Tonix Pharmaceuticals Holding Corp. 10-K

UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-K (Mark One) ☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the Fiscal Year Ended December 31, 2022 ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 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, 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, a smaller reporting company, or an emerging growth company. See definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and an “emerging growth 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 has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐ If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐ Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐ 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, 2022, based on the closing sales price of the common stock as quoted on The NASDAQ Global Market was $ 50,022,154 . 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 13, 2023, there were 62,539,497 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 37 Item 1B. Unresolved Staff Comments 57 Item 2. Properties 57 Item 3. Legal Proceedings 57 Item 4. Mine Safety Disclosures 57 PART II Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities 58 Item 6. Reserved 58 Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations 59 Item 7A. Quantitative and Qualitative Disclosures about Market Risk 69 Item 8. Financial Statements and Supplementary Data F-1 – F-24 Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosures 70 Item 9A. Controls and Procedures 70 Item 9B. Other Information 70 Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 70 PART III Item 10. Directors, Executive Officers and Corporate Governance 71 Item 11. Executive Compensation 75 Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters 83 Item 13. Certain Relationships and Related Transactions, and Director Independence 84 Item 14. Principal Accounting Fees and Services 84 PART IV Item 15. Exhibits, Financial Statement Schedules 85 Signatures 88 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 developing therapeutics and vaccines to treat and prevent human disease and alleviate suffering. We have a rich pipeline of products in development that has been curated from internal discovery, as well as licenses, acquisitions and collaborations with academic institutions and contract research organizations. We continue to build capabilities in synthetic biology, precision medicine, protein engineering, medicinal chemistry, molecular biology, pharmacogenomics and clinical-scale manufacturing. Our therapeutics under development include both small molecules and biologics. Our portfolio consists of central nervous system, or CNS, rare disease, immunology, and infectious disease product candidates. The CNS portfolio includes small molecules and biologics to treat pain, neurologic, psychiatric and addiction conditions. Our rare disease portfolio focuses on developing novel therapies for patients with rare diseases, including those caused by genetic disorders which are characterized by complex symptoms and for which no drug is approved. Our immunology portfolio includes biologics to address organ transplant rejection, autoimmune diseases and cancer. Our infectious disease portfolio includes a vaccine in development to prevent smallpox and mpox (formerly known as monkeypox), next-generation vaccines to prevent COVID-19, a platform to make fully human monoclonal antibodies, or mAbs, to treat COVID-19 and humanized anti-SARS-CoV-2 mAbs. Our vaccine in development to prevent smallpox and mpox also serves as the live virus vaccine platform or recombinant pox vaccine (RPV) platform for other infectious diseases. Our latest stage CNS product candidate is TNX-102 SL*, a proprietary sublingual tablet formulation of cyclobenzaprine (CBP) designed for bedtime administration. TNX-102 SL has active INDs for fibromyalgia, or FM, FM-type Long COVID or PASC (post-acute sequelae of SARS-CoV-2 infection), posttraumatic stress disorder, or PTSD, agitation in Alzheimer’s disease, or AAD, and alcohol use disorder, or AUD. 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 (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 reported topline data from the completed study in March of 2022. As expected, based on interim analysis results, TNX-102 SL did not achieve statistical significance over placebo on the primary endpoint of reduction in daily pain, and relative to the previous positive Phase 3 Study (RELIEF), RALLY had an unexpected increase in study participant adverse event-related discontinuations in both drug and placebo groups. In April 2022, we started a new potentially confirmatory Phase 3 study of TNX-102 SL in FM, RESILIENT. Interim analysis results are expected in the second quarter of 2023 and topline results are expected in the fourth quarter of 2023. Following a positive outcome of the RESILIENT study, Tonix believes we would be positioned to file a New Drug Application (NDA) for TNX-102 SL for the management of FM. TNX-102 SL is also being developed as a potential treatment for a type of Long COVID, the symptoms of which overlap with FM, that we term FM-type Long COVID. We initiated enrollment in the Phase 2 study PREVAIL, in August 2022. The primary endpoint is a change in daily pain scores from baseline. 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 going forward for the indication of treatment of PTSD. Future studies will employ the one month look-back CAPS-5 as the primary endpoint rather than the one week look-back as used in prior studies. 3 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 the treatment of chronic migraine and obesity-associated 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 animal studies to potentiate binding of oxytocin to the oxytocin receptor. We received IND clearance from the FDA in the fourth quarter of 2021 to study TNX-1900 in chronic migraine and we initiated a Phase 2 study in migraine in the first quarter of 2023. We expect interim analysis results from the first 50 percent of patients enrolled in the fourth quarter of 2023. In March 2022, we announced an agreement with Massachusetts General Hospital, a teaching hospital of Harvard Medical School, to conduct an investigator-initiated Phase 2 clinical trial to study TNX-1900 in BED. The Phase 2 clinical trial is expected to start in the second quarter of 2023. We do not own an IND for BED. We also licensed technology to use TNX-1900 for the treatment of insulin resistance from the University of Geneva and also have rights to develop it as a treatment for craniofacial pain, but we are not imminently pursuing clinical trials in either of these indications at this time. TNX-601 ER* (tianeptine hemioxalate extended-release tablets) is a CNS product candidate in development as a treatment for major depressive disorder, or depression, and with possible additional indications of PTSD, and neurocognitive dysfunction associated with corticosteroid use. TNX-601 ER represents a novel approach to treating depression in the U.S., since the active ingredient tianeptine induces a neuroprotective and resilient phenotype in both neurons and microglia under conditions of stress in animals. The dramatic and unique effects of tianeptine are illustrated in animal models by the restoration of dendritic arborization of pyramidal neurons of CA3 region of hippocampus and the dentate gyrus region new neuron formation and integration into hippocampal networks. In contrast, antidepressants that are marketed in the U.S. act by modulating the levels or receptor binding of neurotransmitters in the synapse. We have completed a Phase 1 trial for formulation development outside of the U.S. We expect to initiate a potentially pivotal Phase 2 study in the first quarter of 2023 for the treatment of major depressive disorder and we expect interim analysis results from the first 50 percent of patients enrolled in the fourth quarter of 2023. Another CNS candidate 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. In August of 2022, we received a Federal Grant from the National Institute on Drug Abuse (NIDA) to advance the development of TNX-1300 as a treatment for cocaine intoxication. We expect to initiate a potentially pivotal Phase 2 study of TNX-1300 in emergency rooms in the second quarter of 2023. 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 expected to be developed as a treatment for PTSD, depression and attention-deficit/hyperactivity disorder, or ADHD. TNX-1600 is in the preclinical stage of development. Our rare disease portfolio consists of TNX-2900*, another magnesium-potentiated 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 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 and is in the pre-IND stage of development. Our lead candidate in the immunology pipeline is TNX-1500*, a humanized mAb, directed against CD40-ligand, or CD40L (also known as CD154), 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 or MGH, 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 allogeneic organ transplants in non-human primates. Preliminary results from ongoing experiments in kidney and 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 therapies were associated with an increased risk of blood clots or thrombosis. In the non-human primate studies with TNX-1500 for the prevention of rejection in allogeneic organ transplants, no evidence of thrombosis has been observed so far. We expect to start a Phase 1 study of TNX-1500 in the second quarter of 2023. TNX-1500 also is being studied in combination with other immunosuppressive agents in xenogeneic organ transplants in non-human primates at MGH and at the University of Maryland at Baltimore or UMB. In experiments at UMB, TNX-1500 is being studied to prevent rejection of xenogeneic hearts from genetically engineered pigs developed by the Revivicor division of United Therapeutics Corporation. Our immunology pipeline also includes TNX-1700*, a recombinant Trefoil Factor Family 2, or rTFF2, fusion protein that was licensed from Columbia University in 2019. TNX-1700 consists of TFF2 fused to human serum albumin or HSA and is a biologic being developed to treat gastric and colorectal cancers by an immune-oncology mechanism, in combination with PD1 blockers, and is in the preclinical stage of development. We recently presented data that show a murine version of TNX-1700 consisting of a fusion protein with murine serum albumin or MSA was able to evoke anti-tumor immunity in the MC38 mouse model of colorectal cancer as monotherapy and that TNX-1700 augmented the efficacy of anti-PD1 therapy in both the MC38 model and the CT26.wt mouse models of colorectal cancer. Our infectious disease portfolio includes vaccines based on our live virus vaccine or recombinant pox vaccine, “RPV” platform. Live virus vaccines are believed to protect against poor clinical outcomes of infectious diseases by eliciting T cell responses in addition to antibody responses. TNX-801*, a live attenuated vaccine based on synthesized horsepox, is in the pre-IND stage of development to protect against smallpox and mpox. Non-human primates vaccinated with TNX-801 were protected from mpox in studies reported in the first quarter of 2020. A Phase 1 study of TNX-801 in humans is expected to start in the second half of 2023. TNX-801 also serves as the live virus vaccine platform for other infectious diseases for which subsequent products will be designed by expressing other viral antigens in the horsepox vector. TNX-1850* is a live virus vaccine that expresses the SARS-CoV-2 spike protein from the BA.2 strain that has not yet been tested in animals. 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 out-competed the ancestral Wuhan strain, we began work on 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. Of those, based on the trajectory of COVID-19, the focus is now on TNX-1850. 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 have shown 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. 4 TNX-2300* is a live virus vaccine based on bovine parainfluenza virus in development to protect against COVID-19. In April 2022, Tonix extended a sponsored research agreement with Kansas State University to develop a vaccine candidate, TNX-2300, for the prevention of COVID-19 that utilizes a novel live virus vaccine vector platform based on bovine parainfluenza virus. The efficacy of co-expression of the CD40-ligand, also known as CD154, to stimulate T cell immunity will also be tested. Attenuated bovine parainfluenza virus has previously been shown to be an effective antigen delivery vector in humans. Previous work by others has shown that attenuated BPI3V is well tolerated and immunogenic in non-human primates and human infants and children. We believe the vector is well suited for mucosal immunization using a nasal atomizer, and can also be delivered parenterally. TNX-2300 is in the preclinical stage of development. TNX-3600* and TNX-3800* are mAbs directed against SARS-CoV-2 which are in development as potential therapeutic or preventative agents for COVID-19. Given the unpredictable trajectory of the SARS-CoV-2 virus and new variants, we seek to contribute a broad set of anti-SARS-CoV-2 mAbs, 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 refers to a series of fully human mAbs generated by human-human hybridomas from COVID-19 convalescent volunteers. We are collaborating with Columbia University to produce these fully human mAbs to SARS-CoV-2 spike proteins from variants such as delta, omicron and XBB1.5 and to other viral targets. TNX-3800 refers to three humanized murine mAbs which we licensed exclusively in December 2022 from Curia Global, Inc. for the treatment or prophylaxis of SARS-CoV-2 infection. The initial focus is to develop COVID-19 therapeutic mAbs. We plan to seek indications similar to previously EUA-approved therapeutic mAbs for treating individuals with mild-to-moderate COVID-19 who are at high risk for progression to severe disease or for prophylaxis in individuals with compromised immune systems who are at high risk for severe COVID-19 disease. None of the previously EUA-approved therapeutic or preventative mAbs are still available, because each has become obsolete since the SARS-CoV-2 virus has mutated to evade their binding. TNX-3600 and TNX-3800 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. TNX-3600 and TNX-3800 are in the preclinical stage of development. TNX-3700* is a COVID-19 mRNA vaccine candidate employing a zinc nanoparticle (ZNP) formulation. In collaboration with Kansas State University, we are 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 for COVID-19. We intend 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 2023. TNX-3700 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 within weeks of obtaining sequence information from a novel pathogen. We seek to be a leader in the movement to re-build domestic U.S. research, development and manufacturing capabilities. Because this movement follows a protracted period when domestic research, development and manufacturing were moved out of the U.S., or “off-shore” by other companies to save on labor and other costs, the movement to reverse that trend has been described as “on-shoring” or “re-domestication”. The COVID-19 pandemic taught that national borders may close during a health emergency. Therefore, domestic capabilities are essential for the health security of the U.S., which has also been described as pandemic preparedness and biodefense. 