 

The 5-year relative survival rate is 64.7%. Overall, the lifetime risk of developing colorectal cancer is about 1 in 23 (4.3%) for men and 1 in 25 (4.0%) for women. In 2018, there were an estimated 1,365,135 people living with colorectal cancer in the United States. 

 

Central Nervous System

 

Cocaine Intoxication

 

Cocaine is an illegal recreational drug taken for its pleasurable effects and associated euphoria. Pharmacologically, cocaine blocks the reuptake of the neurotransmitter dopamine from central nervous system synapses, resulting in the accumulation of dopamine within the synapse and an amplification of dopamine signaling that is related to its role in creating positive feeling. With the continued use of cocaine, however, intense cocaine cravings occur resulting in a high potential for abuse and addiction, or dependence, as well as the risk of cocaine intoxication. Cocaine intoxication refers to the deleterious effects on other parts of the body, especially those involving the cardiovascular system.  Common symptoms of cocaine intoxication include tachyarrhythmias and elevated blood pressure, either of which can be life-threatening.  As a result, individuals with known or suspected cocaine intoxication are sent immediately to the emergency department, preferably by ambulance in case cardiac arrest occurs during transit.  There are approximately 505,000 emergency room visits for cocaine abuse each year in the U.S., of which 61,000 require detoxification services.  According to the National Institute on Drug Abuse, over 15,883 individuals died of cocaine overdose in 2019.

 

Fibromyalgia (FM)

 

FM is a chronic syndrome characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. The peak incidence of FM occurs between 20-50 years of age, and 80-90% of diagnosed patients are female. FM may have a substantial negative impact on social and occupational function, including disrupted relationships with family and friends, social isolation, reduced activities of daily living and leisure activities, avoidance of physical activity, and loss of career or inability to advance in career or education.  According to the American Chronic Pain Association, an estimated six to twelve million adults in the U.S. have FM.

 

According to a report by Frost and Sullivan that we commissioned, despite the availability of approved medications, the majority of patients fail therapy due to either insufficient efficacy, poor tolerability, or both. Prescription pain and sleep medications are frequently prescribed off-label for symptomatic relief, despite the lack of evidence that such medications provide a meaningful or durable therapeutic benefit, and many of these medications carry significant safety risks and risk of dependence. For example, approximately 30% of patients diagnosed with FM take chronic opioids, despite the lack of evidence for their effectiveness and the risk of addiction and toxicity, including overdose.

 

Long COVID

 

Long COVID, or PASC, is a condition that some survivors of COVID-19 infection experience in varying degrees of severity. It is a chronic disabling condition that is expected to result in a significant global health and economic burden. The symptoms include intense fatigue, fevers, sleep problems, pain, and cognitive issues (“brain fog”). Post infection, many patients experience one or many of the symptoms of Long COVID: some patients have initial symptoms that become prolonged; others manifest entirely new syndromes that impact more than one system or organ. According to a recent publication in the Journal of American Medical Association (JAMA), over 1 in 10 healthcare workers who had recovered from COVID-19 were still coping with at least one moderate to severe symptom eight months later. Several cohort studies have reported that persistence of symptoms following SARS-CoV-2 infection occurs in more than 30% of patients. There is currently no approved drug for the treatment of Long COVID.

 

 

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Posttraumatic Stress Disorder, or PTSD

 

 PTSD is a chronic condition that may develop after a person is exposed to one or more traumatic events, such as warfare, sexual assault, serious injury, or threat of imminent death. The core symptom clusters of PTSD are avoidance, emotional numbing, hyperarousal, and intrusion, where the triggering traumatic event is commonly re-experienced by the individual through intrusive, recurrent recollections, flashbacks, and nightmares. People with PTSD suffer significant impairment in their daily functioning, including occupational activities and social relations, and are at elevated risk for impulsive violent behaviors toward others and themselves, including suicide. Of those who experience a significant trauma, approximately 20% of women and 8% of men develop PTSD. An estimated 12 million adults annually in the U.S. suffer from PTSD. According to the U.S. Department of Veterans Affairs, the prevalence rate of PTSD in the military population is higher than that among civilians. As of 2012, there were approximately 638,000 veterans receiving treatment for PTSD in the Veterans Health Administration, or VHA. Based on March 2015 VHA data, more than 19% of military veterans involved in recent conflicts in Iraq and Afghanistan were seen at VHA facilities for potential or provisional PTSD.

 

Many patients fail to adequately respond to the medications approved for PTSD and approved medications show little evidence of a treatment effect in men, lack evidence of efficacy in those for whom the traumatic event was combat-related, and carry suicidality warnings. Sleep disturbances are central features of PTSD and are predictive of disease severity, depression, substance abuse, and suicidal ideation, yet are resistant to the approved medications and present a difficult therapeutic challenge. Current PTSD treatments include off-label use of anxiolytics, sedative-hypnotics, and antipsychotics, many of which lack reliable evidence of efficacy, and several have significant safety liabilities and dependence risk.

 

Migraine Headaches

 

Migraine is a primary headache disorder characterized by recurrent headaches that are moderate to severe. Typically, episodes affect one side of the head, are pulsating in nature, and last from a few hours to three days. Associated symptoms may include nausea, vomiting, and sensitivity to light, sound, or smell. The pain is generally made worse by physical activity, although regular exercise may have prophylactic effects. Up to one-third of people affected have aura, typically a short period of visual disturbance that signals that the headache will soon occur. Occasionally, aura can occur with little or no headache following it. Approximately one billion individuals worldwide suffer from migraine (~14% of the population). Migraine is the second leading cause of years lived with disability. Chronic migraine (≥ 15 headache/migraine days per month) affects about 1-2% of individuals (~75-150 million individuals worldwide; 3-7 million in the U.S.). CGRP antibodies are the only migraine specific prophylaxis drugs approved in decades, but they require parenteral administration and there are long term safety concerns with prolonged systemic blockade of CGRP receptor.

 

Prader-Willi Syndrome

 

Prader-Willi syndrome (PWS) is recognized as the most common genetic cause of life-threatening childhood obesity and affects males and females with equal frequency and all races and ethnicities. The hallmarks of PWS are lack of suckling in infants and, in children and adults, severe hyperphagia, an overriding physiological drive to eat, leading to severe obesity and other complications associated with significant mortality. PWS is an orphan disease that occurs in approximately one in 15,000 births. There is currently no approved treatment for the obesity and hyperphagia in adults and older children associated with PWS.

 

Major Depressive Disorder

 

According to the National Institute of Mental Health, depression affects approximately 17 million adults in the U.S., with approximately 2.5 million adults treated with adjunctive therapy. Depression is a condition characterized by symptoms such as a depressed mood or loss of interest or pleasure in daily activities most of the time for two weeks or more, accompanied by appetite changes, sleep disturbances, motor restlessness or retardation, loss of energy, feelings of worthlessness or excessive guilt, poor concentration, and suicidal thoughts and behaviors. These symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The majority of people who suffer from depression do not respond adequately to initial antidepressant therapy.

 

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Infectious Diseases

 

COVID-19

 

SARS-CoV-2 is a contagious virus causing the disease COVID-19 that became a global pandemic in 2019 and has resulted in more than three million deaths. While the infection and mortality rates have slowed in regions of the world with high vaccination rates, the struggle with the pathogen is ongoing and evolving since SARS-CoV-2 is mutating into new variants. COVID-19 is characterized by fever, sore throat, acute shortness of breath, cough, and oxygen desaturation in the blood. At least three major variants have swept across the world in successive waves and overwhelmed healthcare systems during these waves. With new variants of the virus emerging, therapeutic research is addressing the challenge of keeping up with this rapidly mutating virus. The early vaccines have been effective in limiting the severity of disease in vaccinated individuals. Vaccines that elicit strong T cell responses are believed to have the potential to provide long-term or durable protection.

 

Smallpox and Monkeypox

 

Smallpox is an acute contagious disease caused by the variola virus, or VARV, which is a member of the orthopoxvirus family. Smallpox was declared eradicated in 1980 following a global immunization campaign. Smallpox is transmitted from person to person by infective droplets during close contact with infected symptomatic people. Monkeypox is an acute contagious disease caused by the monkeypox virus or MPXV, which is also a member of the orthopoxvirus family. Monkeypox symptoms are similar to those of smallpox, although less severe. Monkeypox is emerging as an important zoonotic infection in humans in Central and West Africa. Some cases of monkeypox have been reported outside of Africa in patients who had been infected while in Africa.

 

Smallpox was eradicated by a World Health Organization program that vaccinated individuals with live replicating vaccinia vaccines wherever smallpox appeared. In the 1970s, vaccination of civilians to protect against smallpox was discontinued in the U.S.; however, smallpox remains a material threat to national security and a proportion of military personnel, including members of the Global Response Force continue to be vaccinated. We are developing TNX-801 as a potential smallpox-preventing vaccine for the U.S. strategic national stockpile and for potential widespread immunization in the event of malicious reintroduction of VARV.

 

Lead Product Candidates

 

We believe that our product candidates offer innovative therapeutic approaches and may provide significant advantages relative to available therapies. We have worldwide commercialization rights to all of our product candidates listed below. The following table summarizes our product candidates:

 

Product Candidate   Indication   Stage of Development  
TNX-1500   Organ transplant rejection   Pre-IND; Phase 1 Start Expected 2H22  
TNX-1300   Cocaine Intoxication   Phase 2 Ready  
TNX-102 SL   Fibromyalgia   Mid-Phase 3  
TNX-102 SL   Posttraumatic stress disorder   Phase 2 ready  
TNX-102 SL   Long COVID   Pre-IND; Phase 2 Start Expected 1H22  
TNX-1900   Binge eating disorder   Non-IND; Phase 2 Start Expected 2H22  
TNX-1900   Migraine   Pre-IND; Phase 2 Start Expected 2H22  
TNX-601 CR   Depression   Pre-IND; Phase 2 Start Expected 1Q23  
TNX-801   Smallpox and monkeypox vaccine   Preclinical  
TNX-1800/1840/1850   COVID-19 vaccine   Preclinical  
TNX-2100   COVID-19 Skin test   Phase 1 ongoing  

 

 

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TNX-1500

 

TNX-1500 is a humanized mAb directed against CD40-ligand, or CD40L, engineered to modulate binding to Fc receptors, that is being developed to prevent and treat organ transplant rejection as well as to treat autoimmune conditions. TNX-1500 incorporates the antigen binding fragment (Fab) region of hu5c8, which has been extensively characterized including at the atomic level in complex with CD40-ligand.

 

In experiments at the Massachusetts General Hospital, a teaching hospital of Harvard Medical School, TNX-1500 is being studied as monotherapy or in combination with immunosuppressive drugs in heart and kidney organ transplants in non-human primates. Preliminary results from an ongoing experiment in heart transplants indicates that TNX-1500 appears to have comparable efficacy to historical experiments using the chimeric mouse/primate version of the anti-CD40L mAb 5c8. In the non-human primate studies with TNX-1500 no evidence of thrombosis has been observed so far.

CD40-ligand is a protein expressed on the surface of activated T lymphocytes that mediates T cell helper function. CD40-ligand is also known as CD154, the T cell-B cell activating molecule (T-BAM), TRAP and gp39. CD154 is a member of the Tumor Necrosis Factor (TNF) Super Family. No mAb against CD154 has been approved for commercial use anywhere in the world. Other TNF Super Family members have been successfully targeted by antagonist mAbs. Approved mAbs against TNFα include: infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), and golimumab (Simponi®) for the treatment of certain autoimmune conditions. Also, etanercept (Enbrel®) is a TNFα antagonist receptor fusion protein. An approved mAb against RANKL (CD254) is denosumab (Prolia® or Xgeva®) for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone.

In January 2021, the World Intellectual Property Organization has published a patent application filed under the Patent Cooperation Treaty covering TNX-1500, a humanized mAb directed against CD40-ligand, which is also known as CD154, T-BAM, 5c8 antigen, TRAP and gp39. The patent application is titled “Anti-CD154 Antibodies and Uses Thereof” and published under International Publication No. WO 2021/001458 A1. The application entered national phase in December 2021. The patent applications include claims related to proprietary anti-human CD40-ligand mAbs that were engineered to have modified effector function, including TNX-1500, which have reduced potential for Fc binding to FcγRII. The patent applications also claim uses of TNX-1500 for preventing and treating conditions, such as organ transplant rejection and autoimmune disorders. If claims are granted, a patent issuing from a national stage of this application could potentially provide U.S. patent coverage for the TNX-1500 composition of matter through 2040 excluding possible patent term extensions or patent term adjustments. We also have filed a PCT patent application, PCT/US2022/011404, in January 2022, entitled “Methods of Inducing Immune Tolerance with Modified Anti-CD154 Antibodies.” It claims methods of inducing immune tolerance in transplant recipients using anti-CD154 antibodies having modified effector functions. We expect to start a Phase 1 study of TNX-1500 in the second half of 2022.

 

Remicade® and Simponi® are trademarks of Janssen; Humira® is a trademark of AbbVie Inc.; Cimzia® is a trademark of UCB S. A.; Enbrel®, Prolia® and Xgeva® are trademarks of Amgen Inc.

 

TNX-1300

 

TNX-1300 (T172R/G173Q double-mutant cocaine esterase 200 mg, i.v. solution) is being developed for the treatment of cocaine intoxication. TNX-1300 is a recombinant protein enzyme produced through rDNA technology in a non-disease-producing strain of E. coli bacteria. Cocaine Esterase (CocE) was identified in bacteria (Rhodococcus) that use cocaine as the sole source of carbon and nitrogen and that grow in soil surrounding coca plants.1 The gene encoding CocE was identified and the protein was extensively characterized.1-4 CocE catalyzes the breakdown of cocaine into metabolite ecgonine methyl ester and benzoic acid. Wild-type CocE is unstable at body temperature, so targeted mutations were introduced in the CocE gene and resulted in the T172R/G173Q double-mutant CocE, which is active for approximately 6 hours at body temperature5.

 

Currently there is no specific pharmacotherapy indicated for cocaine intoxication, a state characterized by acute agitation, hyperthermia, tachycardia, arrhythmias, and hypertension, with the potential life-threatening sequalae of myocardial infarction, cerebrovascular accident, rhabdomyolysis, respiratory failure, and seizures. Patients are currently managed only by supportive care for the adverse effects of cocaine overdose on the cardiovascular and central nervous systems. By targeting the cause of cocaine intoxication, rather than the symptoms like other medicines in emergency usage, we believe TNX-1300 may offer significant advantages to the current standard of care for cocaine overdose. TNX-1300 was developed by Columbia University, University of Kentucky and University of Michigan, and in-licensed by Tonix from Columbia University in 2019. TNX-1300 is designated as a breakthrough therapy by the FDA.

 

In a Phase 2 randomized, double-blind, placebo-controlled clinical study, TNX-1300 at 100 mg or 200 mg i.v. doses was well tolerated and interrupted cocaine effects after cocaine 50 mg i.v. challenge.6 Tonix expects to initiate a Phase 2 open-label, safety study of TNX-1300 to take place in emergency departments in the U.S. in the first half of 2022.

 

As a biologic and new molecular entity, TNX-1300 is eligible for 12 years of U.S. market exclusivity upon approval by the FDA, in addition to expected patent protection through 2029. Since in-licensing, Tonix has requalified existing inventory, developed a lyophilized drug product to facilitate enhanced stability and handling conditions applicable for an ER treatment, updated the process and analytical methods to current standards and are in the process of manufacturing Phase 2/3 drug product clinical supply.

 

1 Bresler MM, Rosser SJ, Basran A, Bruce NC. Gene cloning and nucleotide sequencing and properties of a cocaine esterase from Rhodococcus sp. strain MB1. Appl Environ Microbiol. 2000. 66(3):904-8.

2 Larsen NA, Turner JM, Stevens J, Rosser SJ, Basran A, Lerner RA, Bruce NC, Wilson IA. Crystal structure of a bacterial cocaine esterase. Nat Struct Biol. 2002. 9(1):17-21.

3 Turner JM, Larsen NA, Basran A, Barbas CF 3rd, Bruce NC, Wilson IA, Lerner RA. Biochemical characterization and structural analysis of a highly proficient cocaine esterase. Biochemistry. 2002. 41(41):12297-307.

4 Gao D, Narasimhan DL, Macdonald J, Brim R, Ko MC, Landry DW, Woods JH, Sunahara RK, Zhan CG. Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol Pharmacol. 2009. 75(2):318-23.

5 Overdose Death Rates - National Institute on Drug Abuse - https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates; accessed May 11, 2019

6 Nasser AF, Fudala PJ, Zheng B, Liu Y, Heidbreder C. A randomized, double-blind, placebo-controlled trial of RBP-8000 in cocaine abusers: pharmacokinetic profile of rbp-8000 and cocaine and effects of RBP-8000 on cocaine-induced physiological effects. J Addict Dis. 2014;33(4):289-302. 

 

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TNX-102 SL

 

Overview

 

TNX-102 SL, in clinical development for registration in five indications. TNX-102 SL is a proprietary sublingual tablet formulation of CBP that efficiently delivers CBP across the oral mucosal membrane into the systemic circulation. We are developing TNX-102 SL as a bedtime treatment for FM, PTSD, PASC or Long Covid and AAD and AUD. We own all rights to TNX-102 SL in all geographies, and we bear no obligations to third-parties for any future development or commercialization. Excipients used in TNX-102 SL are approved for pharmaceutical use. Some of the excipients were specially selected to promote a local oral environment that facilitates mucosal absorption of cyclobenzaprine or CBP. 

 

 The current TNX-102 SL sublingual tablets contain 2.8 mg of CBP. For the treatment of FM, TNX-102 SL 5.6 mg (two 2.8 mg tablets) at bedtime is in Phase 3 development. We selected this dose with the goal of providing a balance of efficacy, safety, and tolerability that would be acceptable as a first-line therapy and for long-term use, and in-patient populations characterized by burdensome symptoms and sensitivity to medications.

 

The active ingredient in TNX-102 SL, is CBP, a serotonin-2A and alpha-1 adrenergic receptor antagonist as well as an inhibitor of serotonin and norepinephrine reuptake. In addition, TNX-102 SL acts upon other receptors in the central nervous system including muscarinic M1 and histaminergic H1 receptors.

 

CBP is the active ingredient of two products that are approved in the U.S. for the treatment of muscle spasm: Flexeril® (5 mg and 10 mg oral immediate-release, or IR, tablet) and Amrix® (15 mg and 30 mg oral extended-release capsule). The Flexeril brand of CBP IR tablet has been discontinued since May 2013. There are numerous generic versions of CBP IR tablets on the market. CBP-containing products are approved for short term use (two to three weeks) only as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. CBP IR tablets are recommended for three times per day dosing, which results in relatively stable blood levels of CBP after several days of treatment. Extended-release CBP capsules taken once a day mimic, and flatten, the pharmacokinetic profile of three times per day CBP IR tablets.

 

We designed TNX-102 SL to be administered once-daily at bedtime and with the intention for long-term use. We believe the selected dose of TNX-102 SL and its unique pharmacokinetic profile will enable it to achieve a desirable balance of efficacy, safety, and tolerability. Our Phase 1 comparative trials showed that, on a dose-adjusted basis, TNX-102 SL results in faster systemic absorption and significantly higher plasma levels of CBP in the first hour following sublingual administration relative to oral IR CBP tablets. It also showed that the sublingual route of administration, which largely bypasses the “first pass” hepatic metabolism that swallowed medications undergo, results in a higher plasma ratio of CBP to its main active metabolite, norcyclobenzaprine. In clinical studies, TNX-102 SL 2.8 mg and TNX-102 SL 5.6 mg were generally well-tolerated, with no drug-related serious and unexpected adverse reactions reported in these studies. Some subjects experienced transient numbness of the tongue after TNX-102 SL administration.

 

We have successfully completed the pivotal exposure bridging study with TNX-102 SL compared to Amrix.  Results from this study support the approval of TNX-102 SL under Section 505(b)(2) of the Federal Food, Drug and Cosmetic Act, or FDCA, with Amrix as the reference listed drug, or RLD. In general, the development timeline for a 505(b)(2) NDA is shorter and less expensive than an NDA developed under Section 505(b)(1), which is for new chemical entities, or NCEs, that have never been approved in the U.S. We believe that TNX-102 SL has the potential to provide clinical benefit to FM, PTSD and Long COVID patients and possibly other CNS (central nervous system) indications that are underserved by currently marketed products or have no approved treatment.

 

TNX-102 SL – FM program 

 

We are developing TNX-102 SL as a bedtime treatment for FM under an active IND application. The potential approval of TNX-102 SL for FM is expected to be under Section 505(b)(2) of the FDCA.

 

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Clinical Development Plan

 

Phase 3 RALLY Study (F306)

 

The Phase 3 RALLY study is clinically complete. We enrolled the first patient in September 2020. The RALLY study is a double-blind, randomized, placebo-controlled adaptive design trial designed to evaluate the efficacy and safety of TNX-102 SL in FM. The trial was expected to enroll approximately 670 patients across approximately 40 U.S. sites. For the first two weeks of treatment, there was a run-in period in which patients started on TNX-102 SL 2.8 mg (1 tablet) or placebo. After the first two weeks, all patients had the dose increased to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets for 12 weeks. The primary endpoint was daily diary pain severity score change from baseline to Week 14 (using the weekly averages of the daily numerical rating scale scores), analyzed by mixed model repeated measures with multiple imputation.

 

The RALLY study had one pre-specified unblinded interim analysis by an Independent Data Monitoring Committee, or IDMC, to be conducted when the study has results from approximately the first 50% of efficacy-evaluable patients. In July 2021, we reported interim analysis and, based on the recommendation from the IDMC that the RALLY trial was unlikely to demonstrate a statistically significant improvement in the primary endpoint, we stopped enrollment of new participants but allowed those participants who were already enrolled to complete the study. We expect to report topline data from the completed study in the first quarter of 2022. We expect to analyze the RALLY results to improve the design of subsequent Phase 3 studies. In addition, we plan to employ pharmacogenomic techniques to compare the RALLY and RELIEF study populations, which may provide a path to precision medicine-based companion diagnostics for TNX-102 SL in FM.

 

Tonix intends to initiate a new Phase 3 study in FM, F307, in the first half of 2022. Following analysis of F306 results, including pharmacogenomic comparison of RELIEF and RALLY, Tonix may modify the protocol for this next Phase 3 study.

 

Completed Phase 3 RELIEF Study (F304)

 

In the fourth quarter of 2020, we announced the results of a randomized, double-blind, placebo-controlled, 12-week Phase 3 study of TNX-102 SL in 503 participants with FM, which we refer to as the RELIEF study. The primary objective of this study was to evaluate the potential clinical benefit of using TNX-102 SL to treat FM at a dose of 5.6 mg, administered sublingually once daily at bedtime for 12 weeks. The primary endpoint of the RELIEF trial was the daily diary pain severity score change from baseline to Week 14 (using the weekly averages of the daily numerical rating scale scores), analyzed by mixed model repeated measures with multiple imputation. The RELIEF study achieved statistical significance on the primary efficacy endpoint: change from baseline in the weekly average of daily diary pain severity numerical rating scale (NRS) scores for TNX-102 SL 5.6 mg (LS mean [SE]: -1.9 [0.12] units) versus placebo (-1.5 [0.12] units), analyzed by mixed model repeated measures with multiple imputation (LS mean [SE] difference: -0.4 [0.16] units, p=0.010). The statistically significant improvement in pain is further substantiated when diary pain was analyzed by another standard statistical approach, a 30 percent responder analysis, with 46.8% on active and 34.9% on placebo having a 30 percent or greater reduction in pain (logistic regression; odds ratio [95% CI]: 1.67 [1.16, 2.40]; p=0.006). Consistent with the proposed mechanism that TNX-102 SL acts in fibromyalgia through improving sleep quality, TNX-102 SL showed nominal improvement of sleep by several measures. For daily diary sleep quality ratings, TNX-102 SL (-2.0 [0.12] units) compared to placebo (-1.5 [0.12] units) was nominally significant (LS mean difference: -0.6 [0.17] units; p<0.001). For the PROMIS Sleep Disturbance instrument, TNX-102 SL was also nominally significant over placebo on T-scores (LS mean difference: -2.9 [0.82] units; p<0.001). The effect sizes on the diary sleep ratings and PROMIS Sleep Disturbance instrument were 0.31 and 0.32, respectively.

 

In the RELIEF study, TNX-102 SL was similarly well tolerated as in the Phase 2 BESTFIT and Phase 3 AFFIRM studies, which both studied TNX-102 SL at a lower dose of 2.8 mg daily. There were no new safety signals observed in the RELIEF study at the 5.6 mg daily dose. Among participants randomized to the TNX-102 SL and placebo arms, 82.3% and 83.5%, respectively, completed the 14-week dosing period. As expected based on prior TNX-102 SL studies, administration site reactions are the most commonly reported adverse events and were higher in the TNX-102 SL treatment group, including rates of oral numbness (17.3% vs. 0.8%), oral pain/discomfort (11.7% v. 2.0%), taste impairment (6.5% vs. 0.4%), and oral tingling (5.6% v. 0.4%). Oral numbness or tingling and taste impairment were local administration site effects nearly always temporally related to dose administration and transiently expressed (<60 minutes) in almost all occurrences. The only systemic treatment-emergent adverse events that occurred at a rate of 5.0% or greater in either arm was somnolence/sedation at 5.6 percent in the TNX-102 SL arm vs. 1.2% in placebo, which was consistent with known side effects of marketed oral cyclobenzaprine. Adverse events resulted in premature study discontinuation in 8.9% of those who received TNX-102 SL compared with 3.9% of placebo recipients. There were a total of seven serious adverse events reported during the study, none of which were deemed related to investigational product; five in placebo arm, and two in TNX-102 SL arm. Of the two in the TNX-102 SL arm, one was a motor vehicle accident with multiple bone fractures, and the other was a pneumonia secondary to an infection.

 

 Completed Phase 3 AFFIRM Study (F301)

 

In the third quarter of 2016, we announced the results of a randomized, double-blind, placebo-controlled, 12-week Phase 3 study of TNX-102 SL in 519 participants with FM, which we refer to as the AFFIRM study. The primary objective of this study was to evaluate the potential clinical benefit of using TNX-102 SL to treat FM at a dose of 2.8 mg, administered sublingually once daily at bedtime for 12 weeks. The primary endpoint of the AFFIRM trial was the 30% pain responder analysis in which a responder is defined as a subject for whom pain intensity was reduced by at least 30% at Week 12 as compared to baseline. AFFIRM did not achieve statistical significance at the primary endpoint (p=0.095). Yet, statistical significance was achieved when pain was analyzed instead as a continuous variable, either by MMRM (p<0.001) or by MMRM with multiple imputation for missing data (p=0.005), a generally accepted approach to pain data. TNX-102 SL also showed statistically significant improvements in the declared secondary analyses of the Patient Global Impression of Change, or PGIC (p=0.038) and the Fibromyalgia Impact Questionnaire-Revised, or FIQ-R (p<0.001). The study also showed statistically significant improvement with TNX-102 SL on measures of sleep quality, including the Patient-Reported Outcomes Measurement Information System, or PROMIS, Sleep Disturbance instrument (p<0.001).

 

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TNX-102 SL was well tolerated in the AFFIRM trial. Among patients randomized to the active and control arms, 78% and 86%, respectively, completed the 12-week dosing period. The most common adverse events were local in nature, with transient tongue or mouth numbness occurring in 40% of participants on TNX-102 SL vs. 1% on placebo. These local adverse events did not appear to affect either rates of retention of study participants or their compliance with taking TNX-102 SL. Systemic adverse events were similar between TNX-102 SL and placebo. No serious adverse events were reported.

 

Other NDA Requirements

 

The Agreed Initial Pediatric Study Plan, or Agreed iPSP, was accepted by the FDA in September 2015. An amendment to the Agreed iPSP will be submitted for FDA agreement prior to marketing application.

 

Based on our discussions with the FDA and the FDA official meeting minutes, we will not have to conduct special populations, such as geriatric and renal/hepatic impaired patients, drug-drug interaction or cardiovascular safety studies to support the TNX-102 SL NDA filing since the pivotal systemic exposure bridging study using Amrix as the reference listed drug, or RLD, has been successfully completed. Due to the well-established safety profile of CBP at much higher doses than we proposed for FM and the long-term safety data in PTSD, up to 15 months, on TNX-102 SL 5.6 mg, the FDA has not requested a risk management plan or medication guide for this product.

 

Phase 1 Bioequivalence, Bridging PK, Food-Effect and Dose-Proportionality Studies

 

We have completed the required Phase 1 bioequivalence, multi-dose bridging pharmacokinetic, and food effect and dose-proportionality studies.

 

Cyclobenzaprine Hydrochloride Nonclinical Development

 

In October 2016, we completed the six-month repeated-dose toxicology study of the active ingredient, CBP, in rats and a nine-month repeated-dose toxicology study in dogs required for the NDA filing. These chronic toxicity studies were requested by the FDA to augment the nonclinical information in the AMRIX prescribing information, or labeling, which is necessary to support the TNX-102 SL labeling for long-term use. Due to the lack of evidence of potential abuse in clinical studies of TNX-102 SL, the FDA agreed that nonclinical study to assess CBP abuse and dependency potential is not required to support the TNX-102 SL NDA filing.

 

Tonix is planning to develop TNX-102 SL for the treatment of FM in Japan. Cyclobenzaprine, the active ingredient of TNX-102 SL, has not been approved in Japan, and is considered a NCE (new chemical entity). In February 2022, Tonix held an End of Phase 2 Consultation with the Pharmaceuticals and Medical Devices Agency, or PMDA, an independent administrative institution responsible for ensuring the safety, efficacy and quality of pharmaceuticals and medical devices in Japan, to discuss the Japan development plan. Agreement was reached on the design of a Phase 1 bridging study (TNX-CY-F108/F108) in ethnic Japanese healthy volunteers to enable clinical studies of TNX-102 SL in Japan. PMDA also provided guidance on the overall nonclinical package to support a Japan NDA filing for TNX-102 SL for the treatment of FM.

 

The F108 Phase 1 study will be initiated in March 2022.

 

Tonix has initiated nonclinical safety, pharmacology and embryo-fetal development toxicology studies as part of the agreed IND-enabling nonclinical data package to support clinical studies of TNX-102 SL in Japan. 

 

 TNX 102 SL – Long COVID Program

 

We are developing TNX-102 SL as a bedtime treatment for Long COVID. The potential approval of TNX-102 SL for Long COVID is expected to be under Section 505(b)(2) of the FDCA. 

 

Tonix completed a pre-IND meeting with the FDA in August 2021 to develop TNX-102 as a potential treatment for Long COVID. Tonix expects to initiate a Phase 2 study of TNX-102 SL as an indicated treatment for a subset of patients affected by Long COVID whose symptoms overlap with fibromyalgia. Long COVID is a protracted syndrome experienced by many people following SARS-CoV-2 infection that can include a number of persistent disabling symptoms, including fatigue, widespread pain, sleep disturbance, brain fog or difficulty concentrating, arthralgias, diffuse myalgia, olfactory dysfunction, and headache. The Phase 2 study will focus on Long COVID patients whose primary symptoms overlap with fibromyalgia, and, therefore, the Long COVID program leverages learnings about the pharmacodynamic activity of TNX-102 SL from more than 1,000 participants who have been or are enrolled in Tonix’s fibromyalgia trials to date. Long COVID has been compared to fibromyalgia because of the common symptoms of sleep disturbance, persistent widespread pain, fatigue, and brain fog. Additionally, Long COVID, like fibromyalgia, is experienced by women at a rate approximately four times that of men.

 

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TNX-102 SL – Posttraumatic Stress Disorder Program

 

We are developing TNX-102 SL as a bedtime treatment of PTSD under an active IND application. The potential approval of TNX-102 SL for PTSD is expected to be under Section 505(b)(2) of the FDCA. 