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 believe we have established the infrastructure necessary to support the pandemic preparedness goals established in the AP3, specifically with respect to our RPV vaccine and potentially to other vaccine and therapeutic platforms. This infrastructure consists of (i) our R&D Center, or “RDC”, (ii) our Advanced Development Center, or “ADC”, and (iii) our Commercial Manufacturing Center, or “CMC”. We acquired the RDC in Frederick, Maryland consisting of one building totaling approximately 48,000 square feet. The acquisition closed in October 2021 and the facility is operational. The RDC facility focuses on our development of vaccines and antiviral drugs against SARS-CoV-2, its variants, and other infectious diseases. The RDC also conducts research on central nervous systema and immunology drugs. The RDC facility is mostly biosafety level 2 (BSL-2), with some components designated BSL-3. We completed the substantial renovation of the ADC located in the New Bedford business park in Dartmouth, Massachusetts, which became operational as of the fourth quarter 2022. This approximately 45,000 square foot BSL-2 facility is intended to accelerate development and clinical scale manufacturing of live-virus vaccines and biologics to support clinical trials. We also plan to build the CMC in Hamilton, Montana, where we purchased approximately 44 acres of land and have built a field office to manage construction of the facility. The CMC will focus on developing and manufacturing commercial scale live-virus vaccines and biologics and is also intended to be BSL-2. Site enabling work is expected to be initiated for the CMC in 2023. Together, we expect these facilities may qualify the RPV vaccine platform for programs that are designed to carry out the goals of AP3. *All of our 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 address is www.tonixpharma.com. 5 Our Strategy Our strategy is to use our integrated development engine to advance innovative programs across multiple therapeutic areas into the clinic while maximizing asset potential, with the objective of developing and commercializing our product candidates. The principal components of our strategy are to: ● Pursue CNS, rare disease, immunology, and infectious disease indications with high unmet medical need and significant commercial potential. Within the therapeutic areas that Tonix is focusing on, 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, a condition which 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 using TNX-102 SL for FM-type Long COVID, a condition for which there is no currently approved therapy. Our broader development strategy is to leverage the patented formulation and proven mechanism of action to explore the clinical potential of TNX-102 SL in multiple other, psychiatric, and addiction conditions, including PTSD, Agitation in Alzheimer’s disease 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-1900 to treat chronic migraine, TNX-601 ER to treat major depressive disorder and TNX-1300 to treat cocaine intoxication. Although a number of drugs are approved for chronic migraine and major depressive disorder, there remains dissatisfaction with available options. Cocaine intoxication is one of the leading causes of overdose deaths and for which there is no currently approved drug. 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. Within infectious diseases, we are currently focusing on the development of TNX-801 to prevent smallpox and mpox, and TNX-1850 to protect against COVID-19. While there are FDA-approved vaccines to prevent smallpox and mpox, we believe TNX-801 has potential to provide durable protection. While there are FDA-approved COVID-19 vaccines which use mRNA technology, or other technologies, we believe that there are limitations to these vaccines relating to durability of protection and their relative inability to block forward transmission. ● 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 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-1300, TNX-1900, TNX-2900, and TNX-1700. We own patents outright for TNX-601 ER and have filed patent applications for TNX-1500 and TNX-3700. 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 ER, 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 as vaccines for future pandemics, infectious diseases generally and oncology, in addition to smallpox and mpox. 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. Central Nervous System 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. We are focusing development of TNX-102 SL on FM-type Long COVID. The symptoms include intense fatigue, sleep problems, multi-site pain, and cognitive issues (“brain fog”). The proposed indication is for the management of multi-site pain associated with PASC. 6 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 2021 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. Research shows that Long COVID occurs in approximately 13% of recovered COVID-19 patients. There is currently no approved drug for the treatment of Long COVID. 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 or its receptor. Major Depressive Disorder According to the Substance Abuse and Mental Health Services Administration, an estimated 21.0 million adults in the U.S. in 2020 experienced at least one major depressive episode, representing 8.4% of all U.S. adults. 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. 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, cocaine-involved deaths rose nearly 54% from 2019 to 2021, resulting in over 24,486 deaths total. 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. 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. Rare Disease 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 morbidity and mortality. PWS is an orphan disease that occurs in approximately one in 15,000 births. There is currently no approved treatment for obesity and hyperphagia in adults and older children associated with PWS. 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. 7 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 diseases. 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 33.3%. According to 2017-2019 data, approximately 0.8 percent of men and women will be diagnosed with stomach cancer during their lifetime. In 2019, there were an estimated 123,920 people living with stomach cancer in the U.S. 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 65.1%, per the National Cancer Institute. According to 2017-2019 data, approximately 4.1 percent of men and women will be diagnosed with colorectal cancer during their lifetime. In 2019, there were an estimated 1,369,005 people living with colorectal cancer in the United States. Infectious Diseases Smallpox and Mpox 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. Mpox is an acute contagious disease caused by the monkeypox virus or MPXV, which is also a member of the orthopoxvirus family. Mpox symptoms are similar to those of smallpox, although less severe. Mpox is emerging as an important zoonotic infection in humans in Central and West Africa. Until 2022, only a few cases of mpox had been reported outside of Africa in patients who had been infected while in Africa. Starting in May of 2022, mpox cases spread rapidly in the U.S. and other countries. More than 30,000 cases in the U.S. have been reported according to the U.S. Centers for Disease Control and Prevention. 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. Vaccines for smallpox and mpox are stockpiled by the U.S. government in the strategic national stockpile and for potential widespread immunization in the event of malicious reintroduction of VARV. 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. 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 later stage product candidates that are in or nearing the clinic: Product Candidate Indication Stage of Development TNX-102 SL Fibromyalgia Mid-Phase 3, >50% enrolled TNX-102 SL FM-type Long COVID Phase 2 enrolling TNX-1900 Chronic migraine Phase 2, enrolling TNX-601 ER Depression Phase 2, targeted 1Q 2023 start TNX-1300 Cocaine Intoxication Mid-Phase 2, targeted 2Q 2023 start TNX-1500 Kidney Transplant Rejection Phase 1, targeted 2Q 2023 start TNX-801 Smallpox and Mpox vaccine Phase 1, targeted 2H 2023 start TNX-2900 Prader-Willi Syndrome Phase 1 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, 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. 8 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, Long COVID, and PTSD 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. Clinical Development Plan Phase 3 RESILIENT (F307) The first patient was enrolled in the potentially pivotal Phase 3 RESILIENT study in April 2022. The RESILIENT 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 two-arm trial is expected to enroll approximately 470 participants in the U.S. and was 50% enrolled as of December 2022. The first two weeks of treatment consist of a run-in period in which participants start on TNX-102 SL 2.8 mg (1 tablet) or placebo. Thereafter, all participants increase their dose to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets for the remaining 12 weeks. The primary endpoint is the daily diary pain severity score change (TNX-102 SL 5.6 mg vs. placebo) 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. An interim analysis by an IDMC will be conducted on the primary endpoint based on the first 50% of enrolled participants for a potential sample size adjustment or early stop for futility. Interim data is expected in the second quarter of 2023. Topline data is expected in the fourth quarter of 2023. Completed Phase 3 RALLY Study (F306) We reported pre-planned interim analysis results from a Phase 3 study, RALLY (F306), in July 2021. 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 reported topline data from the completed study in March of 2022. As expected based on interim analysis results, TNX-102 SL did not achieve statistical significance over placebo on the primary endpoint of reduction in daily pain, and relative to the previous positive Phase 3 Study (RELIEF), RALLY had an unexpected increase in study participant adverse event-related discontinuations in both drug and placebo groups. The RALLY study was a double-blind, randomized, placebo-controlled adaptive design trial intended 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. 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). 9 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% 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 was 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). 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 potential is not required to support the TNX-102 SL NDA filing. We are 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, we 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. 10 The F108 Phase 1 study was initiated in March 2022 and the clinical phase was completed in May 2022 and we are awaiting the final study report at the time of this filing. We are completing 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 – FM-type Long COVID Program We are developing TNX-102 SL as a bedtime treatment for FM-type Long COVID. The potential approval of TNX-102 SL for Long COVID is expected to be under Section 505(b)(2) of the FDCA. Phase 2 PREVAIL Study (PA201) We initiated a Phase 2 study of TNX-102 SL as a treatment for FM-type Long COVID, which is a subset of patients affected by Long COVID whose symptoms overlap with fibromyalgia. The trial initiated in August 2022. The study is a randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of TNX-102 SL for FM-type Long COVID. We completed a pre-IND meeting with the FDA in August 2021 to develop TNX-102 SL as a potential treatment for Long COVID. 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 currently enrolling Phase 2 study focuses 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 our 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. 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 (IA) results of the first 50% of enrolled participants, an IDMC 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; effect size (ES)=0.15). TNX-102 SL separated from placebo in the first key secondary endpoint, CGI-S scale (p=0.024; ES=0.36) and in the PGIC, (p=0.007; ES=0.43). TNX-102 SL also trended for improvement on the PROMIS Sleep Disturbance scale (p=0.055; ES=0.30), 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 next PTSD study can use 1 month look-back CAPS-5 as endpoint v. 1 week look-back. 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. 11 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. 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 36-month 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 – Migraine, Craniofacial Pain and Obesity-Associated Binge Eating Disorder 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 an 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 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 system resulting in binding of oxytocin to receptors on neurons in the trigeminal system, inhibiting the release of CGRP and transmission of pain signals. 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 binding as well as its effects on trigeminal neurons and craniofacial analgesic effects in animal models. Intranasal oxytocin has been well tolerated in several clinical trials in both adults and children. 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 antibodies. 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 initiated a Phase 2 study in chronic migraine in the first quarter of 2023. 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 BED in an investigator-initiated Phase 2 clinical trial. The Phase 2 clinical trial is expected to start in the second quarter of 2023. 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. TNX-601 ER – Depression, PTSD, Neurocognitive Dysfunction from Corticosteroids We announced the development of TNX-601 ER in July 2022, a potential abuse deterrent, extended-release formulation of tianeptine hemioxalate. TNX-601 ER is designed for once-daily daytime dosing and is being developed as a treatment for major depressive disorder (MDD), posttraumatic stress disorder, and neurocognitive dysfunction associated with corticosteroid use. TNX-601 ER represents a novel approach to treating depression in the U.S., since the active ingredient tianeptine induces a neuroprotective and resilient phenotype in both neurons and microglia under conditions of stress in animals. The dramatic and unique effects of tianeptine are illustrated in animal models by the restoration of dendritic arborization of pyramidal neurons of CA3 region of hippocampus and the dentate gyrus region new neuron formation and integration into hippocampal networks. In contrast, antidepressants that are marketed in the U.S. act by modulating the levels or receptor binding of neurotransmitters in the synapse. Tianeptine sodium (amorphous) immediate release (IR) tablets have been available in Europe and many countries in Asia and Latin America for the treatment of MDD over the more than three decades since it was first marketed in France in 1989. No tianeptine-containing product has been approved by the FDA. The proposed mechanism of action of TNX-601 ER is distinct from traditional monoaminergic antidepressants in the U.S. In addition to its glutamatergic properties central to its antidepressant effect, tianeptine has weak µ-opioid receptor agonist properties and has been linked to illicit misuse at much higher doses than those reported to be effective in the treatment of MDD (reported to be used daily at 8-80 times the antidepressant daily dose). Previously, we were developing a naloxone-containing tablet, TNX-601 CR (tianeptine oxalate and naloxone controlled-release) for MDD, that was designed to mitigate the risk of parenteral abuse. 12 We intend to develop TNX-601 ER under Section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (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 ER to be used in Phase 2 testing will be 39.4 mg tianeptine hemioxalate for once daily treatment of MDD (which is equivalent in tianeptine content to three 12.5 mg doses of tianeptine sodium). Based on the clearance of IND 152371 by the FDA, we expect to initiate a Phase 2 study in the first quarter of 2023. The Phase 2 study is planned to be a randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of TNX-601 ER 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 300 individuals with MDD at a 1:1 ratio to two arms of 150 each for drug and placebo at approximately 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. An IA will be conducted once the first 50 percent of the sample has completed the study, estimated to occur in the fourth quarter of 2023. TNX-1300 – Cocaine Intoxication 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. The gene encoding CocE was identified and the protein was extensively characterized. 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 temperature. 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. 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. In August 2022, we announced that we received a Cooperative Agreement grant from the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH), to support development of TNX-1300. The Company expects to initiate a new Phase 2 clinical study of TNX-1300 for the treatment of cocaine intoxication in the second quarter of 2023, pending agreement on protocol design with the U.S. Food and Drug Administration (FDA). The Phase 2 trial is a single-blind, open-label, placebo-controlled, randomized study comparing the safety of a single 200 mg dose of TNX-1300 to standard of care alone in approximately 60 emergency department patients presenting with cocaine intoxication. A positive Phase 2a study of volunteer cocaine users in a controlled laboratory setting has been previously completed. TNX-1300 has been granted Breakthrough Therapy designation by the FDA. 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 is in the process of manufacturing Phase 2/3 drug product clinical supply. TNX-2900 – Prader-Willi Syndrome TNX-2900 is based on our 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. Tonix completed a pre-IND meeting with the FDA in November 2022 to discuss the most efficient and appropriate investigational plan to establish the safety and effectiveness evidence to support the approval of TNX-2900. 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. TNX-1500 – Organ Transplant Rejection/Autoimmune Conditions TNX-1500 is a humanized mAb directed against CD40-ligand, or CD40L (also known as CD154), 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 ongoing animal experiments in kidney and heart allogeneic transplants indicate that TNX-1500 appears to have comparable efficacy to historical experiments using the chimeric mouse/primate version of the anti-CD40L mAb 5c8, but to date has not shown evidence of the thromboembolic adverse events associated with the first generation mAb directed against CD40L. 13 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 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. 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. Tonix completed a pre-IND meeting with the FDA in October 2022 to discuss the most efficient and appropriate investigational plan to establish the safety and effectiveness evidence to support the licensure of TNX-1500. We expect to start a Phase 1 study of TNX-1500 in the second quarter of 2023. 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-801 – Potential Smallpox and Mpox Vaccine TNX-801 is a novel potential smallpox- and mpox-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 mpox. 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- and mpox-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. Mpox is a growing problem in certain regions of Africa. Starting in May of 2022, cases of mpox have been reported outside of Africa in patients who had not been infected while in Africa. More than 30,000 cases in the U.S. have been reported according to the U.S. Centers for Disease Control and Prevention. 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. Those studies were published as an article in the peer reviewed journal, Viruses in 2023. We hold a U.S. Patent for TNX-801 smallpox and mpox vaccine and Recombinant Pox Virus (RPV) platform technology. This patent is expected to provide Tonix with U.S. market exclusivity until 2037, excluding any possible patent term extensions or patent term adjustments. 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. 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. A Phase 1 study of TNX-801 is expected to be initiated in the second half of 2023. TNX-1850 – Potential COVID-19 Vaccine Our infectious disease portfolio includes a platform for vaccines for COVID-19. TNX-1800 is live virus vaccine based on our 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 are designed to 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. 14 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 10 6 TCID50) and intra-nasal (1 x 10 6 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 10 6 Plaque Forming Units [PFU] and 3 x 10 6 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 10 6 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. 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-1850, in addition to ultimately planning to utilize our in-house manufacturing capabilities which are currently in development. Tonix announced the issuance of U.S. Patent for TNX-801 smallpox and mpox vaccine and Recombinant Pox Virus (RPV) platform technology. This patent is expected to provide Tonix with U.S. market exclusivity until 2037, excluding any possible patent term extensions or patent term adjustments, and also expect 12 years of non-patent-based exclusivity under PPACA. Our preclinical pipeline of drugs and biologic candidates also includes TNX-1600, a preclinical candidate for PTSD, ADHD and depression; TNX-1700 a preclinical candidate for cancers of the gastrointestinal system; TNX-2300, a live-virus vaccine based on bovine parainfluenza virus for COVID-19; TNX-3600, a COVID-19 therapeutic platform; TNX-3700, a COVID-19 vaccine; TNX-3800, a COVID-19 Therapeutic/Preventative. 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 of a novel pathogen. We seek to be a leader in the movement to re-build domestic U.S. research, development and manufacturing capabilities. Because this movement follows a protracted period when domestic research, development and manufacturing were moved out of the U.S., or “off-shore” by other companies to save on labor and other costs, the movement to reverse that trend has been described as “on-shoring” or “re-domestication”. The COVID-19 pandemic taught that national borders may close during a health emergency. Therefore, domestic capabilities are essential for the health security of the U.S., which has also been described as pandemic preparedness and biodefense. 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 platform and potentially to other vaccine and therapeutic platforms. The Research & Development Center (RDC) We own the approximately 48,000 square foot RDC facility in Frederick, Maryland. The RDC facility is operational and focuses on our development of vaccines and antiviral drugs against COVID-19, its variants, and other infectious diseases. The RDC also conducts research on CNS and immunology drugs. The RDC facility is biosafety level 2 (BSL-2) with BSL-3 components. The RDC currently employs 26 staff. At full capacity, the RDC can employ 80-100 scientists and technical support staff. The Advanced Development Center (ADC) The ADC located in the New Bedford business park in Dartmouth, Massachusetts is operational and intended to accelerate development and clinical scale manufacturing of live-virus vaccines and biologics to support Phase 1 and Phase 2 clinical trials. ADC includes single-use bioreactors and purification suites with equipment for Good Manufacturing Practice (GMP) production of vaccines for and biologics clinical trials, including the capability of producing sterile vaccines in glass bottles. The ADC is an approximately 45,000 square foot BSL-2 facility that currently employs 35 staff. At full capacity, the facility can employ up to 70 researchers, scientists, manufacturing, and technical support staff. 15 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 biologics and is also intended to be BSL-2. We have constructed a field office on the site to direct construction. 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. 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 Virios Therapeutics, Axsome Therapeutics, Tryp Therapeutics, Biomind Labs, Cortene, and Sorrento 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 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. Also, Nurtec ODT® (Rimegepant) was more recently approved as both a preventive and an acute treatment for episodic migraine, marketed by Pfizer; and Qulipta® (atogepant) was approved for prevention of episodic migraine, marketed by AbbVie. We are aware of other companies working to develop therapeutics for the treatment or prophylaxis of migraine including Astrocyte Pharmaceuticals, Protox, Kallyope, Crystec Pharma, Pulmatrix, and Epalex. 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), as well as the norepinephrine-dopamine reuptake inhibitor, bupropion. Recently, Auvelity, developed by Axsome Therapeutics, and Vraylar, developed by Allergan, received FDA approval. Tonix is aware of several companies developing novel prescription medicines for depression including Janssen, Neumora Therapeutics (formerly BlackThorn Therapeutics), Sage Therapeutics, Relmada Therapeutics, Clexio Biosciences Ltd., Otsuka, Seelos Therapeutics, Biomind Labs, FSD Pharma, Bright Minds Bioscienes, Vistagen, Alto Neuroscience, Addex Therapeutics, and BetterLife Pharma. Long COVID (Post-Acute Sequelae of SARS-CoV-2 Infection 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 Direct Biologics, American CryoStem, HopeBiosciences, Axcella Health Inc., Ampio Pharmaceuticals, Pieris Pharmaceuticals, Resolve Therapeutics, PaxMedia, GeNeuro, Organicell, Ampio Pharmaceuticals, Lyramid, Virios Therapeutics, Berlin Cures, and Statera Biopharma. 