 

Phase 3 RECOVERY Study (P302)

 

We initiated the RECOVERY study (P302) in March 2019. The RECOVERY Phase 3 study was a double-blind, randomized, placebo-controlled study of TNX-102 SL 5.6 mg (2 x 2.8 mg sublingual tablets) over 12 weeks of treatment. The RECOVERY study was conducted at approximately 30 U.S. sites.  The study planned to enroll 250 participants with civilian and military-related PTSD.  RECOVERY restricts enrollment of study participants to individuals with PTSD who experienced an index trauma within nine years of screening. The two previous PTSD studies of TNX-102 SL (P201 and P301) restricted enrollment to participants who experienced traumas during military service since 2001.  The primary efficacy endpoint in P302 was the Week 12 mean change from baseline in the severity of PTSD symptoms as measured by CAPS-5 between those treated with TNX-102 SL and those receiving placebo.  Based on interim analysis results of the first 50% of enrolled participants, an Independent Data Monitoring Committee recommended stopping the Phase 3 RECOVERY trial (P302) in PTSD for futility as TNX-102 SL was unlikely to demonstrate a statistically significant improvement in the primary endpoint of overall change from baseline in the severity of PTSD symptoms between those treated with TNX-102 SL and those receiving placebo. New enrollment for the RECOVERY study was stopped in February 2020, but we continued studying those participants currently enrolled until completion and proceeded with a full analysis of the unblinded data to determine the next steps in this program. Topline data was reported during the fourth quarter of 2020, which revealed that the RECOVERY study did not achieve statistical significance in the prespecified primary efficacy endpoint of change from baseline to Week 12 in the CAPS-5 between TNX-102 SL and placebo (p=0.343). TNX-102 SL separated from placebo in the first key secondary endpoint, CGI-S scale (p=0.024) and in the PGIC, (p=0.007). TNX-102 SL also trended for improvement on the PROMIS Sleep Disturbance scale (p=0.055), consistent with the proposed mechanism of targeting the PTSD sleep disturbance. TNX-102 SL is generally well tolerated and no new safety signals were observed. Tonix met with the FDA to discuss potential new endpoints for the indication of treatment of PTSD. The new PTSD study can use 1 month look-back CAPS-5 as endpoint v. 1 week look-back.

 

Tonix intends to initiate a new Phase 2 study of TNX-102 SL in police in Kenya in the first half of 2022.

 

Discontinued Phase 3 HONOR Study (P301)

 

In the third quarter of 2018, we announced the results of a randomized, double-blind, placebo-controlled Phase 3 study of TNX-102 SL, planned for enrollment of approximately 550 participants with military-related PTSD conducted at approximately 40 U.S. sites, which we refer to as the HONOR study. This study was an adaptive design study based on the results of the Phase 2 AtEase study. The study design was very similar to the Phase 2 AtEase study, except there was one planned IA and the involvement of an IDMC, which reviewed the unblinded IA results. In addition, only one active dose (5.6 mg administered as 2 x 2.8 mg tablets) was investigated and the baseline severity entrance criterion was a CAPS-5 total score ≥ 33 in this Phase 3 study. The primary efficacy endpoint of the HONOR study was the 12-week mean change from baseline in the severity of PTSD symptoms as measured by the Clinician-Administered PTSD Scale for DSM-5, or CAPS-5, between those treated with TNX-102 SL and those receiving placebo. The CAPS-5 is a standardized structured clinical interview and serves as the standard in research for measuring the symptom severity of PTSD.  The IA was conducted when approximately 50% of the initially planned participant enrollment was evaluable for efficacy. HONOR was discontinued after the results of the IA indicated a pre-defined threshold p-value for continuing enrollment was not achieved, i.e. IDMC recommended stopping for futility.  The modified Intent-to-Treat (mITT) population analyzed at the time of the IA included 252 participants.

 

The most common adverse events were mostly related to local administration site reactions, such as oral hypoaesthesia (37.3%), abnormal product taste (11.9%), and oral paraesthesia (9.7%). The most common systemic adverse event was somnolence (15.7%).

 

Retrospective analysis of the HONOR study revealed a treatment effect in participants who experienced trauma less than or equal to nine years prior to screening. In the participants who experienced trauma within nine years, the p-value of the CAPS-5 primary endpoint at Week 12, using mixed model repeated measures with multiple imputation (MMRM with MI), was 0.039, with a least-squares mean difference from placebo of -5.9 units. In contrast, there was no difference in CAPS-5 in the participants who experienced trauma more than nine years prior to screening compared to placebo. This analysis defined an optimal treatment window for treatment with TNX-102 SL for PTSD of the first nine years after the index trauma that resulted in PTSD and guided the design of the next Phase 3 study in PTSD, RECOVERY.

 

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Long-Term Safety Exposure Study for TNX-102 SL

 

In October 2019, we completed long-term safety exposure studies in participants with PTSD to evaluate the tolerability of TNX-102 SL 5.6 mg to support an NDA for the treatment of PTSD.  The data provide us with exposure data of daily dosing of TNX-102 SL 5.6 mg for at least 12 months in more than 50 individuals, and daily dosing of TNX-102 SL 5.6 mg for at least 6 months in more than 100 individuals. The data was collected in OLE studies of the PTSD program.  Based on the FDA’s guidance, the long-term safety exposure studies in PTSD are also expected to support an NDA for the management of FM.

 

Other NDA Requirements

 

An Agreed Initial Pediatric Study Plan, or Agreed iPSP, is required for the initial NDA submission. We submitted a revised iPSP in the first quarter of 2017, which incorporated the FDA comments received on our iPSP submitted in the third quarter of 2016. Additional comments from the FDA were received in second quarter of 2017 on our revised iPSP. We plan to submit an Agreed PSP once a therapeutic dose in adults is established. An acceptable Pediatric Study Plan will be determined at the time of the NDA approval.

 

Based on our discussions with the FDA and the FDA official meeting minutes, we will not have to conduct special populations (geriatric and renal/hepatic impaired), drug-drug interaction or cardiovascular safety studies to support the TNX-102 SL NDA filing since the pivotal systemic exposure bridging study using AMRIX as the reference listed drug, or RLD, has been successfully completed. Due to the well-established safety profile of CBP at much higher doses than we proposed for PTSD and the long-term safety data (up to 15 months) on TNX-102 SL 2.8 mg in a prior FM program, the FDA has not requested a risk management plan or medication guide for this product.

 

Manufacturing

 

TNX-102 SL drug product for Phase 3 and the associated registration batches for the NDA were manufactured at commercial cGMP facilities. We currently have in excess of 24 months stability data in the proposed packaging configurations ready for commercialization. The FDA has reviewed the proposed CMC data package to support TNX-102 SL’s NDA approval and commercial manufacturing plans as part of the IND process. Tonix is ready to manufacture TNX-102 SL commercial product for the forecasted FM market.

 

TNX-1900

 

TNX-1900 (intranasal potentiated oxytocin) is a proprietary formulation of oxytocin in development for BED, prophylaxis of chronic migraine and for the treatment of craniofacial pain, insulin resistance and related conditions. In 2020, TNX-1900 was acquired from Trigemina, Inc. and licensed from Stanford University. TNX-1900 is a drug-device combination product, based on an intranasal actuator device that delivers oxytocin into the nose.

 

Oxytocin is a naturally occurring human hormone that acts as a neurotransmitter in the brain. Oxytocin has no recognized addiction potential. It has been observed that low oxytocin levels in the body can lead to increase in migraine headache frequency, and that increased oxytocin levels can relieve migraine headaches. Certain other chronic pain conditions are also associated with decreased oxytocin levels. Migraine attacks are caused, in part, by the activity of pain-sensing trigeminal nerve cells which, when activated, release of CGRP which binds to receptors on other nerve cells and starts a cascade of events that is believed to result in headache. Oxytocin when delivered via the nasal route, concentrates in the trigeminal system1 resulting in binding of oxytocin to receptors on neurons in the trigeminal system, inhibiting the release of CGRP and transmission of pain signals.2 Blocking CGRP release is a distinct mechanism compared with CGRP antagonist and anti-CGRP antibody drugs, which block the binding of CGRP to its receptor.

 

With TNX-1900, the addition of magnesium to the oxytocin formula enhances oxytocin receptor binding3 as well as its effects on trigeminal neurons and craniofacial analgesic effects in animal models5. Intranasal oxytocin has been well tolerated in several clinical trials in both adults and children4. Targeted nasal delivery results in low systemic exposure and lower risk of non-nervous system, off-target effects which could potentially occur with systemic CGRP antagonists such as anti-CGRP antibodies6. For example, CGRP has roles in dilating blood vessels in response to ischemia, including in the heart. We believe nasally targeted delivery of oxytocin could translate into selective blockade of CGRP release in the trigeminal ganglion and not throughout the body, which could be a potential safety advantage over systemic CGRP inhibition. In addition, daily dosing is more quickly reversible, in contrast to monthly or quarterly dosing, as is the case with anti-CGRP antibodies, giving physicians and their patients greater control.

 

We intend to initiate a Phase 2 study in chronic migraine in the second half of 2022. We also plan to develop TNX-1900 for treatment of episodic migraine, craniofacial pain and insulin resistance. Tonix has a license with the University of Geneva to use TNX-1900 for the treatment of insulin resistance and related conditions. TNX-1900 is also being studied as a potential treatment for binge eating disorder in an investigator-initiated Phase 2 clinical trial. The Phase 2 clinical trial is expected to start in the second half of 2022. In March 2022, we announced an agreement with Massachusetts General Hospital, a teaching hospital of Harvard Medical School, to conduct this study. Tonix does not own this IND.

 

1 Yeomans DC, et al. Transl Psychiatry. 2021. 11(1) :388.

2 Tzabazis A, et al. Cephalalgia. 2016. 36(10):943-50.

3 Antoni FA and Chadio SE. Biochem J. 1989. 257(2):611-4.

4 Yeomans, DC et al. 2017. US patent US2017368095.

5 Cai Q, et al., Psychiatry Clin Neurosci. 2018. Mar;72(3):140-151.

6 MaassenVanDenBrink A, et al. Trends Pharmacol Sci. 2016. 37(9):779-788.

 

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TNX-2900

 

TNX-2900 is based on Tonix’s patented intranasal potentiated oxytocin formulation, or TNX-1900, but being developed for Prader-Willi syndrome. Tonix licensed technology using oxytocin-based therapeutics for the treatment of Prader-Willi syndrome and non-organic failure to thrive disease from the French National Institute of Health and Medical Research (Inserm). The licensing agreement has been negotiated and signed by Inserm Transfert, the private subsidiary of Inserm, on behalf of Inserm (the French National Institute of Health and Medical Research), Aix-Marseille Université and Centre Hospitalier Universitaire of Toulouse. Prader-Willi syndrome is recognized as the most common genetic cause of life-threatening childhood obesity and affects males and females with equal frequency and all races and ethnicities. There is currently no approved treatment for either the suckling deficit in infants or the obesity and hyperphagia in older children associated with Prader-Willi syndrome. Since Prader-Willi syndrome is an orphan disease that occurs in approximately one in 15,000 births, Tonix has been granted Orphan Drug Designation for TNX-2900 by the FDA.

 

In 2022, Tonix entered into a research collaboration with Inserm involving in vitro and in vivo animal studies designed to validate and characterize the role of oxytocin in suckling and in the maturation of feeding behavior during infancy in order to support an intranasal therapeutic approach to restore a normal nutritive suckling. The studies will include mice that have been engineered to precisely recapitulate the genetic issue underlying Prader-Willi in humans. The mechanisms involved in suckling activity required for normal feeding and the role of oxytocin system in this process will be investigated. The results of this work are expected to be useful in the clinical care of infants requiring support to achieve efficient suckling behavior. Intranasal oxytocin has previously been shown to improve suckling in newborn animals and suppress feeding behaviors in adult animal models.

 

Our preclinical pipeline of drugs and biologic candidates includes TNX-801, a smallpox vaccine, TNX-3500, a COVID-19 antiviral; TNX-3600, a COVID-19 therapeutic platform; TNX-3700, a COVID-19 vaccine; TNX-701, a drug candidate for radioprotection; TNX-1700 a preclinical candidate for cancers of the gastrointestinal system and TNX-1600, a preclinical candidate for PTSD, ADHD and depression.

 

TNX-601 CR

 

TNX-601 CR is a novel oral formulation of tianeptine oxalate designed for once-daily daytime dosing that is currently in development for the treatment of major depressive disorder (MDD), but may also be developed for PTSD and neurocognitive disorder from corticosteroids. Tianeptine sodium (amorphous) immediate release was first marketed for depression in France in 1989 and has been available for decades in Europe, Russia, Asia, and Latin America for the treatment of depression. Tianeptine sodium has an established safety profile from decades of use in these jurisdictions. Currently there is no tianeptine-containing product approved in the U.S. and no controlled-release tianeptine product approved in any jurisdiction. Tonix discovered a novel oxalate salt of tianeptine that may provide improved stability, consistency, and manufacturability compared to known forms of tianeptine. Tianeptine is believed to work in depression as a modulator of the glutamatergic system. Tianeptine modulates the glutamatergic system indirectly since it does not directly bind to NMDA, AMPA or kainate receptors. In animals, tianeptine has been shown to reverse the adverse neuroplastic changes that are observed during periods of stress and elevated corticosteroid exposure. Tianeptine and its MC5 metabolite are weak µ-opioid receptor agonists. Tonix has added naloxone to the TNX-601 CR tablet to mitigate potential for parenteral abuse as tianeptine has been linked to illicit misuse at much higher doses than the reported therapeutic dose in the treatment of MDD. Neither tianeptine nor MC5 have been shown to bind other neurotransmitter receptors. Tianeptine’s reported pro-cognitive and anxiolytic effects as well as its ability to attenuate the neuropathological effects of excessive stress responses suggest that it may also be used to treat post-traumatic stress disorder by a different mechanism of action than TNX-102 SL.

 

We intend to develop TNX-601 CR under Section 505(b)(2) of the FDCA. Tonix completed a Phase 1 clinical trial for formulation development outside of the U.S in 2019. Based on this study, the final formulation of TNX-601 CR to be used in Phase 2 testing will be 39.4 mg tianeptine oxalate and 1 mg naloxone for once daily treatment of MDD. Naloxone is included in the formulation to mitigate the potential for high dose parenteral abuse. Tianeptine has weak off-target activity at the µ-opioid receptor that presents the potential for parenteral abuse with doses on the order of eight to 80 times the therapeutic daily dose for depression. Based on official minutes from a pre-IND meeting with the FDA, we expect to initiate a pharmacokinetic study, in the third quarter of 2022, and a Phase 2 study in the first quarter of 2023.

 

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The Phase 2 study, expected to start in the first quarter of 2023, is expected to be a randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of TNX-601 CR monotherapy compared to placebo in MDD. Treatment duration will be six weeks, preceded by up to five weeks in screening and followed by a two-week safety follow-up period (total up to 13 weeks of participation). We plan to randomize approximately 260 individuals with MDD at a 1:1 ratio to two arms of 130 each for drug and placebo at approximately 25-30 U.S. sites. The primary efficacy endpoint will be the change from baseline to Week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.

 

TNX-801 – Potential Smallpox and Monkeypox Vaccine

 

TNX-801 is a novel potential smallpox-preventing vaccine based on a synthetic version of live horsepox virus, grown in cell culture. Though it shares structural characteristics with vaccinia-based vaccines, TNX-801 has unique properties that we believe indicate potential safety advantages over existing live replicating vaccinia virus vaccines, which have been associated with adverse side effects such as myopericarditis in some individuals.  Emergent BioSolutions’ ACAM2000® is the only replicating vaccinia virus vaccine currently approved by the FDA to protect against smallpox. We believe replicating virus vaccines have potential efficacy advantages over non-replicating vaccines, relating to the stimulation of cell mediated immunity. Bavarian Nordic’s Jynneos® is the only non-replicating virus vaccine currently approved by the FDA to protect against smallpox and monkeypox. We believe TNX-801 has the potential to have improved tolerability relative to replicating vaccinia vaccines and the potential to have improved efficacy relative to non-replicating vaccinia vaccines.

 

Smallpox was eradicated by a World Health Organization program that vaccinated individuals with live replicating vaccinia vaccines wherever smallpox appeared. In the 1970s, vaccination of civilians to protect against smallpox was discontinued in the U.S.; however, smallpox remains a material threat to national security and a proportion of military personnel, including members of the Global Response Force, continue to be vaccinated. We are developing TNX-801 as a potential smallpox-preventing vaccine for the U.S. strategic national stockpile and for potential widespread immunization in the event of malicious reintroduction of variola, the virus that causes smallpox.

 

Monkeypox is a growing problem in certain regions of Africa. Some cases of monkeypox have been reported outside of Africa in patients who had been infected while in Africa.

 

In January 2020 at the American Society of Microbiology Biothreats conference, we reported the results of experiments on TNX-801 that were performed in collaboration with Southern Research, that showed TNX-801 vaccinated macaques were protected against monkeypox challenge. The TNX-801 vaccinated macaques showed no overt clinical signs after monkeypox challenge. Furthermore, eight of eight animals vaccinated with two different doses of TNX-801 showed no lesions after monkeypox challenge.