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, Nobilis Therapeutics, Bright Minds Biosciences, Alto Neuroscience, Addex Therapeutics, Ophidion, Artelo Biosciences, Roche, Boehringer Ingelheim, NRx Pharmaceuticals, Nanomerics, Seelos Therapeutics, and the Multidisciplinary Association of Psychedelic Studies (MAPS). Acadia Pharmaceuticals is testing Nuplazid® (pimavanserin) for the treatment of insomnia in veterans with PTSD. 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. Anti-CD40-ligand Monoclonal Antibodies Tonix is aware of several companies developing biologics that target the CD40L molecule and block its interaction with CD40 including UCB/Biogen, Eledon Pharmaceuticals, Horizon Therapeutics Plc. (which is being acquired by Amgen), Lundbeck (in partnership with Aprilbio), and Sanofi. Furthermore, Tonix is aware of several companies developing antagonistic anti-CD40 mAbs including Novartis, Boehringer Ingelheim, Kiniska Pharmaceuticals, Boston Immune Therapies, and NapaJen Pharma, Inc. Prader-Willi Syndrome There are no approved products for the treatment of Prader-Willi syndrome. Patients generally receive care to best manage individual symptom presentation. Tonix is aware of two companies developing a therapeutic for Prader Willi Syndrome including Acadia (which purchased Levo Therapeutics in 2022) and OT4B. Several other companies are developing treatments for Prader-Willi syndrome including Aadvark Therapeutics, ConSynance Therapeutics, Soleno Therapeutics, Lipidio Pharma, Helsinn, Inversago Pharma, Saniona, 9 Meters Biopharma, Neuren Pharmaceuticals, Neuracle Science, Harmony Biosciences, and Notitia Biotechnologies. 16 Gastric and Colorectal Cancer Tonix is developing a small peptide/biologic for the treatment of gastric and colorectal cancer. Tonix is aware of several other companies developing biologics for the treatment of gastric and colorectal cancer including Bexion Pharmaceuticals Inc., Faeth Therapeutics Inc., PDS Biotechnology Corp, and F-star Alpha Ltd. COVID-19 Vaccine 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 FDA approval for limited use. Covovax® (NVX-CoV2373), developed by Novavax, has received EUA from the FDA. Other vaccines have received EUA in international markets. Smallpox and Mpox Vaccines and Antivirals Vaccines approved for the prevention of smallpox include ACAM2000®, marketed by Emergent BioSolutions and JYNNEOS®, marketed by Bavarian Nordic. JYNNEOS® is also approved for the prevention of mpox. Approved antivirals for smallpox include TPOXX®, marketed by SIGA and TEMBEXA®, marketed by Chimerix. These antivirals are not FDA approved for the treatment of mpox. Tonix is aware of other companies developing treatments for smallpox and mpox including EpiVax, HK inno.N, BioFactura, Blue Water Vaccines, NightHawk Biosciences, Ascletis, and Hyundai Biosciences. Intellectual Property We believe that we have an extensive patent portfolio and substantial know-how relating to TNX-102 SL, TNX-1300, TNX-1500, TNX-601 ER, TNX-801 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, 2023, the patents we are either the owner of record of or own the contractual right to include 34 issued U.S. patents and 271 issued non-U.S. patents. We are actively pursuing an additional 32 U.S. patent applications, of which 7 are provisional and 25 are non-provisional, 11 international patent applications, and 247 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. The patent portfolios for our proprietary technology platform and our most advanced product candidates as of March 8, 2023 are summarized below. 17 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, fatigue, e.g., CAP rates, post-acute sequelae of SARS-CoV-2 infection, 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, U.S. Patent No. 10,864,175, and U.S. Patent No. 11,026,898. 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. The Technical Board of the European Patent Office has canceled the April 27, 2023 Oral Proceedings pending the decision of the Enlarged Board of Appeal in G 2/21 (plausibility), which seeks to clarify whether a technical effect can be relied on when proof for the effect rests solely in post-published evidence and what role, if any, plausibility should play in this assessment. 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. On August 3, 2022, European Patent No. 2861223, entitled “Compositions and Methods for Transmucosal Absorption,” issued. These claims relate to the pharmacokinetic profile of TNX-102 SL. 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. 18 On April 8, 2021, U.S. non-provisional Patent Application No. 17/226,058 and International Patent Application No. PCT/US2021/026492, entitled “Cyclobenzaprine Treatment for Sexual Dysfunction” were filed. The PCT application is now nationalized in Australia, Canada, China, European Patent Office and Japan. On October 5, 2022, International Patent Application No. PCT/US2022/045791, entitled “Cyclobenzaprine Treatment for Sexual Dysfunction” was filed. The claims of these applications 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. On December 11, 2018, U.S. non-provisional Patent Application No. 16/215,952 and International Patent Application No. PCT/IB2018/001509, entitled “Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions,” were filed. The PCT application is now nationalized in 16 countries. The claims are directed to methods for treating or preventing agitation, cognitive decline, psychosis, and associated symptoms thereof using pharmaceutical compositions and combinations with cyclobenzaprine or pharmaceutically acceptable salts of cyclobenzaprine. On August 20, 2019, International Patent Application No. PCT/IB2019/000940, entitled “Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder,” was filed. The PCT application is now nationalized in 18 countries. The claims are directed to methods of treating acute stress disorder or post-traumatic stress disorder in a subject who has experienced a traumatic event using pharmaceutical compositions with cyclobenzaprine, amitriptyline or pharmaceutically acceptable salts of cyclobenzaprine or amitriptyline. On November 19, 2021, International Patent Application No. PCT/US2021/060011, entitled “Cyclobenzaprine Treatment for Alcohol Use Disorder,” was filed. The claims are directed to methods for treating alcohol use disorder and associated symptoms using pharmaceutical compositions with cyclobenzaprine or pharmaceutically acceptable salts of cyclobenzaprine. On December 7, 2021, International Patent Application No. PCT/US2021/062244, entitled, “Cyclobenzaprine Treatment for Fibromyalgia,” was filed. The claims are directed to methods for treating fibromyalgia and its associated symptoms of pain, sleep disturbance and/or fatigue by transmucosally administering a eutectic with cyclobenzaprine hydrochloride and mannitol in dosage units with a basifying agent. 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 Nos. 9,629,894 and 11,389,473, 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. TNX-2900 — Oxytocin-based therapeutics treatments 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 and TNX-601 ER— 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. 19 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. Our patent portfolio for TNX-601 CR includes International Patent Application No. PCT/US2022/020406, entitled “Tianeptine Oxalate and Naloxone Treatment for Major Depressive Disorder,” was filed March 15, 2022. It includes claims directed to compositions with tianeptine and naloxone or pharmaceutically acceptable salts of tianeptine and naloxone and methods of preventing or treating major depressive disorder using the compositions. 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-1500 — anti-CD40L Therapeutics We are developing 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 U.S., Canada, China, 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-801 — Live Horsepox Vaccine for Prevention of Smallpox and Mpox We own the rights to develop a potential biodefense technology, TNX-801, a live horsepox that is being developed as a new smallpox and mpox 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 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. On May 31, 2022, U.S. Patent No. 11,345,896 was issued. The claims recite a synthetic chimeric orthopoxvirus (scOPV), a synthetic chimeric horsepox virus (scHPXV), methods of generating the scOPV and scHPXV, and compositions comprising the scOPV or scHPXV. TNX-1850 — Live Modified Horsepox Vaccine for Prevention of COVID-19 We are developing TNX-1850, 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, entitled “Recombinant Poxvirus Based Vaccine Against SARS-CoV-2.” On the same date, we also filed applications in Argentina and Taiwan and we filed U.S. Application No. 17/187,678. The PCT application is not nationalized in 18 countries. 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. 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.” The PCT application is now nationalized in 12 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. 20 On May 7, 2021, we filed International Patent Application No. PCT/US2021/031441, entitled “Radio-and Chemo-Protective Compounds,” and U.S. non-provisional Patent Application No. 17/315,258, entitled “Radio-Protective and Chemo-Protective Substituted Thiols.” The PCT application is now nationalized in 10 countries. The applications claim compounds, compositions and methods of use in radioprotection. On January 31, 2023, U.S. Patent No. 11,566,032 issued. The claims recite compounds of a formula I or a pharmaceutically acceptable salt thereof or stereoisomer thereof and a pharmaceutical composition comprising a compound of formula I. 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, entitled “Synthetic Chimeric Vaccinia Virus,” include U.S. non-provisional Patent Application No. 17/050,946 and International Patent Application No. PCT/US2019/030486 (now nationalized in 16 countries) and applications filed in Argentina, Taiwan and Venezuela. We believe that this technology, after further development, may be of interest to biodefense agencies in the U.S. and other countries. TNX-2300 — Bovine Parainfluenza 3 Virus vaccine We have an exclusive field-of-use option agreement with Kansas State University Research Foundation to develop TNX-2300, a bovine parainfluenza virus vaccine, as a new COVID-19 preventing vaccine or treatment. The patent applications in this agreement include International Patent Application No. PCT/US2020/070725, entitled “Broadly Protective Bovine Parainfluenza 3 Virus and Bovine Viral Diarrhea Virus Vaccine” (nationalized in U.S. as Patent Application No. 17/755,359), and International Patent Application No. PCT/US2022/072433, entitled “SARS-Coronavirus 2 (SARS-CoV-2) Spike Protein Subunit Vaccines.” TNX-3700 — Zinc Nanoparticle mRNA vaccine We have an exclusive field-of-use option agreement with Kansas State University Research Foundation to develop TNX-3700, a zinc nanoparticle mRNA vaccine, as a new COVID-19 preventing vaccine or treatment. The patent applications in this agreement include International Patent Application No. PCT/US2022/070739, entitled “RNA Stabilizing Nanoparticles,” and International Patent Application No. PCT/US2022/075944, entitled “mRNA Vaccine Formulations and Methods of Using the Same.” TNX-3900 — antiviral drugs We have acquired the intellectual property rights of Healion Bio, Inc. to develop antiviral drugs. These rights include International Patent Application No. PCT/US2021/032461 (nationalized in 4 countries) and U.S. Patent Application No. 18/055,596, both entitled “Compositions and Methods for Increasing Efficacy of a Drug,” as well as International Patent Application No. PCT/US2021/052664, entitled “Methods and Compositions for the Treatment of Viral Diseases.” TNX-4100 — murine anti-SARS-CoV-2 antibodies We have exercised the option to obtain an exclusive license from Columbia University to develop, TNX-4100, a series of murine and humanized anti-SARS-CoV-2 mAbs as new COVID-19 preventatives or treatments. 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. 