 

We have filed a patent application to protect the TNX-801 vaccine candidate. In addition, we expect that TNX-801 will be eligible for 12 years of non-patent-based exclusivity under the Patient Protection and Affordable Care Act, or PPACA. Following the passage of the 21st Century Cures Act, a law designed to help accelerate medical product development, we believe TNX-801 will qualify as a medical countermeasure and would therefore be eligible for a Priority Review Voucher upon receiving FDA approval. However, the Priority Review Voucher program provision of the 21st Century Cures Act is set to expire in 2023. If TNX-801 does not receive FDA approval by 2023, we may not be able to capitalize on the incentives contained in the 21st Century Cures Act unless the provision allowing for the Priority Review Voucher Program is extended until such time as TNX-801 is approved by the FDA.  

 

We intend to meet with the FDA to discuss the most efficient and appropriate investigational plan for TNX-801, to establish the safety and effectiveness evidence to support the licensure TNX-801. We are currently working to develop a vaccine that meets cGMP quality to support a clinical study.

 

TNX-1840 and TNX-1850 – Potential COVID-19 Vaccines

 

Tonix’s infectious disease portfolio includes a platform for vaccines for COVID-19. TNX-1800 is live virus vaccine based on Tonix’s RPV platform that expresses the SARS-CoV-2 spike protein from the ancestral Wuhan strain. Because the subsequent omicron variant has out-competed the ancestral Wuhan strain, we are now planning new versions of this vaccine, TNX-1840 and TNX-1850, that express spike protein from the omicron variant and from the BA.2 variant, respectively. Each of these RPV vaccines is being developed to protect against COVID-19 primarily by eliciting T cell responses. The COVID-19 vaccines that are approved for use, or have emergency use authorization, or EUA, in the U.S. have provided significant health benefits to the vaccinated population; however, they are showing limitations in the durability of protection conferred and in their ability to block forward transmission. Live virus vaccines that protect against other viral diseases by eliciting T cell responses have shown durability of protection that lasts years to decades and some live virus vaccines have significantly inhibited forward transmission.

 

We reported positive efficacy data for the TNX-1800 (spike from Wuhan strain) from animal challenge studies using live SARS-CoV-2 in the first quarter of 2021. In this study, TNX-1800 vaccinated, SARS-CoV-2 challenged animals had undetectable SARS-CoV-2 in the upper airways, which we believe relates to potential inhibition of forward transmission of this respiratory pathogen. This study of non-human primates compared TNX-1800 (modified horsepox virus encoding CoV-2 spike protein) to TNX-801 (horsepox virus, live vaccine) at two doses. A control group received a placebo. Each of these five groups (TNX-1800 high and low dose; TNX-801 high and low dose and placebo) included four animals. At day 41 after vaccination (or placebo), each animal was exposed to SARS-COV-2 by intra-tracheal (1 x 106 TCID50) and intra-nasal (1 x 106 TCID50) administration. Upper airway virus was studied by oropharyngeal swabs and lower airway virus by tracheal lavage using qRT-PCR to determine the number of genome copies of SARS-CoV-2 present in the samples. Six days after challenge, no (0/8) samples taken from animals vaccinated with TNX-1800 showed infection (more than 1,000 genome copies of SARS CoV-2) in either upper or lower airway samples. In contrast, all (8/8) animals vaccinated with the control vaccine TNX-801 showed infection in either the upper or lower airway samples as did all (4/4) monkeys vaccinated with vehicle control. At day 14 after a single vaccination, all eight of the TNX-1800 vaccinated animals made anti-CoV-2 neutralizing antibodies (≥1:40 titer) and, as expected, none of the eight TNX-801 vaccinated control animals, or any of the four animals in the placebo group made anti-CoV-2 neutralizing antibodies (≤1:10 titer). At 6 days after CoV-2 challenge, TNX-1800 vaccinated animals showed neutralizing antibody titers of (≥1:1280 titer). The level of neutralizing anti-CoV-2 antibody production was similar between the low and high dose TNX-1800 groups (1 x 106 Plaque Forming Units [PFU] and 3 x 106 PFU, (respectively). For unvaccinated animals challenged with SARS-CoV-2, neutralizing antibodies were measurable after vaccination (≥1:40 titer) that were lower and appeared later than neutralizing antibodies in TNX-1800 vaccinated animals. TNX-1800 and TNX-801 were well tolerated at both doses. Further, as an expected additional outcome, all 16 animals vaccinated with either dose of TNX-1800 or the control TNX-801 manifested a “take”, or cutaneous response, signaling that the horsepox vector elicits a strong T cell immune response. These results support the expectation that TNX-1800 at the low dose of 1 x 106 PFU is an appropriate dose for a one-shot vaccine in humans and indicate that 100 doses per vial is the target format for commercialization, which is well suited to manufacturing and distribution at large scale.

 

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Together, these data show that TNX-1800 induces protection against SARS-COV-2 infection in non-human primates. These data confirm that “take” is a biomarker of protection of upper and lower airways from SARS-CoV-2 challenge, and a biomarker of immunological response to TNX-1800’s cargo COVID-19 antigen, which is the CoV-2 spike protein. Tonix completed a pre-IND meeting with the FDA to discuss the most efficient and appropriate investigational plan to establish the safety and effectiveness evidence to support the licensure of TNX-1800. We believe that the animal data and manufacturing process information that we have developed for TNX-1800 will facilitate expedited development of TNX-1840 and TNX-1850. In addition, we believe the RPV platform can be engineered to express relevant protein antigens from different infectious diseases to make a variety of vaccines.

 

 In June 2020, we announced a partnership with FUJIFILM Diosynth Biotechnologies (FDBT) to provide contract manufacturing and development services to support the manufacturing of our COVID-19 vaccine candidate at the time, TNX-1800, for clinical trial supply. In February 2022, this contract ended. We continue to work with other third party CMOs for the manufacturing and development of TNX-1800, TNX-1840 and TNX-1850, in addition to ultimately planning to utilize our in-house manufacturing capabilities which are currently in development.

 

We have filed patent applications on the COVID-19 vaccines TNX-1800, TNX-1840 and TNX-1850 and also expect 12 years of non-patent-based exclusivity under PPACA.

 

 TNX-2100

 

TNX-2100 is a diagnostic product candidate (a COVID skin test) comprising three different mixtures of synthetic peptides (TNX-2110, -2120 and -2130), which are designed to represent different protein components of the SARS-CoV-2 virus. TNX-2110 (SARS-CoV-2 multi-antigen peptides) represents epitopes of multiple proteins from SARS-CoV-2. TNX-2120 (SARS-CoV-2 spike peptides) represents only the spike protein. TNX-2130 (SARS-CoV-2 non-spike peptides) represents non-spike proteins. Each of these three synthetic peptide mixtures is expected to be administered as part of the same procedure, at separate locations on the forearm, and each is expected to elicit a DTH response after approximately 48 hours in individuals with pre-existing T cell immunity to peptides in that mixture. Individuals who have been infected by or exposed to SARS-CoV-2 would be expected to respond to all three mixtures. In contrast, a successfully vaccinated individual who has not been exposed or infected by SARS-CoV-2 would be expected to respond only to TNX-2120 (SARS-CoV-2 spike peptides), since the currently available vaccines only encode spike protein. In the clinical protocol for testing TNX-2100, positive skin test controls are being used to confirm that study participants have intact T cell immunity and are not immunodeficient.

 

The test is designed to be administered in the same manner as skin tests for tuberculosis, or TB, sold as Tubersol® or Aplisol® or generically as the Mantoux tuberculin purified protein derivative (PPD) test. A thin gauge needle is used to apply each of the three separate TNX-2100 peptide mixtures into the skin, or intradermally, on the inner surface of the forearm between the wrist and the elbow. In a typical positive test, the skin surrounding the injection site is expected to become red, raised and hardened, or “indurated”, after approximately 48 hours. Induration above a threshold level would signify a positive result and the diameter of the induration would indicate the amount of T cell immunity to the test peptides. DTH skin test responses are believed to reflect functional in vivo immunity. Clinical trials are expected to correlate skin test results with clinical history and laboratory findings to inform estimates about the sensitivity and specificity of the test as a marker of T cell immunity in individuals who are pre- and post-COVID-19 vaccination, recovered from COVID-19, or exposed but asymptomatic.

 

Discovered in 1882 by Robert Koch, the DTH reaction has been used for more than a century as a clinical test for T cell-mediated immune reactions1. In the 1940s, Landsteiner and Chase demonstrated that the reaction was mediated by the cellular and not the antibody arm of the immune system2. The DTH reaction has been shown to be dependent on the presence of memory T cells. Both the CD4+ and CD8+ T cells have been shown to participate in this response. DTH skin tests have been commonly used to detect T cell responses to tuberculosis, fungal pathogens, and mumps virus.

 

TNX-2100 has the potential to serve as: (i) a biomarker for T cell protective immunity and durability of vaccine protection; (ii) a personalized approach for vaccine boosters; (ii) a method to stratify participants in COVID-19 vaccine trials with a more complete picture of immune status; (iv) an endpoint in COVID-19 vaccine trials for vaccines that elicit T cell immunity, and (v) public health surveillance. Tonix received IND clearance in the fourth quarter of 2021 and initiated enrollment in a first-in-human study of TNX-2100 in the first quarter of 2022. We expect topline data from this study in the first half of 2022.

 

1 Black CA. Delayed type hypersensitivity: current theories with an historic perspective. Dermatol Online J. 1999;5:7.

2 Landsteiner K, Chase MW. Studies on the sensitization of animals with simple chemical compounds: vii. Skin sensitization by intraperitoneal injections. J Exp Med. 1940;71:237.

Tubersol® is a trademark of Sanfi Pasteur.

Aplisol® is a trademark of Par Pharmaceutical, Inc.

 

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Tonix’s Facilities Overview

 

Relating to our COVID-19 and other infectious disease development programs, we are developing the resources necessary to enable internal research, development and manufacturing capabilities necessary to meet the goal of producing new vaccine candidates within 100 days and new diagnostics within weeks of obtaining sequence information. As articulated in the American Pandemic Preparedness Plan, or AP3 released by the U.S. Office of Science and Technology Policy, this 100-day goal for vaccines is a key component of preparedness for future pandemics. We are establishing the infrastructure necessary to support the pandemic preparedness goals established in the AP3, specifically with respect to our RPV vaccine and skin test platforms and potentially to other vaccine, diagnostic and therapeutic platforms.

 

The Infectious Disease Research & Development Center (RDC)

 

We acquired the infectious disease RDC in Frederick, Maryland consisting of two buildings totaling approximately 48,000 square feet. The acquisition closed in October 2021 and was operational at closing, but as of December 31, 2021, the facility was not ready for its intended use. It is our intention to have the facility ready for use in the first half of 2022. The RDC facility will focus on our development of vaccines and antiviral drugs against COVID-19, its variants, and other infectious diseases. The RDC facility is currently biosafety level 2 (BSL-2) but we intend to upgrade components to BSL-3. At full capacity, the RDC can employ 80-100 scientists and technical support staff.

 

The Advanced Development Center (ADC)

 

We are in the process of a substantial renovation of the ADC located in the New Bedford business park in Dartmouth, Massachusetts. This facility is intended to accelerate development and clinical scale manufacturing of live-virus vaccines to support Phase 1 and Phase 2 clinical trials. Plans for the ADC include single-use bioreactors and purification suites with equipment for Good Manufacturing Practice (GMP) production of vaccines for clinical trials, including when fully operational, the capability of producing sterile vaccines in glass bottles.

 

The ADC is currently being constructed and will be an approximately 45,000 square foot BSL-2 facility, once completed. At full capacity, the facility can employ up to 70 researchers, scientists, manufacturing, and technical support staff. It is expected to be partially operational in the first half of 2022.

 

The Commercial Manufacturing Center (CMC)

 

We intend to build the CMC in Hamilton, Montana where we purchased approximately 44 acres of land. The site is on land designated by Ravalli County as a Target Economic Development District. The CMC will focus on developing and manufacturing Phase 3 and commercial scale live-virus vaccines and is also intended to be BSL-2. Site enabling work is expected to be initiated for the CMC in 2022. 

 

Competition

 

Our industry is highly competitive and subject to rapid and significant technological change. Our potential competitors include large pharmaceutical and biotechnology companies, specialty pharmaceutical and generic drug companies, academic institutions, government agencies and research institutions. We believe that key competitive factors that will affect the development and commercial success of our product candidates are efficacy, safety, tolerability, reliability, price and reimbursement level. Many of our potential competitors, including many of the organizations named below, have substantially greater financial, technical, and human resources than we do and significantly greater experience in the discovery and development of product candidates, obtaining the FDA’s and other regulatory approvals of products and the commercialization of those products. Accordingly, our competitors may be more successful than we may be in obtaining FDA approval for drugs and achieving widespread market acceptance. Our competitors’ drugs may be more effective, or more effectively marketed and sold, than any drug we may commercialize and may render our product candidates obsolete or non-competitive before we can recover the expenses of developing and commercializing any of our product candidates. We anticipate that we will face intense and increasing competition as new drugs enter the market and advanced technologies become available. Further, the development of new treatment methods for the conditions we are targeting could render our drugs non-competitive or obsolete. Summarized below is the competitive landscape for the indications in which Tonix has product candidates in or nearing the clinical stages of development.

 

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Anti-CD40-ligand mAbs

 

Tonix is aware of several companies developing biologics that target CD40-L or CD40, including UCB S.A., Belgium/Biogen Inc., Eledon Pharmaceuticals, Inc., Horizon Therapeutics Plc. and Sanofi S.A. Furthermore, Tonix is aware of several companies developing antagonistic anti-CD40 mAbs including Novartis, Boehringer Ingelheim, Kiniska Pharmaceuticals, and Boston Immune Technologies.

 

Cocaine Intoxication

 

There are no approved antidotes for the treatment of cocaine intoxication. Patients generally receive supportive care. Tonix is not aware of any drugs in development for the treatment of cocaine intoxication.

 

Fibromyalgia

 

 Products approved for the treatment of fibromyalgia include Lyrica® (pregabalin), marketed by Pfizer; Cymbalta (duloxetine), marketed by Eli Lilly; and Savella (milnacipran), marketed by Allergan (acquired by AbbVie). Tonix is aware of several other companies developing treatments for fibromyalgia, including Aptinyx, Virios Therapeutics, Teva Pharmaceuticals, and Axsome Therapeutics.

 

Long COVID (Post-Acute Sequelae of COVID-19 or PASC)

 

There currently are no approved products for the treatment of Long COVID/PASC. Tonix is aware of several other companies developing therapeutics for Long COVID, including PureTech Health, Direct Biologics, American CryoStem, HopeBiosciences, Axcella Health Inc., Ampio Pharmaceuticals, CytoDyn, Pieris Pharmaceuticals, Resolve Therapeutics, PaxMedia, GeNeuro and Organicell.

 

PTSD

 

Products approved for the treatment of PTSD include Paxil® (paroxetine), marketed by GlaxoSmithKline and Zoloft® (sertraline), marketed by Pfizer. Tonix is aware of other companies working to develop therapeutics for the treatment of PTSD including Bionomics, Otsuka/Lundbeck, Aptinyx, Nobilis Therapeutics, the Multidisciplinary Association of Psychedelic Studies (MAPS) and Tryp Therapeutics.

 

Chronic or Episodic Migraine Prophylaxis

 

Currently there are several classes of drugs that are approved for the prophylactic treatment of chronic or episodic migraine, including generic beta blockers (propranolol, timolol), and anticonvulsants (divalproex, topiramate). Other drug classes that are used off-label to treat migraine prophylaxis, include tricyclic antidepressants (e.g., amitriptyline). Also, Allergan markets Botox® (onabotulinumtoxinA). More recently, several products have received FDA approval for the treatment of migraine, including Aimovig® (erenumab), which is marketed by Amgen/Novartis; Ajovy® (fremanezumab), which is marketed by Teva Pharmaceuticals; Emgality® (galcanezumab) which is marketed by Eli Lilly; and Yvepti® (eptinezumab), which is marketed by Lundbeck. Other therapies are approved as abortive treatment for acute migraine.

 

Prader-Willi Syndrome

 

There are no FDA approved therapies for the treatment of Prader-Willi syndrome. Patients generally receive care to best manage individual symptom presentation. Tonix is aware of several companies developing treatments for Prader-Willi syndrome including Aadvark Therapeutics, Radius, Levo Therapeutics, ConSynance Therapeutics, Soleno Therapeutics, Lipidio Pharma, Helsinn, Inversago Pharma, Saniona, 9 Meters Biopharma, Neuren Pharmaceuticals, Neuracle Science, Harmony Biosciences, Notitia Biotechnologies, and Taysha Gene Therapies.

 

 Major Depressive Disorder

 

Many antidepressant medications are beyond their patent life and are generally produced by generic drug companies, including several compounds in the tricyclic class (e.g., amitriptyline), the serotonin-selective reuptake inhibitor class (e.g, fluoxetine, paroxetine and sertraline), the serotonin-norepinephrine reuptake inhibitor class (e.g., venlafaxine, duloxetine), as well as the norepinephrine-dopamine reuptake inhibitor, bupropion. A number of companies are marketing prescription drugs for depression, including Johnson & Johnson’s Janssen division. Tonix is aware of several companies developing novel prescription medicines for depression including Axsome Therapeutics, Janssen, Neumora Therapeutics (formerly BlackThorn Therapeutics), Sage Therapeutics, Relmada Therapeutics, Clexio Biosciences Ltd., Allergan (acquired by AbbVie) and Otsuka.

 

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Smallpox vaccines and antivirals

 

Vaccines approved for the treatment of smallpox include ACAM2000, marketed by Emergent BioSolutions and JYNNEOS®, marketed by Bavarian Nordic. Approved antivirals include TPOXX®, marketed by SIGA and TEMBEXA®, marketed by Chimerix. Tonix is aware of other companies developing treatments for smallpox including EpiVax, HK inno.N, and BioFactura.

 

COVID-19 Vaccine

 

The environment for developing vaccines for COVID-19 is competitive and includes over 150 companies and academic institutions in various stages of development. Vaccines granted full FDA regulatory approval include Comirnaty (BNT162b2), marketed by Pfizer-BioNTech, and Spikevax (mRNA-1273), marketed by Moderna. Ad.26.COV2S, developed by Janssen, has received emergency use authorization (EUA) from the FDA. Other vaccines have received EUA in international markets. Tonix is aware of 120 vaccines currently in clinical trials, and more than 75 vaccines in preclinical development.

 

Skin Test for COVID-19 (measure of T cell immune response)

 

There currently is no standardized laboratory test available to measure T cell immune responses to SARS-CoV-2, however the FDA granted EUA to T-Detect™ COVID test by Adaptive Biotechnologies Corporation in March 2021. The only other currently available methods to detect T cell immunity to SARS-CoV-2 require several tubes of blood from the test subject, a multi-step sample preparation process including isolation of peripheral blood mononuclear cells, tissue culture with in vitro T cell stimulation in highly specialized laboratories that have fluorescent activated cells sorting (FACS) flow cytometry technology, methodologies that have not been amenable to standardization or scalability for commercial clinical services. Tonix is aware of other companies developing diagnostics to identify T cell immune response to SARS-CoV-2 , including Biovaxys.

 

 Intellectual Property

 

We believe that we have an extensive patent portfolio and substantial know-how relating to TNX-1800, TNX-801, TNX-102 SL and our other product candidates. Our patent portfolio, described more fully below, includes claims directed to various compositions and methods of use related to our product candidates. As of March 8, 2022, the patents we are either the owner of record of or own the contractual right to include 31 issued U.S. patents and 213 issued non-U.S. patents. We are actively pursuing an additional 31 U.S. patent applications, of which 4 are provisional and 27 are non-provisional, 13 international patent applications, and 218 non-U.S./non-international patent applications. 

 

We strive to protect the proprietary technology that we believe is important to our business, including our proprietary technology platform, our product candidates, and our processes. We seek patent protection in the U.S. and internationally for our products, their methods of use and processes of manufacture, and any other technology to which we have rights, where available and when appropriate. We also rely on trade secrets that may be important to the development of our business.

 

Our success will depend on 1) the ability to obtain and maintain patent and other proprietary rights in commercially important technology, inventions and know-how related to our business, 2) the validity and enforceability of our patents, 3) the continued confidentiality of our trade secrets, and 4) our ability to operate without infringing the valid and enforceable patents and proprietary rights of third parties. We also rely on continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary position.

 

We cannot be certain that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications we may own or license in the future, nor can we be certain that any of our existing patents or any patents we may own or license in the future will be useful in protecting our technology. For this and more comprehensive risks related to our intellectual property, please see “Risk Factors — Risks Relating to Our Intellectual Property.”

 

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, the patent term is 20 years from the date of filing the first non-provisional priority application. In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the PTO in granting a patent or may be shortened if a patent is terminally disclaimed over another patent.  

 

The term of a U.S. patent that covers a drug approved by the FDA or methods of making or using that drug may also be eligible for patent term extension, which permits patent term restoration as compensation for the patent term lost during the FDA regulatory review process. The Drug Price Competition and Patent Term Restoration Act, also known as the Hatch-Waxman Act, is a federal law that encourages new drug research by restoring patent term lost to regulatory delays by permitting a patent term extension of up to five years beyond the statutory 20-year term of the patent for the approved product or its methods of manufacture or use if the active ingredient has not been previously approved in the U.S. The length of the patent term extension is related to the length of time the drug is under regulatory review. A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug may be extended. Similar provisions are available in Europe and some other foreign jurisdictions to extend the term of a patent that covers an approved drug. When possible, depending upon the length of clinical trials and other factors involved in the filing of an NDA, we expect to apply for patent term extensions for patents covering our product candidates and their methods of use.

 

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The patent portfolios for our proprietary technology platform and our five most advanced product candidates as of March 8, 2022 are summarized below.

 

TNX-1500 — anti-CD40L Therapeutics

 

We are collaborating with Harvard Medical School to develop TNX-1500, a humanized mAb that targets CD40L for the prevention and treatment of organ transplant rejection.  In this regard, we filed International Application No. PCT/EP2020/068589, entitled “Anti-CD154 antibodies and uses thereof” on July 1, 2020 (nationalized in 15 countries). We also filed International Patent Application No. PCT/US2020/028002 on April 13, 2020, entitled “Inhibitors of CD40-CD154 Binding” (nationalized in Canada, European Patent Office and Japan). We also filed International Patent Application No. PCT/US2022/011404, entitled “Methods of Inducing Immune Tolerance with Modified Anti-CD154 Antibodies” on January 6, 2022.

 

 TNX-1300 — Cocaine Intoxication Treatment

 

We have licensed rights from The Trustees of Columbia University in the City of New York, The Regents of the University of Michigan, and University of Kentucky Research Foundation to develop a potential product, TNX-1300, for the treatment of cocaine intoxication.  The licensed patents are directed to mutant cocaine esterase polypeptides and methods of using these polypeptides as anti-cocaine therapeutics.  They include U.S. Patent Nos. 8,318,156 and 9,200,265, entitled “Anti-Cocaine Compositions and Treatment” and various counterpart patents outside of the U.S (e.g., European Patent 2046368). These patents provide TNX-1300 with US market exclusivity until February 2029, and market exclusivity outside of the U.S. until July 10, 2027, subject to any patent term extensions.

 

TNX-102 SL — Central Nervous System Conditions

 

Our patent portfolio for TNX-102 SL includes patent applications directed to compositions of matter of CBP, formulations containing CBP, and methods for treating CNS conditions, such as TNX-102 SL for PTSD, for acute stress disorder, for sleep disturbances in fibromyalgia, for alcohol abuse, for disordered sleep, for sexual dysfunction, for depression in fibromyalgia and for agitation in neurodegenerative conditions, e.g., AAD, utilizing these compositions and formulations.

 

Certain eutectic compositions were discovered by development partners and are termed the “Eutectic Technology.” The patent portfolio for TNX-102 SL relating to the Eutectic Technology includes patent applications directed to eutectic compositions containing CBP, eutectic CBP formulations, methods for treating PTSD and other CNS conditions utilizing eutectic CBP compositions and formulations, and methods of manufacturing eutectic CBP compositions. The Eutectic Technology patent portfolio includes U.S. patents, such as U.S. Patent No. 9,636,408, U.S. Patent No. 9,956,188, U.S. Patent No. 10,117,936, U.S. Patent No. 10,357,465; and U.S. Patent No. 10,864,175. If U.S. and non-U.S. patents claiming priority from those applications issue, those patents would expire in 2034 or 2035, excluding any patent term adjustments or extensions.

 

The unique pharmacokinetic profile of TNX-102 SL, or the PK Technology, was discovered by Tonix and its development partners. The patent portfolio for TNX-102 SL relating to the PK Technology includes patent applications directed to compositions of matter of CBP, formulations containing CBP, methods for treating PTSD, agitation in neurodegenerative conditions, and other CNS conditions utilizing these compositions and formulations. The PK Technology patent portfolio includes U.S. Patent Application No. 13/918,692. If U.S. and non-U.S. patents claiming priority from those applications issue, those patents would expire in 2033, excluding any patent term adjustments or extensions.

 

On May 2, 2017, U.S. Patent No. 9,636,408 entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The patent claims recite pharmaceutical compositions comprising the eutectic. The patent claims also recite methods of manufacturing the eutectic.

 

On September 13, 2017, European patent 2,501,234, entitled “Methods and Compositions for Treating Symptoms Associated with PTSD Using Cyclobenzaprine”, issued. This patent recites the use of CBP for the treatment of PTSD, which covers the use of TNX-102 SL for the treatment of PTSD, since the active ingredient in TNX-102 SL is CBP and provides TNX-102 SL with European market exclusivity until 2030 and may be extended based on the timing of the European marketing authorization of TNX-102 SL for PTSD.  In response to an opposition filed in June 2018 by a German law firm, the European Patent Office’s Opposition Division in October 2019 upheld the patent in unamended form.  Opponent has appealed.

 

On December 15, 2017, Japanese Patent No. 6259452, entitled “Compositions and Methods for Transmucosal Absorption”, issued.  These claims relate to the pharmacokinetic profile of TNX-102 SL.

 

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On March 20, 2018, U.S. Patent No. 9,918,948 entitled “Methods and Compositions for Treating Symptoms Associated with PTSD Using Cyclobenzaprine”, issued. The claims recite a method of using TNX-102 SL’s active ingredient cyclobenzaprine to treat PTSD and provides TNX-102 SL with US market exclusivity until 2030, excluding any patent term extensions.

 

On March 23, 2018, Japanese Patent No. 6310542 entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued.  The claims recite pharmaceutical compositions comprising the eutectics and methods of manufacturing these eutectic formulations.

 

On May 1, 2018, U.S. Patent No. 9,956,188, entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The claims recite a eutectic of cyclobenzaprine hydrochloride and mannitol and methods of making those eutectics.

 

On November 6, 2018, U.S. Patent No. 10,117,936, entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The claims recite pharmaceutical compositions of eutectics of cyclobenzaprine hydrochloride and mannitol and methods of making those compositions.

 

On April 16, 2019, Chinese Patent No. ZL 201480024011.1 entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The claims recite pharmaceutical compositions comprising eutectics of cyclobenzaprine hydrochloride and mannitol and methods of making those compositions.

 

On July 23, 2019, U.S. Patent No. 10,357,465 entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride”, issued. The claims recite pharmaceutical compositions comprising eutectics of cyclobenzaprine hydrochloride and mannitol and methods of making those compositions.

 

On December 11, 2019, European patent 2968992, entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride”, issued. This patent recites pharmaceutical compositions comprising a eutectic of mannitol and Cyclobenzaprine HCl and methods of making the same. In response to an opposition filed in September 2020 by Hexal AG, the European Patent Office’s Opposition Division upheld the patent in unamended form in the January 2022 oral proceedings. The written decision is pending.

 

On December 25, 2019, European patent 2,683,245, entitled “Methods and Compositions for Treating Depression Using Cyclobenzaprine”, issued. The claims recite the use of CBP for the treatment of depression in a FM patient.  This patent provides TNX-102 SL with European market exclusivity until March 2032 and may be extended based on the timing of the European marketing authorization of TNX-102 SL for depression in a FM patient. In September 2020, Hexal AG filed an opposition against this patent. The European Patent Office’s Opposition Division upheld the patent claims in unamended form at the February 2022 oral proceedings. The written decision is pending. 

 

On December 15, 2020, U.S. Patent No. 10,864,175 entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The claims recite a eutectic comprising cyclobenzaprine hydrochloride and beta-mannitol.

 

On April 8, 2021, U.S. non-provisional Patent Application No. 17/226,058 and International Patent Application No. PCT/US2021/026492 were filed, entitled “Cyclobenzaprine Treatment for Sexual Dysfunction”. The claims are directed to methods using pharmaceutical compositions and combinations for treating sexual dysfunction with cyclobenzaprine or pharmaceutically acceptable salts of cyclobenzaprine.

 

On October 25, 2016 and July 28, 2020, U.S. Patent No. 9,474,728 and U.S. Patent No. 10,722,478, entitled “Methods and Compositions for Treating Fatigue Associated with Disordered Sleep Using Very Low Dose Cyclobenzaprine”, issued, respectively. The claims are directed to a method for monitoring the effectiveness of cyclobenzaprine treatment for disordered sleep and method for reducing CAP rates A2 or A3 by treating a subject with a pharmaceutical composition comprising cyclobenzaprine.

 

TNX-1900 — Oxytocin-based treatments for Migraine, Pain, Insulin Resistance, Diabetes and Obesity

 

We have acquired the migraine and pain treatment technologies of Trigemina, Inc., and have assumed its license rights to related technologies from The Board of Trustees of the Leland Stanford Junior University. TNX-1900, an enhanced formulation of nasal oxytocin, has demonstrated activity in several non-clinical studies in pain, including migraine. As part of our acquisition, we acquired International Patent Application No. PCT/US2016/012512, filed on January 7, 2016, entitled “Magnesium-Containing Oxytocin Formulations and Methods of Use” (nationalized in 13 countries). We also acquired U.S. Patent No. 9,629,894, entitled “Magnesium-Containing Oxytocin Formulations and Methods of Use”, which will expire in January 2036, excluding any patent term extensions. We also have rights to International Patent Application No. PCT/US2019/020419, filed on April 12, 2017, entitled “Labeled Oxytocin and Method of Manufacture and Use” (nationalized in the U.S., European Patent Office and Japan).

 

We have entered into an exclusive license to the University of Geneva’s technology for using oxytocin to treat insulin resistance and related syndromes, including obesity. This license expands our intranasal potentiated oxytocin development program, TNX-1900, into cardiometabolic syndromes. Under the license, we have rights to European Patent No. EP2571511B1, entitled “New Uses of Oxytocin-like Molecules and Related Methods”. We also have rights to U.S. Patent No. 9,101,569, entitled “Methods for the Treatment of Insulin Resistance”. The U.S. and non-U.S. patents expire in May 2031, excluding any patent term adjustments or extensions.

 

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TNX-2900 — Oxytocin-based therapeutics for Prader-Willi syndrome

 

We have licensed technology using oxytocin-based therapeutics for the treatment of Prader-Willi syndrome and non-organic failure to thrive disease from the French National Institute of Health and Medical Research (INSERM). The co-exclusive license relates to TNX-2900, an intranasal potentiated oxytocin, for the treatment of Prader-Willi syndrome and other feeding disorders. Under the license, we have rights to European Patent No. EP2575853B1, entitled “Methods and Pharmaceutical Composition for the Treatment of a Feeding Disorder with Early-Onset in a Patient”; U.S. Patent No. 8,853,158, entitled “Methods for the Treatment of a Feeding Disorder with Onset During Neonate Development Using an Agonist of the Oxytocin Receptor”; and U.S. Patent No. 9,125,862, entitled “Methods for the Treatment of Prader-Willi-like Syndrome or Non-Organic Failure to Thrive (NOFITT) Feeding Disorder Using an Agonist of the Oxytocin Receptor”. The U.S. and non-U.S. patents expire in May 2031, excluding any patent term extensions.

 

TNX-601 — Depression, Posttraumatic Stress Disorder, Neurocognitive Dysfunction

 

Our patent portfolio for tianeptine oxalate includes U.S. Patent No. 9,314,469 and European Patent No. 2,299,822, both entitled “Method for Treating Neurocognitive Dysfunction”, which issued on April 29, 2016 and July 26, 2017, respectively.  The ’822 patent recites pharmaceutical compositions comprising various compounds (which include tianeptine) and uses thereof.  This patent provides TNX-601 with European market exclusivity until April 2029 and may be extended based on the timing of the European marketing authorization of TNX-601 for neurocognitive side effects associated with the use of corticosteroids. The ‘469 patent claims methods of treating cognitive impairment associated with corticosteroid treatment using compounds, including tianeptine, excluding patent term extensions, the patent provides TNX-601 with US marketing exclusivity until 2028.