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 21 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 2861223 Compositions and Methods for Transmucosal Absorption European Patent Office – Italy, Albania, Austria, Belgium, Bulgaria, Cyprus, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Latvia, Lithuania, Luxembourg, Malta, Monaco, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom, San Marino, Serbia, Croatia, North Macedonia and Turkey June 14, 2033 236268 Compositions for Transmucosal Delivery and Uses Thereof Israel June 14, 2033 2015/00288 Compositions and Methods for Transmucosal Absorption South Africa June 14, 2033 BR112014031394-6 Compositions and Methods for Transmucosal Absorption Brazil June 14, 2033 1209361 Compositions and Methods for Transmucosal Absorption Hong Kong June 14, 2033 398632 Compositions and Methods for Transmucosal Absorption Mexico June 14, 2033 A059897 Compositions and Methods for Transmucosal Absorption Venezuela June 14, 2033 MY-194495-A Compositions and Methods for Transmucosal Absorption Malaysia June 14, 2033 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 2,829,200 Methods and Compositions for Treating Depression Using Cyclobenzaprine Canada 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 22 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 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 23 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, AL/P/2019/906 in Albania, MK/P/2020/67 in Republic of North Macedonia, 3102655 in Greece, 502020000007756 in Italy) 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 277814 Eutectic Formulations of Cyclobenzaprine Hydrochloride and Methods of Producing Same Israel September 18, 2034 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 398845 Eutectic Formulations of Cyclobenzaprine Hydrochloride India September 18, 2035 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 11,389,473 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 388286 Magnesium-Containing Oxytocin Formulations and Methods of Use Mexico January 7, 2036 253347 Magnesium-Containing Oxytocin Formulations and Methods of Use Israel January 7, 2036 7030517 Magnesium-Containing Oxytocin Formulations and Methods of Use Japan January 7, 2036 ZL201680013809.5 Magnesium-Containing Oxytocin Formulations and Methods of Use China January 7, 2036 7093559 Magnesium-Containing Oxytocin Formulations and Methods of Use Japan April 12, 2037 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 24 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 2,769,347 Methods for treatment of pain Canada July 27, 2030 413642 Methods for treatment of pain India July 27, 2030 Tianeptine Hemioxalate – 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 2017385958 Tianeptine Oxalate Salts and Polymorphs Australia December 28, 2037 IDP000082485 Tianeptine Oxalate Salts and Polymorphs Indonesia December 28, 2037 754797 Tianeptine Oxalate Salts and Polymorphs New Zealand 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 and E911827 in Austria) Method for Treating Neurodegenerative Dysfunction European Patent Office – 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 European Patent Office – Austria, Belgium, Switzerland, Germany, Spain, France, United Kingdom, Ireland, Luxembourg, Monaco, Portugal April 30, 2029 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 25 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 Synthetic Chimeric Poxviruses Patent No. Title Country / Region Expiration Date 11,345,896 Synthetic Chimeric Poxviruses U.S.A November 2, 2037 397516 Synthetic Chimeric Poxviruses Mexico November 2, 2037 2019/02868 Synthetic Chimeric Poxviruses South Africa November 2, 2037 Radioprotection therapeutics Patent No. Title Country / Region Expiration Date 11,566,032 Radio-Protective and Chemo-Protective Substituted Thiols U.S.A May 7, 2041 Pending Patent Applications Our current pending patent applications are as follows: CD40 and anti-CD154 Therapeutics Application No. Title Country / Region 17/623,710 Anti-CD154 antibodies and uses thereof U.S.A. 2020300002 Anti-CD154 antibodies and uses thereof Australia BR112021026410-8 Anti-CD154 antibodies and uses thereof Brazil 3145453 Anti-CD154 antibodies and uses thereof Canada 202080059891.1 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 784548 Anti-CD154 antibodies and uses thereof New Zealand 11202114433Y Anti-CD154 antibodies and uses thereof Singapore 2022/01378 Anti-CD154 antibodies and uses thereof South Africa 62022063693.5 Anti-CD154 antibodies and uses thereof Hong Kong 62022062573.0 Anti-CD154 antibodies and uses thereof Hong Kong 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 17/603,260 Inhibitors of CD40-CD154 Binding U.S.A. 202080033531.4 Inhibitors of CD40-CD154 Binding China 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 (Allowed) 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 3392/KOLNP/2015 Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride India 2021-105582 Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride Japan 2021-169539 Eutectic Formulations of Cyclobenzaprine Hydrochloride Japan 26 Application No. Title Country / Region PI 2015703142 Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride Malaysia PI 20233000078 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 Not Yet Assigned Compositions and Methods for Transmucosal Absorption Argentina 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 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 42020020336.2 Compositions and Methods for Transmucosal Absorption Hong Kong P-00 2021 01421 Compositions and Methods for Transmucosal Absorption Indonesia 2021-100154 Compositions and Methods for Transmucosal Absorption Japan 10201605407T Compositions and Methods for Transmucosal Absorption Singapore CBP – PTSD Application No. Title Country / Region 17/951,723 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. 27 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 CBP – Depression Application No. Title Country / Region 13/412,571 Methods and Compositions for Treating Depression Using Cyclobenzaprine U.S.A. 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 Amitriptyline Analogs of Cyclobenzaprine and Amitriptyline Analogs of Cyclobenzaprine and Amitriptyline Analogs of Cyclobenzaprine and Amitriptyline Analogs of Cyclobenzaprine and Amitriptyline U.S.A. Canada China European Patent Office 2020-526592 Analogs of Cyclobenzaprine and Amitriptyline 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 BR112021003107-3 Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder Brazil 3109258 Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder Canada 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 202117011223 Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder India P00202101716 Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder Indonesia 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 MX/a/2021/002012 Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder Mexico 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 CBP – Fibromyalgia Application No. Title Country / Region PCT/US2021/062244 Cyclobenzaprine Treatment for Fibromyalgia PCT 28 CBP – Alcohol Use Disorder Application No. Title Country / Region PCT/US2021/060011 Cyclobenzaprine Treatment for Alcohol Use Disorder PCT CBP – Sexual dysfunction Application No. Title Country / Region PCT/US2022/045791 Cyclobenzaprine Treatment for Sexual Dysfunction PCT 17/226,058 Cyclobenzaprine Treatment for Sexual Dysfunction U.S.A 2021253592 Cyclobenzaprine Treatment for Sexual Dysfunction Australia 3179754 Cyclobenzaprine Treatment for Sexual Dysfunction Canada 202180040673.8 Cyclobenzaprine Treatment for Sexual Dysfunction China 21721779.3 Cyclobenzaprine Treatment for Sexual Dysfunction European Patent Office 2022-562023 Cyclobenzaprine Treatment for Sexual Dysfunction Japan CBP – Post-Acute Sequelae of SARS-CoV-2 (PASC) Application No. Title Country / Region 63/354,215 Cyclobenzaprine Treatment for Post-Acute Sequelae of (SARS)-CoV-2 Infection (PASC) U.S.A. Oxytocin therapeutics Application No. Title Country / Region 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 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 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 (Allowed) 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 (Allowed) China 2023100344997 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 2022-60727 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 787097 Magnesium-Containing Oxytocin Formulations and Methods of Use New Zealand Nociceptin/Orphanin FQ therapeutics Application No. Title Country / Region BR122021007932-3 Methods for Treatment of Pain Brazil Tianeptine Hemioxalate – Salts and Crystalline Forms Application No. Title Country / Region 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 267708 Tianeptine Oxalate Salts and Polymorphs, Compositions Comprising Same and Uses Thereof Israel 201917029300 Tianeptine Oxalate Salts and Polymorphs India 2019-535330 2022-180549 MX/a/2019/007891 PI2019003711 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 Japan Mexico Malaysia Saudi Arabia Singapore 29 Tianeptine and Naloxone – Major Depressive Disorder Application No. Title Country / Region PCT/US2022/020406 Tianeptine Oxalate and Naloxone Treatment for Major Depressive Disorder PCT Synthetic Chimeric Poxviruses Application No. Title Country / Region 17/827,320 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 BR122023000373-0 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 2022-140113 Synthetic Chimeric Poxviruses Japan PI2019002462 Synthetic Chimeric Poxviruses Malaysia 752893 11201903893P Synthetic Chimeric Poxviruses Synthetic Chimeric Poxviruses New Zealand Singapore 2022/04981 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 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 30 Poxvirus vaccine against COVID-19 Application No. Title Country / Region 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. 1202200348 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus African Intellectual Property Organization AP/P/2022/014318 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus African Regional Intellectual Property Organization 2021226592 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Australia BR112022016992-2 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Brazil 3173996 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Canada 202180027983.6 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus China 202292431 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Eurasian Patent Office 21715007.7 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus European Patent Office 202217053476 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus India P00202210244 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Indonesia 295925 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Israel 2022-551297 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Japan PI 2022004613 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Malaysia MX/a/2022/010588 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Mexico 791924 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus New Zealand 10-2022-7033014 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Republic of Korea 522440323 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus Saudi Arabia 2022/09895 Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus South Africa 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 62022054457.6 Salt forms of S-(N, N-diethylcarbamolyl) glutathione Hong Kong 62022057646.1 Salt forms of S-(N, N-diethylcarbamolyl) glutathione Hong Kong TFF2 therapeutics Application No. Title Country / Region 17/638,761 Modified TFF2 polypeptides U.S.A. 2020338947 Modified TFF2 polypeptides Australia 3152665 Modified TFF2 polypeptides Canada 202080071768.1 Modified TFF2 polypeptides China 20781063.1 Modified TFF2 polypeptides European Patent Office 202217016249 Modified TFF2 polypeptides India 290910 Modified TFF2 polypeptides Israel 2022-513154 Modified TFF2 polypeptides Japan MX/a/2022/002337 Modified TFF2 polypeptides Mexico 786004 Modified TFF2 polypeptides New Zealand 2022/03355 Modified TFF2 polypeptides South Africa 62023066535.3 Modified TFF2 polypeptides Hong Kong 62023066928.0 Modified TFF2 polypeptides Hong Kong Radioprotection therapeutics Application No. Title Country / Region 17/991,292 Radio-Protective and Chemo-Protective Substituted Thiols U.S.A. 17/923,831 Radio-and Chemo-Protective Compounds U.S.A. 2021269125 Radio-and Chemo-Protective Compounds Australia 3182014 Radio-and Chemo-Protective Compounds Canada Not Yet Assigned Radio-and Chemo-Protective Compounds China 21728771.3 Radio-and Chemo-Protective Compounds European Patent Office 202217070148 Radio-and Chemo-Protective Compounds India 298025 Radio-and Chemo-Protective Compounds Israel 2022-567802 Radio-and Chemo-Protective Compounds Japan 793900 Radio-and Chemo-Protective Compounds New Zealand 522441204 Radio-and Chemo-Protective Compounds Saudi Arabia 11202254727V Radio-and Chemo-Protective Compounds Singapore 31 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. Monoclonal Antibodies – anti-SARS-CoV-2 Spike Application No. Title Country / Region 63/421,137 Anti-SARS-CoV-2-Spike Monoclonal Antibodies and Antigen-Binding Fragments Thereof and Use in Treating SARS-CoV-2 Infection U.S.A. 63/421,138 Anti-SARS-CoV-2-Spike Monoclonal Antibodies and Antigen-Binding Fragments Thereof and Use in Treating SARS-CoV-2 Infection U.S.A. 63/421,141 Anti-SARS-CoV-2-Spike Monoclonal Antibodies and Antigen-Binding Fragments Thereof and Use in Treating SARS-CoV-2 Infection U.S.A. Nanoparticles – T cell Immune Response Application No. Title Country / Region 63/338,217 Nanoparticles for Inducing a TH1 T Cell Immune Response U.S.A. Nanoparticles – mRNA vaccine Application No. Title Country / Region PCT/US2022/070739 RNA Stabilizing Nanoparticles PCT PCT/US2022/075944 mRNA Vaccine Formulations and Methods of Using the Same PCT Virus Vaccine – Bovine Parainfluenza Virus Vaccine Application No. Title Country / Region 17/755,359 Broadly Protective Bovine Parainfluenza 3 Virus and Bovine Viral Diarrhea Virus Vaccine U.S.A. PCT/US2022/072433 SARS-Coronavirus 2 (SARS-CoV-2) Spike Protein Subunit Vaccines PCT Antiviral Drugs – Cathepsin Inhibitors Application No. Title Country / Region 63/327,431 Therapeutic Agents and Combinations for Treating Viral Diseases U.S.A. 18/055,596 Compositions and Methods for Increasing Efficacy of a Drug U.S.A. 2021271806 Compositions and Methods for Increasing Efficacy of a Drug Australia 21803283.7 Compositions and Methods for Increasing Efficacy of a Drug European Patent Office 2022-569505 Compositions and Methods for Increasing Efficacy of a Drug Japan 202217072271 Compositions and Methods for Increasing Efficacy of a Drug India PCT/US2021/052664 Methods and Compositions for the Treatment of Viral Diseases 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). We are the owner of the following marks for which applications for U.S. federal registration are currently pending: FYMRALIN (Serial No. 97/458017, filed June 14, 2022), MODALTIN (Serial No. 97/424052, filed May 23, 2022), RAPONTIS (Serial No. 97/424058, filed May 23, 2022), PROTECTIC (Serial No. 97/424071, filed May 23, 2022), 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 94 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 RDC in Frederick, Maryland consisting of two buildings totaling approximately 48,000 square feet. The acquisition closed in October 2021 and is operational. 