 

On February 27, 2019, European Patent No. 3,246,031 entitled “Method for Treating Neurodegenerative Dysfunction”, issued. The claims recite the use of TNX-601, or tianeptine oxalate and other salts, for treating neurocognitive dysfunction associated with corticosteroid treatment. This patent provides TNX-601 with European market exclusivity until April 2029 and may be extended based on the timing of the European market authorization of TNX-601 for neurocognitive disfunction associated with corticosteroid treatment.

 

On October 22, 2019, U.S. Patent No. 10,449,203 issued.  The claims recite anhydrous crystalline oxalate salts of tianeptine and provides TNX-601 with US market exclusivity until 2037, excluding any patent term extensions.

 

On March 16, 2021, U.S. Patent No. 10,946,027 issued. The claims recite pharmaceutical compositions of anhydrous crystalline oxalate salts of tianeptine and provides TNX-601 with US market exclusivity until 2037, excluding any patent term extensions.

 

Our patent portfolio for TNX-601 also includes International Patent Application PCT/IB2017/001709 (now nationalized in 16 countries). It includes claims directed to crystalline tianeptine oxalate and compositions of those crystal forms, and disclosures directed to methods of using those crystalline forms and their compositions.

 

TNX-801 — Live Horsepox Vaccine for Prevention of Smallpox and Monkeypox

 

We own the rights to develop a potential biodefense technology, TNX-801, a live horsepox that is being developed as a new smallpox and monkeypox preventing vaccine, we have filed patent applications directed to synthetic chimeric poxviruses and methods of using these poxviruses to protect individuals against smallpox. These applications include U.S. non-provisional Patent Application No. 15/802,189 and International Patent Application No. PCT/US2017/059782 (nationalized in 15 countries and filed in 4 non-PCT countries). We also own the rights to develop other vaccine candidates against smallpox.  With respect to these vaccine candidates, we own U.S. Patent Application No. 14/207,727 and International Patent Application No. PCT/US2019/030486 and the non-convention and national phase applications related thereto (nationalized in 17 countries and filed in 2 non-PCT countries). The smallpox vaccine technologies relate to proprietary forms of live horsepox and vaccinia vaccines which may be safer than ACAM2000, the only currently available replication competent, live vaccinia vaccine to protect against smallpox disease. We believe that this technology, after further development, may be of interest to biodefense agencies in the U.S. and other countries.

 

TNX-1800 — Live HPXV Vaccine for Prevention of COVID-19

 

We are developing TNX-1800, a live HPXV that is being developed as a new COVID-19 preventing vaccine. On February 26, 2021, we filed International Patent Application No. PCT/US2021/020119 (as well as applications in 2 non-PCT countries) and U.S. Application No. 17/187,678, entitled “Recombinant Poxvirus Based Vaccine Against SARS-CoV-2”. These applications are directed to synthetic poxviruses comprising a SARS-CoV-2 protein, poxvirus delivery vectors for SARS-CoV-2 proteins and methods of using these modified poxviruses to protect individuals against COVID-19.

 

25

 

 

TNX-1700 — Recombinant Trefoil Family Factor 2 (rTFF2) to Treat Gastric and Pancreatic Cancers

 

We have licensed rights from The Trustees of Columbia University in the City of New York to develop a potential product, TNX-1700, for the treatment of gastric and pancreatic cancers.  The licensed patents are directed to TFF2 compositions and methods of treatment.  The licensed patents U.S. Patent No. 10,124,037 and U.S. Patent No. 11,167,010.   The licensed patents provide TNX-1700 with US market exclusivity until April 2033, subject to any patent term extensions. On August 27, 2020, we filed International Patent Application No. PCT/IB2020/000699 entitled “Modified TFF2 Polypeptides” (being nationalized in 11 countries).

 

TNX-1600 — Triple Reuptake Inhibitor to Treat PTSD

 

We have licensed rights from Wayne State University to develop a potential product, TNX-1600, for PTSD treatment.  The licensed patents directed to pyran-based derivatives and analogues.  They include U.S. Patent Nos. 7,915,433, 8,017,791, 8,519,159, 8,841,464, and 8,937,189, entitled “Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives” and U.S. Patent No. 9,458,124, entitled “Substituted Pyran Derivatives”.  These patents provide TNX-1600 with US market exclusivity between April 2024 and February 2034, respectively, subject to any patent term extensions.

 

TNX-701 — Radioprotection Biodefense Technology

 

We own the rights to develop a potential biodefense technology, which is a potential radioprotective therapy. For protection of our intellectual property, we have not disclosed the identity of the new development candidate. On May 7, 2021, we filed International Patent Application No. PCT/US2021/031441 and U.S. non-provisional Patent Application No. 17/315,258. They claim compounds, compositions and methods of use in radioprotection.

 

TNX-1200 — Smallpox Vaccine Technology

 

We own the rights to develop a potential biodefense technology, TNX-1200, a live vaccinia virus that is being developed as a new smallpox preventing vaccine, we have patent applications directed to synthetic chimeric poxviruses and methods of using these poxviruses to protect individuals against smallpox. These applications include U.S. non-provisional Patent Application No. 17/050,946 and International Patent Application No. PCT/US2019/030486 (nationalized in 16 countries and filed in 3 non-PCT countries). We believe that this technology, after further development, may be of interest to biodefense agencies in the U.S. and other countries.

 

TNX-3500 — Sangivamycin for Treatment of COVID

 

We have entered into an exclusive license to OyaGen, Inc.’s antiviral technology for use in treating coronavirus infections (including SARS-CoV-2), Ebola virus, arenaviridae infections and poxviridae infections. This license expands our pipeline for developing a potential treatment, TNX-3500, for COVID-19 and emerging variants. Under the license, we have rights to U.S. non-provisional Patent Application No. 16/851,047 and International Patent Application Nos. PCT/US2020/028567 and PCT/US2021/016472, entitled “Methods for Treating Coronavirus Infections”. We also have rights to U.S. non-provisional Patent Application No. 16/348,867 and European Patent Application No. 17869003.8, entitled “Methods of Treating and Inhibiting Ebola Virus Infection”. We also have rights to International Patent Application Nos. PCT/US2021/027352 and PCT/US2021/027354, entitled “Method for Treating Arenaviridae Infections” and “Method for Treating Poxviridae Infection,” respectively. 

 

Trade Secrets

 

In addition to patents, we rely on trade secrets and know-how to develop and maintain our competitive position. For example, significant aspects of our proprietary technology platform are based on unpatented trade secrets and know-how. Trade secrets and know-how can be difficult to protect. We seek to protect our proprietary technology and processes, in part, by confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors, and commercial partners. These agreements are designed to protect our proprietary information and, in the case of the invention assignment agreements, to grant us ownership of technologies that are developed through a relationship with a third party. We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems. While we have confidence in these individuals, organizations and systems, agreements or security measures may be breached, and we may not have adequate remedies for any breach. In addition, our trade secrets may otherwise become known or be independently discovered by competitors. To the extent that our contractors use intellectual property owned by others in their work for us, disputes may arise as to rights in related or resulting inventions and know-how.

 

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Issued Patents

 

Our current patents owned or licensed include:

 

Anti-Cocaine Therapeutics

 

Patent No.   Title   Country / Region   Expiration 
Date
8,318,156   Anti-Cocaine Compositions and Treatment   U.S.A.   February 14, 2029
9,200,265   Anti-Cocaine Compositions and Treatment   U.S.A.   December 30, 2027
2007272955   Anti-Cocaine Compositions and Treatment   Australia   July 10, 2027
2014201653   Anti-Cocaine Compositions and Treatment   Australia   July 10, 2027
2657246   Anti-Cocaine Compositions and Treatment   Canada   July 10, 2027
612929   Anti-Cocaine Compositions and Treatment   New Zealand   July 10, 2027
2046368 (602007045044.6 in Germany; 502016000056543 in Italy)   Anti-Cocaine Compositions and Treatment   Europe – (Germany, Spain, France, United Kingdom, and Italy)   July 10, 2027
2009/00197   Anti-Cocaine Compositions and Treatment   South Africa   July 10, 2027
305483   Anti-Cocaine Compositions and Treatment   Mexico   July 10, 2027
196411   Anti-Cocaine Compositions and Treatment   Israel   July 10, 2027

 

Sublingual CBP/Amitriptyline

 

Patent No.   Title   Country / Region   Expiration 
Date
6259452   Compositions and Methods for Transmucosal Absorption   Japan   June 14, 2033
631144   Compositions and Methods for Transmucosal Absorption   New Zealand   June 14, 2033
I590820   Compositions and Methods for Transmucosal Absorption   Taiwan R.O.C.   June 14, 2033
2013274003   Compositions and Methods for Transmucosal Absorption   Australia   June 14, 2033
I642429   Compositions and Methods for Transmucosal Absorption   Taiwan R.O.C.   June 14, 2033
726488   Compositions and Methods for Transmucosal Absorption   New Zealand   June 14, 2033
I683660   Compositions and Methods for Transmucosal Absorption   Taiwan R.O.C.   June 14, 2033
2018241128   Compositions and Methods for Transmucosal Absorption   Australia   June 14, 2033
2876902   Compositions and Methods for Transmucosal Absorption   Canada   June 14, 2033
IDP000076019   Compositions and Methods for Transmucosal Absorption   Indonesia   June 14, 2033
382516   Compositions and Methods for Transmucosal Absorption   Mexico   June 14, 2033

 

27

 

 

CBP – Depression 

 

Patent No.   Title   Country / Region   Expiration 
Date
2012225548  

Methods and Compositions for Treating Depression Using Cyclobenzaprine

  Australia   March 6, 2032
2016222412  

Methods and Compositions for Treating Depression Using Cyclobenzaprine 

  Australia   March 6, 2032
2018204633  

Methods and Compositions for Treating Depression Using Cyclobenzaprine

  Australia   March 6, 2032
2020203874  

Methods and Compositions for Treating Depression Using Cyclobenzaprine

  Australia   March 6, 2032
614725  

Methods and Compositions for Treating Depression Using Cyclobenzaprine

  New Zealand   March 6, 2032
714294  

Methods and Compositions for Treating Depression Using Cyclobenzaprine

  New Zealand   March 6, 2032
2683245  

Methods and Compositions for Treating Depression Using Cyclobenzaprine

 

  European Patent Office – Albania, Austria, Belgium, Bulgaria, Switzerland, Cyprus, Czechia, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Monaco, Republic of North Macedonia, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Sweden, Slovenia, Slovakia, San Marino, and Turkey   March 6, 2032

 

CBP – PTSD   

 

Patent No.   Title   Country / Region   Expiration 
Date
9,918,948   Methods and Compositions for Treating Symptoms Associated with Post-Traumatic Stress Disorder Using Cyclobenzaprine   U.S.A.   November 18, 2030

2501234

 

(AL/P/17/691 in Albania; 602010045270.0 in Germany; 3094254 in Greece; 502017000142469 in Italy; MK/P/17/000807 in Republic of North Macedonia; 56634 in Serbia; SM-T-201700578 in San Marino; 201717905 in Turkey) 

 

  Methods and Compositions for Treating Symptoms Associated with Post-Traumatic Stress Disorder Using Cyclobenzaprine   European Patent Office – Albania, Austria, Belgium, Bulgaria, Switzerland, Cyprus, Czechia, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Monaco, Republic of North Macedonia, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Sweden, Slovenia, Slovakia, San Marino, Turkey   November 16, 2030
HK1176235   Methods and Compositions for Treating Symptoms Associated with Post-Traumatic Stress Disorder Using Cyclobenzaprine   Hong Kong   November 16, 2030

 

28

 

 

CBP Fatigue

 

Patent No.   Title   Country / Region   Expiration 
Date
9,474,728   Methods and Compositions for Treating Fatigue Associated with Disordered Sleep Using Very Low Dose Cyclobenzaprine   U.S.A.   June 9, 2031
10,722,478   Methods and Compositions for Treating Fatigue Associated with Disordered Sleep Using Very Low Dose Cyclobenzaprine   U.S.A.   June 9, 2031

 

CBP/Amitriptyline Eutectic Formulations 

 

 Patent No.   Title   Country / Region   Expiration 
Date
631152   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   New Zealand   March 14, 2034
747040   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   New Zealand   March 14, 2034
9,636,408   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   U.S.A.   March 14, 2034
9,956,188   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   U.S.A.   March 14, 2034
10,117,936   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   U.S.A.     March 14, 2034
10,322,094   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   U.S.A.   March 14, 2034
10,357,465   Eutectic Formulations of Cyclobenzaprine Hydrochloride   U.S.A.   September 18, 2035 
10,736,859   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   U.S.A.   March 14, 2034
10,864,175   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   U.S.A.   March 14, 2034
10,864,176   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   U.S.A.   March 14, 2034
11,026,898   Eutectic Formulations of Cyclobenzaprine Hydrochloride   U.S.A.   September 18, 2035
6310542   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Japan   March 14, 2034
6614724   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Japan   September 18, 2035
6717902   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Japan   September 18, 2035
6088   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Saudi Arabia   March 14, 2034
ZL201480024011.1   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   China   March 14, 2034
ZL.201580050140.2   Eutectic Formulations of Cyclobenzaprine Hydrochloride   China   September 18, 2035
2014233277   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Australia   March 14, 2034
2015317336   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Australia   September 18, 2035
I661825    Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Taiwan R.O.C.   March 14, 2034
I740136   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Taiwan R.O.C.   March 14, 2034
IDP000055516   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Indonesia   March 14, 2034
IDP000063221   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Indonesia   September 18, 2035
IDP000076872   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Indonesia   March 14, 2034

2968992

(1211591 in Austria, CZ2014-762323 in Czechia, 602014058260.5 in Germany, E018723 in Estonia, P20200055 in Croatia, 201361792757 P in Ireland, 2020.67 in Monaco, P-2020/0094 in Serbia, 201431487 in Slovenia, 33269 in Slovakia, 2020000045 in San Marino)

 

  Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   European Patent Office -Albania, Austria, Belgium, Bulgaria, Croatia, Cyprus, Czechia, Denmark, Estonia, Finland, France, Republic of North Macedonia, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Monaco, Netherlands, Norway, Poland, Portugal, Romania, San Marino, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, United Kingdom  

March 14, 2034

 

241353   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Israel   March 14, 2034
251218   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Methods of Producing Same   Israel   September 18, 2035
370021   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Mexico   March 14, 2034
387402   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Mexico   September 18, 2035
388137   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Mexico   March 14, 2034
2015/07443   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride  

South Africa

 

  March 14, 2034
2017/01637   Eutectic Formulations of Cyclobenzaprine Hydrochloride   South Africa   September 18, 2035
BR112015022095-9   Pharmaceutical Composition, Method of Fabrication, Eutectic Composition and Use of Compositions Containing Cyclobenzaprine HCl and Mannitol   Brazil   March 14, 2034
2904812   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Canada   March 14, 2034
HK1218727   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Hong Kong   March 14, 2034
MY-186047-A   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Malaysia   September 18, 2035

  

29

 

 

 Oxytocin therapeutics

 

Patent No.   Title   Country / Region   Expiration 
Date
9,629,894   Magnesium-Containing Oxytocin Formulations and Methods of Use   U.S.A.   January 7, 2036
11201705591P   Magnesium-Containing Oxytocin Formulations and Methods of Use   Singapore   January 7, 2036
Not Yet Assigned   Magnesium-Containing Oxytocin Formulations and Methods of Use   Mexico   January 7, 2036
2575853   Methods and Pharmaceutical Composition for the Treatment of a Feeding Disorder with Early-Onset in a Patient   Europe – (Spain, France, and United Kingdom)   May 25, 2031
8,853,158   Methods for the Treatment of a Feeding Disorder with Onset During Neonate Development Using an Agonist of the Oxytocin Receptor   U.S.A.   May 25, 2031
9,125,862   Methods for the Treatment of Prader-Willi-like Syndrome or Non-Organic Failure to Thrive (NOFITT) Feeding Disorder Using an Agonist of the Oxytocin Receptor   U.S.A.   May 25, 2031
             
2571511   New Uses of Oxytocin-like Molecules and Related Methods   Europe – (Switzerland, Spain, France, United Kingdom, and Ireland)   May 17, 2031
9,101,569   Methods for the Treatment of Insulin Resistance   U.S.A.   June 22, 2031

 

30

 

 

Nociceptin/Orphanin FQ therapeutics

 