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- and mpox-preventing vaccine candidate is a biologic and employs a 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. 32 On September 28, 2020, we completed the purchase of our 45,000 square foot facility in Massachusetts, to house our new Advanced Development Center for accelerated development and manufacturing of vaccines and biologics. As of October 1, 2022, the facility was ready for its intended use and is operational. 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, 2022, the facility was not ready for its intended use. 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. 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. 33 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 commercial value of the product. In addition, the FDA may require us to conduct Phase 4 testing which involves clinical trials designed to further assess a drug’s safety and effectiveness after NDA or BLA approval, and may require surveillance programs to monitor the safety of approved products which have been commercialized. Once issued, the FDA may withdraw product approval if ongoing regulatory requirements are not met or if safety or efficacy questions are raised after the product reaches the market. Section 505(b) NDAs There are two types of NDAs: the Section 505(b)(1) NDA, or full NDA, and the Section 505(b)(2) NDA. We intend to file Section 505(b)(2) NDAs for TNX-102 SL for FM, Long COVID and PTSD, for TNX-1900 for chronic migraine and TNX-2900 for Prader Willi Syndrome and for certain other products, that might, if accepted by the FDA, save time and expense in the development and testing of our product candidates. We may need to file a Section 505(b)(1) NDA for certain other products in the future. A full NDA is submitted under Section 505(b)(1) of the FDCA, and must contain full reports of investigations conducted by the applicant to demonstrate the safety and effectiveness of the drug. A Section 505(b)(2) NDA may be submitted for a drug for which one or more of the investigations relied upon by the applicant was not conducted by or for the applicant and for which the applicant has no right of reference from the person by or for whom the investigations were conducted. A Section 505(b)(2) NDA may be submitted based in whole or in part on published literature or on the FDA’s finding of safety and efficacy of one or more previously approved drugs, which are known as reference drugs. Thus, the filing of a Section 505(b)(2) NDA may result in approval of a drug based on fewer clinical or nonclinical studies than would be required under a full NDA. The number and size of studies that need to be conducted by the sponsor depends on the amount and quality of data pertaining to the reference drug that are publicly available, and on the similarity of and differences between the applicant’s drug and the reference drug. In some cases, extensive, time-consuming, and costly clinical and nonclinical studies may still be required for approval of a Section 505(b)(2) NDA. Our drug approval strategy for our new formulations of approved chemical entities is to submit Section 505(b)(2) NDAs to the FDA. As such, we plan to submit an NDA under Section 505(b)(2) for TNX-102 SL for FM, Long COVID and PTSD; TNX-1900 for chronic migraine, and TNX-2900 for Prader Willi Syndrome. The FDA may not agree that these product candidates are approvable as a Section 505(b)(2) NDA. If the FDA determines that a Section 505(b)(2) NDA is not appropriate and that a full NDA is required, the time and financial resources required to obtain FDA approval could substantially and materially increase and be less likely to be approved. If the FDA requires a full NDA or requires more extensive testing and development for some other reason, our ability to compete with alternative products that arrive on the market more quickly than our product candidates would be adversely impacted. If reference listed products are withdrawn from the market by the FDA for a safety reason, we may not be able to reference such products to support our anticipated 505(b)(2) NDAs, and we may be required to follow the requirements of Section 505(b)(1). Patent Protections An applicant submitting a Section 505(b)(2) NDA must certify to the FDA with respect to the patent status of the reference drug upon which the applicant relies in support of approval of its drug. With respect to every patent listed in the FDA’s Orange Book, which is the FDA’s list of approved drug products, as claiming the reference drug or an approved method of use of the reference drug, the Section 505(b)(2) applicant must certify that: (1) there is no patent information listed in the orange book for the reference drug; (2) the listed patent has expired; (3) the listed patent has not expired, but will expire on a particular date; (4) the listed patent is invalid or will not be infringed by the manufacture, use, or sale of the product in the Section 505(b)(2) NDA; or (5) if the patent is a use patent, that the applicant does not seek approval for a use claimed by the patent. If the applicant files a certification to the effect of clause (1), (2) or (5), FDA approval of the Section 505(b)(2) NDA may be made effective immediately upon successful FDA review of the application, in the absence of marketing exclusivity delays, which are discussed below. If the applicant files a certification to the effect of clause (3), the Section 505(b)(2) NDA approval may not be made effective until the expiration of the relevant patent and the expiration of any marketing exclusivity delays. 34 If the Section 505(b)(2) NDA applicant provides a certification to the effect of clause (4), referred to as a paragraph IV certification, the applicant also must send notice of the certification to the patent owner and the holder of the NDA for the reference drug. The filing of a patent infringement lawsuit within 45 days of the receipt of the notification may prevent the FDA from approving the Section 505(b)(2) NDA for 30 months from the date of the receipt of the notification unless the court determines that a longer or shorter period is appropriate because either party to the action failed to reasonably cooperate in expediting the action. However, the FDA may approve the Section 505(b)(2) NDA before the 30 months have expired if a court decides that the patent is invalid or not infringed, or if a court enters a settlement order or consent decree stating the patent is invalid or not infringed. Notwithstanding the approval of many products by the FDA pursuant to Section 505(b)(2), over the last few years certain brand-name pharmaceutical companies and others have objected to the FDA’s interpretation of Section 505(b)(2). If the FDA’s interpretation of Section 505(b)(2) is successfully challenged in court, the FDA may be required to change its interpretation of Section 505(b)(2) which could delay or even prevent the FDA from approving any Section 505(b)(2) NDA that we submit. The pharmaceutical industry is highly competitive, and it is not uncommon for a manufacturer of an approved product to file a citizen petition with the FDA seeking to delay approval of, or impose additional approval requirements for, pending competing products. If successful, such petitions can significantly delay, or even prevent, the approval of the new product. Moreover, even if the FDA ultimately denies such a petition, the FDA may substantially delay approval while it considers and responds to the petition. Marketing Exclusivity Market exclusivity provisions under the FDCA can delay the submission or the approval of Section 505(b)(2) NDAs, thereby delaying a Section 505(b)(2) product from entering the market. The FDCA provides five-year marketing exclusivity to the first applicant to gain approval of an NDA for an NCE, meaning that the FDA has not previously approved any other drug containing the same active moiety. This exclusivity prohibits the submission of a Section 505(b)(2) NDA for any drug product containing the active ingredient during the five-year exclusivity period. However, submission of a Section 505(b)(2) NDA that certifies that a listed patent is invalid, unenforceable, or will not be infringed, as discussed above, is permitted after four years, but if a patent infringement lawsuit is brought within 45 days after such certification, FDA approval of the Section 505(b)(2) NDA may automatically be stayed until 7½ years after the NCE approval date. The FDCA also provides three years of marketing exclusivity for the approval of new and supplemental NDAs for product changes, including, among other things, new indications, dosage forms, routes of administration or strengths of an existing drug, or for a new use, if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by FDA to be essential to the approval of the application. Five-year and three-year exclusivity will not delay the submission or approval of another full NDA; however, as discussed above, an applicant submitting a full NDA under Section 505(b)(1) would be required to conduct or obtain a right of reference to all of the nonclinical and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness. Other types of exclusivity in the United States include orphan drug exclusivity and pediatric exclusivity. The FDA may grant orphan drug designation to a drug intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for this type of disease or condition will be recovered from sales in the United States for that drug. Seven-year orphan drug exclusivity is available to a product that has orphan drug designation and that receives the first FDA approval for the indication for which the drug has such designation. Orphan drug exclusivity prevents approval of another application for the same drug for the same orphan indication, for a period of seven years, regardless of whether the application is a full NDA or a Section 505(b)(2) NDA, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity. Pediatric exclusivity, if granted, provides an additional six months to an existing exclusivity or statutory delay in approval resulting from a patent certification. This six-month exclusivity, which runs from the end of other exclusivity protection or patent delay, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study. Section 505(b)(2) NDAs are similar to full NDAs filed under Section 505(b)(1) in that they are entitled to any of these forms of exclusivity if they meet the qualifying criteria. They also are entitled to the patent protections described above, based on patents that are listed in the FDA’s Orange Book in the same manner as patents claiming drugs and uses approved for NDAs submitted as full NDAs. Breakthrough Therapy Designation The Food and Drug Administration Safety and Innovation Act, or FDASIA, Section 902 provides for Breakthrough Therapy designation. A Breakthrough Therapy is a drug: ● intended alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition; and ● preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. Fast Track Designation A Fast Track is a designation by the FDA of an investigational drug which: ● intended alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition; and ● non-clinical or clinical data demonstrate the potential to address an unmet medical need Fast track is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. The benefits of a Fast Track designation include rolling submission of portions of the NDA for the drug candidate and eligibility for priority review of the NDA. Additionally, more frequent meetings and written communication with the FDA regarding the development plan and trial design for the drug candidate are encouraged throughout the entire drug development and review process, with the goal of having earlier drug approval and access for patients. 35 Material Threat Medical Countermeasures In 2016, the 21 st Century Cures Act, or Act, was signed into law to support ongoing biomedical innovation. One part of the Act, Section 3086, is aimed at “Encouraging Treatments for Agents that Present a National Security Threat.” The Act created a new priority review voucher program for approved “material threat medical countermeasure applications.” The Act defines such countermeasures as drug or biological products, including vaccines intended to treat biological, chemical, radiological, or nuclear agents that present a national security threat or to treat harm from a condition that may be caused by administering a drug or biological product against such an agent. The Department of Homeland Security has identified 13 such threats, including anthrax, smallpox, Ebola/Marburg, tularemia, botulinum toxin, and pandemic influenza, which includes the SARS coronavirus 2, known as SARS-CoV-2. Other Regulatory Requirements Maintaining substantial compliance with appropriate federal, state and local statutes and regulations requires the expenditure of substantial time and financial resources. Drug manufacturers are required to register their establishments with the FDA and certain state agencies, and after approval, the FDA and these state agencies conduct periodic unannounced inspections to ensure continued compliance with ongoing regulatory requirements, including cGMPs. In addition, after approval, some types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further FDA review and approval. The FDA may require post-approval testing and surveillance programs to monitor safety and the effectiveness of approved products that have been commercialized. Any drug products manufactured or distributed by us pursuant to FDA approvals are subject to continuing regulation by the FDA, including: ● record-keeping requirements; ● reporting of adverse experiences with the drug; ● providing the FDA with updated safety and efficacy information; ● reporting on advertisements and promotional labeling; ● drug sampling and distribution requirements; and ● complying with electronic record and signature requirements. In addition, the FDA strictly regulates labeling, advertising, promotion and other types of information on products that are placed on the market. There are numerous regulations and policies that govern various means for disseminating information to health-care professionals as well as consumers, including to industry sponsored scientific and educational activities, information provided to the media and information provided over the Internet. Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved label. The FDA has very broad enforcement authority and the failure to comply with applicable regulatory requirements can result in administrative or judicial sanctions being imposed on us or on the manufacturers and distributors of our approved products, including warning letters, refusals of government contracts, clinical holds, civil penalties, injunctions, restitution and disgorgement of profits, recall or seizure of products, total or partial suspension of production or distribution, withdrawal of approvals, refusal to approve pending applications, and criminal prosecution resulting in fines and incarceration. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability. In addition, even after regulatory approval is obtained, later discovery of previously unknown problems with a product may result in restrictions on the product or even complete withdrawal of the product from the market. Coverage and Reimbursement Sales of our product candidates, if approved, will depend, in part, on the extent to which such products will be covered by third-party payors, such as government health care programs, commercial insurance and managed healthcare organizations. These third-party payors are increasingly limiting coverage or reducing reimbursements for medical products and services. In addition, the U.S. government, state legislatures and foreign governments have continued implementing cost-containment programs, including price controls, restrictions on reimbursement and requirements for substitution of generic products. Third-party payors decide which therapies they will pay for and establish reimbursement levels. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own coverage and reimbursement policies. However, decisions regarding the extent of coverage and amount of reimbursement to be provided for any drug candidates that we develop will be made on a payor-by-payor basis. Each payor determines whether or not it will provide coverage for a therapy, what amount it will pay the manufacturer for the therapy, and on what tier of its formulary it will be placed. The position on a payor’s list of covered drugs, or formulary, generally determines the co-payment that a patient will need to make to obtain the therapy and can strongly influence the adoption of such therapy by patients and physicians. Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit our net revenue and results. Decreases in third-party reimbursement for our product candidates or a decision by a third-party payor to not cover our product candidates could reduce physician usage of our product candidates, once approved, and have a material adverse effect on our sales, results of operations and financial condition. Other Healthcare Laws Because of our current and future arrangements with healthcare professionals, principal investigators, consultants, customers and third-party payors, we will also be subject to healthcare regulation and enforcement by the federal government and the states and foreign governments in which we will conduct our business, including our clinical research, proposed sales, marketing and educational programs. Failure to comply with these laws, where applicable, can result in the imposition of significant civil penalties, criminal penalties, or both. 36 The U.S. laws that may affect our ability to operate, among others, include: the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information; certain state laws governing the privacy and security of health information in certain circumstances, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts; the federal healthcare programs’ Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, in exchange for or to induce either the referral of an individual for, or the purchase, order or recommendation of, any good or service for which payment may be made under federal healthcare programs such as the Medicare and Medicaid programs; federal false claims laws which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid, or other third-party payors that are false or fraudulent; federal criminal laws that prohibit executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters; the Physician Payments Sunshine Act, which requires manufacturers of drugs, devices, biologics, and medical supplies to report annually to the U.S. Department of Health and Human Services information related to payments and other transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members; and state law equivalents of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items or services reimbursed by any third-party payor, including commercial insurers. In addition, many states have similar laws and regulations, such as anti-kickback and false claims laws that may be broader in scope and may apply regardless of payor, in addition to items and services reimbursed under Medicaid and other state programs. Additionally, to the extent that our product is sold in a foreign country, we may be subject to similar foreign laws. The Impact of New Legislation and Amendments to Existing Laws The FDCA is subject to routine legislative amendments with a broad range of downstream effects. In addition to new legislation, such as the FDA Reauthorization Act of 2017 or the FDASIA in 2012, Congress introduces amendments to reauthorize drug user fees and address emerging concerns every five years. We cannot predict the impact of these new legislative acts and their implementation of regulations on our business. The programs established or to be established under the legislation may have adverse effects upon us, including increased regulation of our industry. Compliance with such regulation may increase our costs and limit our ability to pursue business opportunities. In addition, the FDA’s regulations, policies and guidance are often revised or reinterpreted by the agency or the courts in ways that may significantly affect our business and our products. We expect that additional federal and state, as well as foreign, healthcare reform measures will be adopted in the future, any of which could result in reduced demand for our products or additional pricing pressure. Human Capital Resources As of March 13, 2023, we had 117 full-time employees, of whom 19 hold M.D. or Ph.D. degrees. We have 94 employees dedicated to research and development. None of our employees are represented by a collective bargaining agreement. We believe that the skills, experience and industry knowledge of our key employees significantly benefit our operations and performance. Our research and development operations are located in Chatham, NJ, San Diego, CA, Dartmouth, MA, Frederick, Maryland, Dublin, Ireland and Montreal, Canada. We have used, and expect to continue to use, third parties to conduct our nonclinical and clinical studies as well as part-time employees. Employee health and safety in the workplace is one of our core values. The COVID-19 pandemic has underscored for us the importance of keeping our employees safe and healthy. In response to the pandemic, we have taken actions aligned with the World Health Organization and the Centers for Disease Control and Prevention in an effort to protect our workforce so they can more safely and effectively perform their work. Employee levels are managed to align with the pace of business and management believes it has sufficient human capital to operate its business successfully. Corporate Information We lease the space for our principal executive offices, which are located at 26 Main Street, Suite 101, Chatham, New Jersey 07928, and our telephone number is (862) 799 8599. Our website address is www.tonixpharma.com. We do not incorporate the information on our websites into this annual report, and you should not consider such information part of this annual report. 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. Item 1A. Risk Factors Summary of Risk Factors ● We have a history of operating losses and may never generate revenues or achieve profitability. ● We expect our operating results to fluctuate, which may make it difficult to predict our future performance. ● Our product candidates are novel and still in development. ● We do not expect to generate any revenues from product sales in the foreseeable future, if at all. ● We are largely dependent on the success of our product candidates and cannot be certain that our product candidates will receive regulatory approval or be successfully commercialized. ● Clinical studies required for our product candidates are expensive and time-consuming, and their outcome is uncertain. ● We are subject to extensive and costly government regulation. ● We have never submitted an NDA before, and may be unable to do so for our product candidates we are developing. 37 ● Our product candidates may cause serious adverse events or undesirable side effects which may delay or prevent marketing approval, or, if approval is received, require them to be taken off the market, require them to include safety warnings or otherwise limit their sales. ● We may be unable to meet our anticipated development and commercialization timelines for approval of any of our product candidates. ● Any breakthrough, fast track or orphan drug designation or grant of priority review status by the FDA may not actually lead to a faster development or regulatory review or approval process, nor assure FDA approval of our product candidates. ● Even if approved, our products may not be accepted by the market. ● We may use our financial and human resources to pursue a particular research program or product candidate and fail to capitalize on programs or product candidates that may be more profitable or for which there is a greater likelihood of success. ● Our independent registered public accounting firm has included an explanatory paragraph relating to our ability to continue as a going concern in its report on our audited financial statements. We may be unable to continue to operate without the threat of liquidation for the foreseeable future. ● We will need additional capital. If additional capital is not available or is available at unattractive terms, we may be forced to delay, reduce the scope of or eliminate our research and development programs, reduce our commercialization efforts or curtail our operations. ● Outbreaks of communicable diseases may materially and adversely affect our business, financial condition and results of operations. ● Competition and technological change may make our product candidates and technologies less attractive or obsolete. ● If we fail to protect our intellectual property rights, our ability to pursue the development of our technologies and products would be negatively affected. ● We may be involved in lawsuits to protect or enforce our patents, which could be expensive and time consuming. ● If we infringe the rights of third parties we could be prevented from selling products, forced to pay damages, and defend against litigation. ● We rely on third parties to conduct, supervise and monitor our clinical studies, and if those third parties perform in an unsatisfactory manner, it may harm our business. ● We will need to expand our operations and increase the size of our company, and we may experience difficulties in managing growth. ● Our executive officers and other key personnel are critical to our business, and our future success depends on our ability to retain them. ● If we are unable to hire additional qualified personnel, our ability to grow our business may be harmed. ● We rely on third parties to manufacture the compounds used in our studies, and we intend to rely on them for the manufacture of any approved products for commercial sale. If these third parties do not manufacture our product candidates in sufficient quantities and at an acceptable cost, clinical development and commercialization of our product candidates could be delayed, prevented or impaired. ● Failure by our third-party manufacturers to comply with the regulatory guidelines set forth by the FDA with respect to our product candidates could delay or prevent the completion of clinical studies, the approval of any product candidates or the commercialization of our products. ● Adverse global conditions, including economic uncertainty, may negatively impact our financial results. ● Our internal computer systems, or those of our CRO’s or other contractors or consultants, may fail or suffer security breaches, which could result in a material disruption of our product development programs. ● Corporate and academic collaborators may take actions to delay, prevent, or undermine the success of our products. ● Data provided by collaborators and others upon which we rely that has not been independently verified could turn out to be false, misleading, or incomplete. ● Our product candidates may face competition sooner than expected. ● If we fail to establish marketing, sales and distribution capabilities, or fail to enter into arrangements with third parties, we will not be able to create a market for our product candidates. ● Our relationships with customers, physicians, and third-party payors will be subject, directly or indirectly, to federal and state healthcare fraud and abuse laws, false claims laws, health information