Patent No.   Title   Country / Region   Expiration 
Date
8,551,949   Methods for treatment of pain   U.S.A.   August 11, 2031
9,238,053   Methods for treatment of pain   U.S.A.   October 12, 2030
2010281436   Methods for treatment of pain   Australia   July 27, 2030
ZL 201080042858.4   Methods for treatment of pain   China   July 27, 2030
2459183 (602010028120.5 in Germany)   Methods for treatment of pain   Europe – (Switzerland, Germany, Denmark, France, and United Kingdom)   July 27, 2030
1169804   Methods for treatment of pain   Hong Kong   July 27, 2030
329837   Methods for treatment of pain   Mexico   July 27, 2030
597763   Methods for treatment of pain   New Zealand   July 27, 2030
10201406930U   Methods for treatment of pain   Singapore   July 27, 2030
201200584   Methods for treatment of pain   South Africa   July 27, 2030

 

Tianeptine Oxalate – Salts and Crystalline Forms  

 

Patent No.   Title   Country / Region   Expiration 
Date
10,449,203   Tianeptine Oxalate Salts and Polymorphs   U.S.A.   December 28, 2037
10,946,027   Tianeptine Oxalate Salts and Polymorphs   U.S.A.   December 28, 2037
2019/04185   Tianeptine Oxalate Salts and Polymorphs   South Africa   December 28, 2037

 

Tianeptine – Neurocognitive Dysfunction

 

Patent No.   Title   Country / Region   Expiration 
Date
9,314,469   Method for Treating Neurocognitive Dysfunction   U.S.A.   September 24, 2030
2723688   Method for Treating Neurodegenerative Dysfunction   Canada   April 30, 2029
2299822 (602009047361.1 in Germany)   Method for Treating Neurodegenerative Dysfunction   Europe – Austria, Belgium, Switzerland, Germany, Spain, France, United Kingdom, Ireland, Luxembourg, Monaco, Portugal   April 30, 2029
3246031 (602009057284.9 in Germany)   Method for Treating Neurocognitive Dysfunction   Europe – Austria, Belgium, Switzerland, Germany, Spain, France, United Kingdom, Ireland, Luxembourg, Monaco, Portugal   April 30, 2029

 

31

 

 

Triple reuptake inhibitor therapeutics

 

Patent No.   Title   Country / Region   Expiration 
Date
7,915,433   Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives   U.S.A  

March 10, 2028

 

8,017,791   Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives   U.S.A.   April 14, 2024
8,519,159   Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives   U.S.A   December 7, 2025
8,841,464   Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives   U.S.A   April 15, 2025
8,937,189   Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives   U.S.A   January 12, 2027
9,458,124   Substituted Pyran Derivatives   U.S.A   February 6, 2034

 

TFF2 therapeutics

 

Patent No.   Title   Country / Region   Expiration 
Date
10,124,037   Trefoil family factor proteins and uses thereof   U.S.A   April 2, 2033
11,167,010   Trefoil family factor proteins and uses thereof   U.S.A   April 2, 2033

 

Pending Patent Applications

 

Our current pending patent applications are as follows:

 

CD40 and CD154 Therapeutics

 

Application No.   Title   Country / Region
17/623,710   Anti-CD154 antibodies and uses thereof   U.S.A.
Not Yet Assigned   Anti-CD154 antibodies and uses thereof   Australia
BR112021026410-8   Anti-CD154 antibodies and uses thereof   Brazil
Not Yet Assigned   Anti-CD154 antibodies and uses thereof   Canada
Not Yet Assigned   Anti-CD154 antibodies and uses thereof   China
20764933.6   Anti-CD154 antibodies and uses thereof   European Patent Office
202217004870   Anti-CD154 antibodies and uses thereof   India
P00202200763   Anti-CD154 antibodies and uses thereof   Indonesia
289354   Anti-CD154 antibodies and uses thereof   Israel
2021-578262   Anti-CD154 antibodies and uses thereof   Japan
PI 2021007835   Anti-CD154 antibodies and uses thereof   Malaysia
MX/a/2022/000133   Anti-CD154 antibodies and uses thereof   Mexico
Not Yet Assigned   Anti-CD154 antibodies and uses thereof   New Zealand
11202114433Y   Anti-CD154 antibodies and uses thereof   Singapore
Not Yet Assigned   Anti-CD154 antibodies and uses thereof   South Africa
PCT/US2022/011404   Methods of Inducing Immune Tolerance with Modified Anti-CD154 Antibodies    PCT
3136725   Inhibitors of CD40-CD154 Binding   Canada
20787970.1   Inhibitors of CD40-CD154 Binding   European Patent Office
2021-560713   Inhibitors of CD40-CD154 Binding   Japan

 

CBP/Amitriptyline Eutectic Formulations

 

Application No.   Title   Country / Region
17/121,547   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   U.S.A.
17/082,949   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   U.S.A.
2020289838   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Australia
BR112017005231-8   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Brazil
BR122020020968-2   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Brazil
2,961,822   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Canada
3,119,755   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Canada

201910263541.6

 

  Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   China
202011576351.9   Eutectic Formulations of Cyclobenzaprine Hydrochloride   China
15841528.1    Eutectic Formulations of Cyclobenzaprine Hydrochloride   European Patent Office
19214535.7   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   European Patent Office
18101200.4   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Hong Kong
42020003105.2   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Hong Kong
42020019748.1   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Hong Kong
42021036749.6   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Hong Kong
         
277814   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Methods of Producing Same (Allowed)   Israel
3392/KOLNP/2015   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   India
201717013182   Eutectic Formulations of Cyclobenzaprine Hydrochloride   India
2021-105582   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Japan
         
2021-169539   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Japan

 

32

 

 

Application No.   Title   Country / Region
PI 2015703142   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Malaysia
730379   Eutectic Formulations of Cyclobenzaprine Hydrochloride   New Zealand
768064   Eutectic Formulations of Cyclobenzaprine Hydrochloride   New Zealand
517381123   Eutectic Formulations of Cyclobenzaprine Hydrochloride   Saudi Arabia

10201707528W

 

10201902203V

 

Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride

 

Eutectic Formulations of Cyclobenzaprine Hydrochloride

 

Singapore

 

Singapore

         
2014-000391   Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride   Venezuela

 

Sublingual CBP/Amitriptyline

 

Application No.   Title   Country / Region
13/918,692   Compositions and Methods for Transmucosal Absorption   U.S.A.
P20130102101   Compositions and Methods for Transmucosal Absorption   Argentina
         
BR112014031394-6   Compositions and Methods for Transmucosal Absorption   Brazil
BR122019024508-8   Compositions and Methods for Transmucosal Absorption   Brazil
3,118,913   Compositions and Methods for Transmucosal Absorption   Canada
202010024102.2   Compositions and Methods for Transmucosal Absorption   China
13804115.7   Compositions and Methods for Transmucosal Absorption   European Patent Office

2013/24661

 

2013/37088

 

 

Compositions and Methods for Transmucosal Absorption

 

Compositions and Methods for Transmucosal Absorption

 

 

Gulf Cooperation Council

 

Gulf Cooperation Council

 

2013/40660   Compositions and Methods for Transmucosal Absorption   Gulf Cooperation Council
15110186.6   Compositions and Methods for Transmucosal Absorption   Hong Kong
42020020336.2   Compositions and Methods for Transmucosal Absorption   Hong Kong
P-00 2021 01421   Compositions and Methods for Transmucosal Absorption   Indonesia
236268   Compositions and Methods for Transmucosal Absorption (Allowed)   Israel
         
2021-100154   Compositions and Methods for Transmucosal Absorption   Japan
MX/a/2021/005317   Compositions and Methods for Transmucosal Absorption   Mexico
PI 2014703784   Compositions and Methods for Transmucosal Absorption   Malaysia
10201605407T   Compositions and Methods for Transmucosal Absorption   Singapore
         
2013-000737   Compositions and Methods for Transmucosal Absorption   Venezuela
2015/00288   Compositions and Methods for Transmucosal Absorption (Allowed)   South Africa

 

33

 

 

CBP – PTSD 

 

Application No.   Title   Country / Region
15/915,688   Methods and Compositions for Treating Symptoms Associated with Post-Traumatic Stress Disorder Using Cyclobenzaprine   U.S.A.

 

Assessing Clinical Response – PTSD

 

Application No.   Title   Country / Region
PCT/US2022/015327   An Improved Method of Assessing Clinical Response in the Treatment of PTSD Symptoms   PCT

  

CBP – Fatigue 

 

Application No.   Title   Country / Region
16/903,965   Methods and Compositions for Treating Fatigue Associated with Disordered Sleep Using Very Low Dose Cyclobenzaprine   U.S.A.

 

CBP – Agitation in Neurodegenerative Condition 

 

Application No.   Title   Country / Region
16/215,952   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   U.S.A.
         
2018383098   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   Australia
BR112020011345-0   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   Brazil
3,083,341   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   Canada
201880079917.1   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   China
18847270.8   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   European Patent Office
P00202004178   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   Indonesia
275289   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   Israel
202017023747   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   India
2020-531611   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   Japan
MX/a/2020/006140   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   Mexico
PI2020002800   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   Malaysia
765792   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   New Zealand
520412146   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   Saudi Arabia
11202004799T   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   Singapore
2020/03243   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   South Africa
6202002246.2   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   Hong Kong
62021029558.5   Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions   Hong Kong

 

34

 

 

CBP – Depression 

 

Application No.   Title   Country / Region
13/412,571   Methods and Compositions for Treating Depression Using Cyclobenzaprine   U.S.A.
2,829,200   Methods and Compositions for Treating Depression Using Cyclobenzaprine (Allowed)   Canada
19214568.8   Methods and Compositions for Treating Depression Using Cyclobenzaprine     European Patent Office

 

Analogs of CBP

 

Application No.   Title   Country / Region

16/630,832 

CA3069699

201880050758.2 

EP18831505.5

 

Analogs of Cyclobenzaprine and Amitryptilene 

Analogs of Cyclobenzaprine and Amitryptilene

Analogs of Cyclobenzaprine and Amitryptilene

Analogs of Cyclobenzaprine and Amitryptilene

Analogs of Cyclobenzaprine and Amitryptilene

 

U.S.A.

Canada 

China

European Patent Office 

2020-526592   Analogs of Cyclobenzaprine and Amitryptilene   Japan
         

CBP – ASD and PTSD 

    

Application No.   Title   Country / Region
2019/38140   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   Gulf Cooperation Council
108129709   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   Taiwan R.O.C.
17/269,106   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   U.S.A.
2019323764   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   Australia
PI2021000802   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   Malaysia
772889   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   New Zealand
             

CBP – Fibromyalgia

 

Application No.   Title   Country / Region
PCT/US2021/062244   Cyclobenzaprine Treatment for Fibromyalgia   PCT

 

CBP – Alcohol Use Disorder

 

Application No.   Title   Country / Region
PCT/US2021/060011   Cyclobenzaprine Treatment for Alcohol Use Disorder   PCT

 

CBP/Amitriptyline – Single Nucleotide Polymorphisms as Predictive Markers

 

Application No.   Title   Country / Region
63/301,313   Single Nucleotide Polymorphisms (SNPs) as Predictive Markers for Treatment with Cyclobenzaprine or Amitriptyline   U.S.A.

 

Application No.   Title   Country / Region
280921   Cyclobenzaprine or Amitriptyline Containing Compositions for Use in Treating Stress Disorders   Israel
2021-509201   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   Japan
BR1120210033107-3   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   Brazil
MX/a/2021/002012   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   Mexico
CA 3109258   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   Canada
11202101443W   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   Singapore
2021/01121   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   South Africa
P00202101716   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   Indonesia
202117011223   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   India
201980062283.3   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   China
19802247.7   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   European Patent Office
62021045278.0   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   Hong Kong
62022046260.5   Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder   Hong Kong

 

35

 

 

CBP – Sexual dysfunction

 

Application No.   Title   Country / Region
PCT/US2021/026492   Cyclobenzaprine Treatment for Sexual Dysfunction   PCT
17/226,058   Cyclobenzaprine Treatment for Sexual Dysfunction   U.S.A

 

Oxytocin therapeutics

 

Application No.   Title   Country / Region
15/541,991   Magnesium-Containing Oxytocin Formulations and Methods of Use   U.S.A.
2020286221   Magnesium-Containing Oxytocin Formulations and Methods of Use   Australia
BR1120170145456   Magnesium-Containing Oxytocin Formulations and Methods of Use   Brazil
2972975   Magnesium-Containing Oxytocin Formulations and Methods of Use   Canada
201680013809.5   Magnesium-Containing Oxytocin Formulations and Methods of Use   China
16735422.4   Magnesium-Containing Oxytocin Formulations and Methods of Use   European Patent Office
18112297.5   Magnesium-Containing Oxytocin Formulations and Methods of Use   Hong Kong
253347   Magnesium-Containing Oxytocin Formulations and Methods of Use (Allowed)   Israel
2017-535877   Magnesium-Containing Oxytocin Formulations and Methods of Use (Allowed)   Japan
2021-179295   Magnesium-Containing Oxytocin Formulations and Methods of Use   Japan
1020177021998   Magnesium-Containing Oxytocin Formulations and Methods of Use   Republic of Korea
734097   Magnesium-Containing Oxytocin Formulations and Methods of Use   New Zealand
771693   Magnesium-Containing Oxytocin Formulations and Methods of Use   New Zealand
201705176   Magnesium-Containing Oxytocin Formulations and Methods of Use   South Africa
16/976,912   Labeled Oxytocin and Method of Manufacture and Use   U.S.A.
19710979.6   Labeled Oxytocin and Method of Manufacture and Use   European Patent Office
2020-545532   Labeled Oxytocin and Method of Manufacture and Use   Japan
16/093,104   Magnesium-Containing Oxytocin Formulations and Methods of Use   U.S.A.
2017250505   Magnesium-Containing Oxytocin Formulations and Methods of Use   Australia
3,020,179   Magnesium-Containing Oxytocin Formulations and Methods of Use   Canada
2017800361853   Magnesium-Containing Oxytocin Formulations and Methods of Use   China
17783080.9   Magnesium-Containing Oxytocin Formulations and Methods of Use   European Patent Office
19128645.9   Magnesium-Containing Oxytocin Formulations and Methods of Use   Hong Kong
2018-553235   Magnesium-Containing Oxytocin Formulations and Methods of Use   Japan
MX/a/2018/012351   Magnesium-Containing Oxytocin Formulations and Methods of Use   Mexico
747221    Magnesium-Containing Oxytocin Formulations and Methods of Use   New Zealand
63/237,727   Cationic Oxytocin Peptide Analogs   U.S.A.

 

Nociceptin/Orphanin FQ therapeutics

 

Application No.   Title   Country / Region
BR122021007932-3   Methods for Treatment of Pain   Brazil
2,769,347   Methods for Treatment of Pain (Allowed)   Canada
1614/CHENP/2012   Methods for Treatment of Pain   India

 

Tianeptine Oxalate – Salts and Crystalline Forms 

 

Application No.   Title   Country / Region
2017385958   Tianeptine Oxalate Salts and Polymorphs (Allowed)   Australia 
BR112019013244-9   Tianeptine Oxalate Salts and Polymorphs   Brazil
3,048,324   Tianeptine Oxalate Salts and Polymorphs   Canada
201780085697.9   Tianeptine Oxalate Salts and Polymorphs   China
17844642.3   Tianeptine Oxalate Salts and Polymorphs   European Patent Office
62020006380.3   Tianeptine Oxalate Salts and Polymorphs   Hong Kong
62020006381.1   Tianeptine Oxalate Salts and Polymorphs   Hong Kong
P00201906474   Tianeptine Oxalate Salts and Polymorphs   Indonesia

267708

  Tianeptine Oxalate Salts and Polymorphs, Compositions Comprising Same and Uses Thereof  

Israel

201917029300   Tianeptine Oxalate Salts and Polymorphs   India

2019-535330 

MX/a/2019/007891

PI2019003711

754797

519402021

11201905974W 

 

Tianeptine Oxalate Salts and Polymorphs 

Tianeptine Oxalate Salts and Polymorphs

Tianeptine Oxalate Salts and Polymorphs

Tianeptine Oxalate Salts and Polymorphs

Tianeptine Oxalate Salts and Polymorphs

Tianeptine Oxalate Salts and Polymorphs 

 

Japan 

Mexico

Malaysia

New Zealand

Saudi Arabia

Singapore

 

36

 

 

Tianeptine Neurocognitive Dysfunction

 

Application No.   Title   Country / Region
16/937,919   Method for Treating Neurocognitive Dysfunction   U.S.A.

 

Tianeptine and Naloxone – Major Depressive Disorder

 

Application No.   Title   Country / Region
63/161,441   Tianeptine Oxalate and Naloxone Treatment for Major Depressive Disorder   U.S.A.

 

Novel Smallpox Vaccines

 

Application No.   Title   Country / Region
14/207,727   Novel Smallpox Vaccines   U.S.A.

 

Synthetic Chimeric Poxviruses 

 

Application No.   Title   Country / Region
15/802,189   Synthetic Chimeric Poxviruses   U.S.A.
P 20170103043   Synthetic Chimeric Poxviruses   Argentina
2017/34209   Synthetic Chimeric Poxviruses   Gulf Cooperation Council
2017/41626   Synthetic Chimeric Poxviruses   Gulf Cooperation Council
106137976   Synthetic Chimeric Poxviruses   Taiwan R.O.C.
2017353868   Synthetic Chimeric Poxviruses   Australia
BR112019008781-8   Synthetic Chimeric Poxviruses   Brazil
3,042,694   Synthetic Chimeric Poxviruses   Canada
201780078546.0   Synthetic Chimeric Poxviruses   China
17868045.0   Synthetic Chimeric Poxviruses   European Patent Office

201917021814

PID201904682 

 

Synthetic Chimeric Poxviruses 

Synthetic Chimeric Poxviruses

 

India

Indonesia 

266399

2019-545700 

Synthetic Chimeric Poxviruses 

Synthetic Chimeric Poxviruses

 

Israel

Japan 

PI2019002462   Synthetic Chimeric Poxviruses   Malaysia

MX/a/2019/005102 

752893

11201903893P

 

Synthetic Chimeric Poxviruses

Synthetic Chimeric Poxviruses 

Synthetic Chimeric Poxviruses

 

Mexico

New Zealand

Singapore 

2019/02868   Synthetic Chimeric Poxviruses   South Africa
2017-000418   Synthetic Chimeric Poxviruses   Venezuela
62020003684.1   Synthetic Chimeric Poxviruses   Hong Kong
62020003675.9   Synthetic Chimeric Poxviruses   Hong Kong

 

Synthetic Vaccinia Virus 

 

Application No.   Title   Country / Region
2019/37492   Synthetic Chimeric Vaccinia Virus    Gulf Cooperation Council 
2019/41458   Synthetic Chimeric Vaccinia Virus    Gulf Cooperation Council 
20190101165   Synthetic Chimeric Vaccinia Virus   Argentina
108115290   Synthetic Chimeric Vaccinia Virus   Taiwan R.O.C.
17/050,946   Synthetic Chimeric Vaccinia Virus   U.S.A.
2019262149   Synthetic Chimeric Vaccinia Virus   Australia
BR112020022181-3   Synthetic Chimeric Vaccinia Virus   Brazil
3099330   Synthetic Chimeric Vaccinia Virus   Canada
201980029677.9   Synthetic Chimeric Vaccinia Virus   China
19796145.1   Synthetic Chimeric Vaccinia Virus   European Patent Office
202017052398   Synthetic Chimeric Vaccinia Virus   India
P00202008694   Synthetic Chimeric Vaccinia Virus   Indonesia
278419   Synthetic Chimeric Vaccinia Virus   Israel
2020-560920   Synthetic Chimeric Vaccinia Virus   Japan
PI 2020005696   Synthetic Chimeric Vaccinia Virus   Malaysia
MX/a/2020/011586   Synthetic Chimeric Vaccinia Virus   Mexico
768999   Synthetic Chimeric Vaccinia Virus   New Zealand
11202010272P   Synthetic Chimeric Vaccinia Virus   Singapore
2020/06350   Synthetic Chimeric Vaccinia Virus   South Africa
62021036744.2   Synthetic Chimeric Vaccinia Virus   Hong Kong
62021038254.0   Synthetic Chimeric Vaccinia Virus   Hong Kong

 

37

 

 

Stem cells-scPV treatment 

 

Application No.   Title   Country / Region
         
2019/37505   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   Gulf Cooperation Council
2019/41460   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   Gulf Cooperation Council
20190101166   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   Argentina
108115294   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   Taiwan R.O.C.
17/049,741   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   U.S.A.
2019262150   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   Australia
3098145   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   Canada
201980029672.6   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   China
19797026.2   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   European Patent Office
278420   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   Israel
2020-561064   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   Japan
62021038255.7   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   Hong Kong
62021031667.0   Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them   Hong Kong
         

Poxvirus vaccine against COVID-19

 

Application No.   Title   Country / Region
PCT/US2021/020119  Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus PCT
17/187,678  Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus U.S.A.
110107179  Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Taiwan
20210100512  Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Argentina
63/315,520  Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus U.S.A.

 

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Salts of glutathione

 

Application No.   Title   Country / Region
17/442,258   Salt forms of S-(N, N-diethylcarbamolyl) glutathione   U.S.A.
2020249868   Salt forms of S-(N, N-diethylcarbamolyl) glutathione   Australia
3,134,875   Salt forms of S-(N, N-diethylcarbamolyl) glutathione   Canada
202080034626.8   Salt forms of S-(N, N-diethylcarbamolyl) glutathione   China
20727359.0   Salt forms of S-(N, N-diethylcarbamolyl) glutathione   European Patent Office
286730   Salt forms of S-(N, N-diethylcarbamolyl) glutathione   Israel
2021-557223   Salt forms of S-(N, N-diethylcarbamolyl) glutathione   Japan

 

TFF2 therapeutics

 

Application No.   Title   Country / Region
17/638,760   Modified TFF2 polypeptides   U.S.A.
Not yet assigned   Modified TFF2 polypeptides   Australia
Not yet assigned   Modified TFF2 polypeptides   Canada
Not yet assigned   Modified TFF2 polypeptides   China
Not yet assigned   Modified TFF2 polypeptides   European Patent Office
Not yet assigned   Modified TFF2 polypeptides   India
290910   Modified TFF2 polypeptides   Israel
2022-513154   Modified TFF2 polypeptides   Japan
MX/a/2022/002337   Modified TFF2 polypeptides   Mexico
Not yet assigned   Modified TFF2 polypeptides   New Zealand
Not yet assigned   Modified TFF2 polypeptides   South Africa

 

Radioprotection therapeutics

 

Application No.   Title   Country / Region
PCT/US2021/031441   Radio- and Chemo-Protective Compounds   PCT
17/315,258   Radio-Protective and Chemo-Protective Substituted Thiols   U.S.A.

 

Detecting SARS-CoV-2

 

Application No.   Title   Country / Region
PCT/US2021/042102   Skin-based Testing for Detection of Cell-Mediated Immune Responses to SARS-CoV-2   PCT
17/378,642   Skin-based Testing for Detection of Cell-Mediated Immune Responses to SARS-CoV-2   U.S.A.
110126495   Skin-based Testing for Detection of Cell-Mediated Immune Responses to SARS-CoV-2   Taiwan

 

Clinical data statistical analysis

 

Application No.   Title   Country / Region
PCT/US2021/056213   Randomization Honoring Methods to Assess the Significance of Interventions on Outcomes in Disorders   PCT
17/508,182   Randomization Honoring Methods to Assess the Significance of Interventions on Outcomes in Disorders   U.S.A.

 

Sangivamycin and nucleoside analogs – Ebola virus

 

Application No.   Title   Country / Region
16/348,867   Methods of Treating and Inhibiting Ebola Virus Infection   U.S.A.
3040540   Methods of Treating and Inhibiting Ebola Virus Infection   Canada
17869003.8   Methods of Treating and Inhibiting Ebola Virus Infection   European Patent Office

 

Sangivamycin and nucleoside analogs – Coronavirus

 

Application No.   Title   Country / Region
PCT/US2020/028567   Method for Treating Coronavirus Infections   PCT
PCT/US2021/016472   Method for Treating Coronavirus Infections   PCT
16/851,047   Method for Treating Coronavirus Infections   U.S.A.

 

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Sangivamycin and nucleoside analogs – Arenaviridae

 

Application No.   Title   Country / Region
PCT/US2021/027352   Method for Treating Arenaviridae Infections   PCT

 

Sangivamycin and nucleoside analogs – Poxviridae

 

Application No.   Title   Country / Region
PCT/US2021/027354   Method for Treating Poxviridae Infections   PCT

 

Trademarks and Service Marks

 

We seek trademark and service mark protection in the United States and outside of the United States where available and when appropriate. We are the owner of the following U.S. federally registered marks: TONIX PHARMACEUTICALS (Reg. No. 4656463, issued December 16, 2014) and TONMYA (Reg. No. 4868328, issued December 8, 2015).

 

We are the owner of the following marks for which applications for U.S. federal registration are currently pending: FYMRALIN (Serial No. 88/064191, filed August 3, 2018), MODALTIN (Serial No. 88/196892, filed November 16, 2018), RAPONTIS  (Serial  No. 88/196897, filed November 16, 2018), PROTECTIC (Serial No. 88/196912, filed November 16, 2018), TONIX PHARMACEUTICALS (Serial No. 88/896150, filed April 30, 2020), and ANGSTRO-TECHNOLOGY (Serial No. 88/690384, filed November 13, 2019) and TONMYA (Serial No. 97/185424, filed December 22, 2021).  

 

 Research and Development

 

We have approximately 52 employees dedicated to research and development. Our research and development operations are located in Chatham, NJ, Dartmouth, MA, Frederick, Maryland, San Diego, CA, Dublin, Ireland and Montreal, Canada. We have used, and expect to continue to use, third parties to conduct our nonclinical and clinical studies. We acquired the infectious disease RDC in Frederick, Maryland consisting of two buildings totaling approximately 48,000 square feet. The acquisition closed in October 2021 and was operational at closing, but as of December 31, 2021, the facility was not ready for its intended use. It is our intention to have the facility ready for use in the first half of 2022.

 

Manufacturing

 

We have contracted with a third-party cGMP-compliant contract manufacturer organization, or CMOs, for the manufacture of TNX-102 SL drug substances and drug products for investigational purposes, including nonclinical and clinical testing. For TNX-102 SL, we have engaged a cGMP facility for manufacturing of to-be-marketed product for Phase 3 clinical and commercial. Our manufacturing operations are managed and controlled in Dublin, Ireland.

 

All of our small molecules drug candidates are synthesized using industry standard processes, and our drug products are formulated using commercially available pharmaceutical grade excipients.

 

Our smallpox-preventing vaccine candidate is a biologic and uses live form of horsepox. Both the drug substance (HPVX and the cell bank) and the drug product (vaccine) will be manufactured by contract cGMP-compliant facilities capable of manufacturing for nonclinical/clinical testing and licensed product.

 

On September 28, 2020, we completed the purchase of our 40,000 square foot facility in Massachusetts, to house our new Advanced Development Center for accelerated development and manufacturing of vaccines. As of December 31, 2021, the facility was not ready for its intended use.

  

On December 23, 2020, we completed the purchase of our approximately 44-acre site in Hamilton, Montana, for the construction of a vaccine development and commercial scale manufacturing facility. As of December 31, 2021, the facility was not ready for its intended use.

  

On March 5, 2021, the Company announced that it entered into a $2.9 million non-binding Purchase and Sale Agreement in connection with a property in Massachusetts, which is expected to close in the second quarter of 2022. The Property is intended for process development activities.

 

Government Regulations

 

The FDA and other federal, state, local and foreign regulatory agencies impose substantial requirements upon the clinical development, approval, labeling, manufacture, marketing and distribution of drug products. These agencies regulate, among other things, research and development activities and the testing, approval, manufacture, quality control, safety, effectiveness, labeling, storage, record keeping, advertising and promotion of our product candidates. The regulatory approval process is generally lengthy and expensive, with no guarantee of a positive result. Moreover, failure to comply with applicable requirements by the FDA or other requirements may result in civil or criminal penalties, recall or seizure of products, injunctive relief including partial or total suspension of production, or withdrawal of a product from the market.

 

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The FDA regulates, among other things, the research, manufacture, promotion and distribution of drugs in the U.S. under the FDCA and other statutes and implementing regulations. The process required by the FDA before prescription drug product candidates may be marketed in the U.S. generally involves the following:

 

  completion of extensive nonclinical laboratory tests, animal studies and formulation studies, all performed in accordance with the FDA’s Good Laboratory Practice regulations;

 

  submission to the FDA of an IND, which must become effective before human clinical trials may begin;

 

  performance of adequate and well-controlled human clinical trials in accordance with the FDA’s regulations, including Good Clinical Practices, to establish the safety and efficacy of the product candidate for each proposed indication;

 

  submission to the FDA of an NDA for drug products, or a Biologics License Application, or BLA, for biologic products;

 

  satisfactory completion of a preapproval inspection by the FDA of the manufacturing facilities at which the product is produced to assess compliance with cGMP regulations; and

 

  the FDA’s review and approval of the NDA or BLA prior to any commercial marketing, sale or shipment of the drug.

 

The testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for our product candidates will be granted on a timely basis, if at all.

 

Nonclinical tests include laboratory evaluations of product chemistry, formulation and stability, as well as studies to evaluate toxicity in animals and other animal studies. The results of nonclinical tests, together with manufacturing information and analytical data, are submitted as part of an IND to the FDA. Some nonclinical testing may continue even after an IND is submitted. The IND also includes one or more protocols for the initial clinical trial or trials and an investigator’s brochure. An IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises concerns or questions relating to the proposed clinical trials as outlined in the IND and places the clinical trial on a clinical hold. In such cases, the IND sponsor and the FDA must resolve any outstanding concerns or questions before any clinical trials can begin. Clinical trial holds also may be imposed at any time before or during studies due to safety concerns or non-compliance with regulatory requirements. An independent Institutional Review Board, or IRB, at each of the clinical centers proposing to conduct the clinical trial must review and approve the plan for any clinical trial before it commences at that center. An IRB considers, among other things, whether the risks to individuals participating in the trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the consent form signed by the trial participants and must monitor the study until completed.

 

Clinical Trials

 

Clinical trials involve the administration of the product candidate to human subjects under the supervision of qualified medical investigators according to approved protocols that detail the objectives of the study, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor participant safety. Each protocol for a U.S. study is submitted to the FDA as part of the IND.

 

Human clinical trials are typically conducted in three sequential phases, but the phases may overlap, or be combined.

 

  Phase 1 clinical trials typically involve the initial introduction of the product candidate into healthy human volunteers. In Phase 1 clinical trials, the product candidate is typically tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and pharmacodynamics.

 

  Phase 2 clinical trials are generally conducted in a limited patient population to gather evidence about the efficacy of the product candidate for specific, targeted indications; to determine dosage tolerance and optimal dosage; and to identify possible adverse effects and safety risks. Phase 2 clinical trials, in particular Phase 2b trials, can be undertaken to evaluate clinical efficacy and to test for safety in an expanded patient population at geographically dispersed clinical trial sites.

 

  Phase 3 clinical trials are undertaken to evaluate clinical efficacy and to test for safety in an expanded patient population at geographically dispersed clinical trial sites. The size of Phase 3 clinical trials depends upon clinical and statistical considerations for the product candidate and disease. Phase 3 clinical trials are intended to establish the overall risk-benefit ratio of the product candidate and provide an adequate basis for product labeling.

 

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Post-approval clinical trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial approval. These clinical trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow-up.

 

Clinical testing must satisfy the extensive regulations of the FDA. Reports detailing the results of the clinical trials must be submitted at least annually to the FDA and safety reports must be submitted for serious and unexpected adverse events. Success in early-stage clinical trials does not assure success in later-stage clinical trials. The FDA, an IRB or we may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.

 

New Drug Applications

 

Assuming successful completion of the required clinical trials, the results of product development, nonclinical studies and clinical trials are submitted to the FDA as part of an NDA (or BLA, in the case of a biologic product). An NDA or BLA also must contain extensive manufacturing information, as well as proposed labeling for the finished product. An NDA or BLA applicant must develop information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the product in accordance with cGMP. The manufacturing process must be capable of consistently producing quality product within specifications approved by the FDA. The manufacturer must develop methods for testing the quality, purity and potency of the final product. In addition, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product does not undergo unacceptable deterioration over its shelf life. Prior to approval, the FDA will conduct an inspection of the manufacturing facilities to assess compliance with cGMP.

 

The FDA reviews all NDAs and BLAs submitted before it accepts them for filing. The FDA may request additional information rather than accept an NDA for filing. In this event, the NDA or BLA must be resubmitted with the additional information and is subject to review before the FDA accepts it for filing. After an application is filed, the FDA may refer the NDA or BLA to an advisory committee for review, evaluation and recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers them carefully when making decisions. The FDA may deny approval of an NDA or BLA if the applicable regulatory criteria are not satisfied. Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data. The FDA may issue a complete response letter, which may require additional clinical or other data or impose other conditions that must be met in order to secure final approval of the NDA or BLA. If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the co