privacy and security laws, and other healthcare laws and regulations. If we are unable to comply, or have not fully complied, with such laws, we could face substantial penalties. ● Coverage and adequate reimbursement may not be available for our current or any future drug candidates, which could make it difficult for us to sell profitably, if approved. ● Healthcare legislative reform measures may have a negative impact on our business and results of operations. ● If we obtain approval to commercialize any approved products outside of the United States, a variety of risks associated with international operations could materially adversely affect our business. ● We face the risk of product liability claims and may not be able to obtain insurance. ● We use hazardous chemicals in our business. Potential claims relating to improper handling, storage or disposal of these chemicals could affect us and be time consuming and costly. ● If we retain collaborative partners and our partners do not satisfy their obligations, we will be unable to develop our partnered product candidates. ● We may be unsuccessful in obtaining a priority review voucher for material threat medical countermeasures. ● Government entities may take actions that directly or indirectly have the effect of limiting opportunities for our vaccines for COVID-19. ● If technology developed for the purposes of developing new medicines or vaccines can be applied to the creation or development of biological weapons, then our technology may be considered “dual use” technology and be subject to limitations on public disclosure or export. ● We face risks in connection with existing and future collaborations with respect to the development, manufacture, and commercialization of our product candidates. ● We face risks in connection with the testing, production and storage of our vaccine product candidates. ● An active trading market for our common stock may not be sustained. ● The market price of our common stock has been extremely volatile and may continue to be volatile due to numerous circumstances beyond our control. ● We could be delisted from Nasdaq, which could seriously harm the liquidity of our stock and our ability to raise capital. ● We do not anticipate paying dividends on our common stock and, accordingly, shareholders must rely on stock appreciation for any return on their investment. ● We expect that our quarterly results of operations will fluctuate, and this fluctuation could cause our stock price to decline. ● If we fail to comply with the rules under the Sarbanes-Oxley Act of 2002 related to accounting controls and procedures, or if we discover material weaknesses and deficiencies in our internal control and accounting procedures, our stock price could decline significantly and raising capital could be more difficult. 38 ● If securities or industry analysts do not publish research or reports about our business, or if they change their recommendations regarding our stock adversely, our stock price and trading volume could decline. ● Other companies may have difficulty acquiring us, even if doing so would benefit our stockholders, due to provisions under our corporate charter and bylaws, as well as Nevada law. ● Other companies may have difficulty acquiring us, even if doing so would benefit our stockholders, due to provisions under our corporate charter and bylaws, as well as Nevada law. ● Our bylaws designate the Eighth Judicial District Court of Clark County, Nevada as the sole and exclusive forum for certain types of actions and proceedings that may be initiated by our stockholders, which could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, officers, employees or agents. RISKS RELATED TO OUR BUSINESS We have a history of operating losses and expect to incur losses for the foreseeable future. We may never generate revenues or, if we are able to generate revenues, achieve profitability. We are focused on product development, and we have not generated any revenues to date. We have incurred losses in each year of our operations, and we expect to continue to incur operating losses for the foreseeable future. These operating losses have adversely affected and are likely to continue to adversely affect our working capital, total assets and shareholders’ equity. We and our prospects should be examined in light of the risks and difficulties frequently encountered by new and early-stage companies in new and rapidly evolving markets. These risks include, among other things, the speed at which we can scale up operations, our complete dependence upon development of our product candidates that currently have no market acceptance, our ability to establish and expand our brand name, our ability to expand our operations to meet the commercial demand of our clients, our development of and reliance on strategic and customer relationships and our ability to minimize fraud and other security risks. The process of developing our products requires significant clinical, nonclinical and CMC development, laboratory testing and clinical studies. In addition, commercialization of our product candidates will require that we obtain necessary regulatory approvals and establish sales, marketing and manufacturing capabilities, either through internal hiring or through contractual relationships with others. We expect to incur substantial losses for the foreseeable future as a result of anticipated increases in our research and development costs, including costs associated with conducting preclinical and nonclinical testing and clinical studies, and regulatory compliance activities. We expect to incur substantial additional operating expenses over the next several years as our research, development, preclinical and nonclinical testing, and clinical study activities increase , and if and when we acquire rights to additional product candidates. The amount of future losses and when, if ever, we will achieve profitability are uncertain. We have no products that have generated any commercial revenue, do not expect to generate revenues from the commercial sale of products in the near future, and might never generate revenues from the sale of products. Our ability to generate revenue and achieve profitability will depend on, among other things, successful completion of the development of our product candidates; obtaining necessary regulatory approvals from the FDA; establishing manufacturing, sales, and marketing arrangements with third parties; successfully commercializing our products; establishing a favorable competitive position; and raising sufficient funds to finance our activities. Many of these factors will depend on circumstances beyond our control. We might not succeed at any of these undertakings. If we are unsuccessful at some or all of these undertakings, our business, prospects, and results of operations may be materially adversely affected. We expect a number of factors to cause our operating results to fluctuate on a quarterly and annual basis, which may make it difficult to predict our future performance. We are a development-stage biopharmaceutical and our operations to date have been primarily limited to developing our technology and undertaking preclinical and nonclinical testing and clinical studies of our latest stage product candidate, TNX-102 SL for FM, Long COVID and potentially other CNS conditions. We have not yet obtained regulatory approvals for TNX-102 SL or any of our other product candidates. Consequently, any predictions made about our future success or viability may not be as accurate as they could be if we had a longer operating history or commercialized products. Our financial condition has varied significantly in the past and will continue to fluctuate from quarter-to-quarter or year-to-year due to a variety of factors, many of which are beyond our control. Factors relating to our business that may contribute to these fluctuations include other factors described elsewhere in this annual report and also include, among other things: ● our ability to obtain additional funding to develop our product candidates; ● delays in the commencement, enrollment and timing of clinical studies; ● the success of our clinical studies through all phases of clinical development, including studies of our most advanced product candidate, TNX-102 SL for FM, Long COVID and potentially other CNS indications; ● any delays in regulatory review and approval of product candidates in clinical development; ● our ability to obtain and maintain regulatory approval for our product candidate TNX-102 SL for FM and Long COVID, TNX-1900 for chronic migraine, TNX-601 ER for depression or any of our other product candidates in the United States and foreign jurisdictions; ● potential nonclinical toxicity and/or side effects of our product candidates that could delay or prevent commercialization, limit the indications for any approved drug, require the establishment of REMS, or cause an approved drug to be taken off the market; ● our ability to establish or maintain collaborations, licensing or other arrangements; ● market acceptance of our product candidates; ● competition from existing products or new products that may emerge; ● the ability of patients or healthcare providers to obtain coverage of or sufficient reimbursement for our products; ● our ability to leverage our proprietary technology platform to discover and develop additional product candidates; 39 ● our ability and our licensors’ abilities to successfully obtain, maintain, defend and enforce intellectual property rights important to our business; and ● potential product liability claims; Accordingly, the results of any quarterly or annual periods should not be relied upon as indications of future operating performance. RISKS RELATED TO PRODUCT DEVELOPMENT, REGULATORY APPROVAL, MANUFACTURING AND COMMERCILAIZATION Our product candidates are novel and still in development. We are a clinical-stage pharmaceutical company focused on the development of drug product candidates, all of which are still in development. Our drug development methods may not lead to commercially viable drugs for any of several reasons. For example, we may fail to identify appropriate targets or compounds, our drug candidates may fail to be safe and effective in clinical studies, or we may have inadequate financial or other resources to pursue development efforts for our drug candidates. Our drug candidates will require significant additional development, clinical studies, regulatory clearances and additional investment by us or our collaborators before they can be commercialized. Further, we and our product candidates are subject to extensive regulation by the FDA and comparable regulatory authorities in other countries governing, among other things, research, testing, clinical studies, manufacturing, labeling, promotion, selling, adverse event reporting and recordkeeping. We are not permitted to market any of our product candidates in the United States until we receive approval of an NDA for a product candidate from the FDA or the equivalent approval from a foreign regulatory authority. Obtaining FDA approval is a lengthy, expensive and uncertain process. We currently have one product candidate, TNX-102 SL, in Phase 3 development for the treatment of FM and Phase 2 development for the treatment of Long COVID, and we have three other products in Phase 2 development for the treatment of chronic migraine, depression and cocaine intoxication. The success of our business currently depends on the successful development, approval and commercialization of our product candidates and TNX-102 SL. Any projected sales or future revenue predictions are predicated upon FDA approval and market acceptance. If projected sales do not materialize for any reason, it would have a material adverse effect on our business and our ability to continue operations. As we have no approved products on the market, we do not expect to generate any revenues from product sales in the foreseeable future, if at all. To date, we have no approved product on the market and have generated no product revenues. We have funded our operations primarily from sales of our securities. We have not received, and do not expect to receive for at least the next couple of years, if at all, any revenues from the commercialization of our product candidates. To obtain revenues from sales of our product candidates, we must succeed, either alone or with third parties, in developing, obtaining regulatory approval for, manufacturing and marketing drugs with commercial potential. We may never succeed in these activities, and we may not generate sufficient revenues to continue our business operations or achieve profitability. We are largely dependent on the success of our lead product candidates, and we cannot be certain that these product candidates will receive regulatory approval or be successfully commercialized. We have not yet submitted an NDA or foreign equivalent or received marketing approval for our lead product candidates anywhere in the world. The clinical development programs may not lead to commercial products for a number of reasons, including if we fail to obtain necessary approvals from the FDA or foreign regulatory authorities because our clinical studies fail to demonstrate to their satisfaction that this product candidate is safe and effective or a clinical program may be put on hold due to unexpected safety issues. We may also fail to obtain the necessary approvals if we have inadequate financial or other resources to advance our product candidates through the clinical study process. Any failure or delay in completing clinical studies or obtaining regulatory approvals for our lead product candidates in a timely manner would have a material adverse impact on our business and our stock price. We may not commence or advance clinical trials for COVID-related products if the COVID-19 disease outbreak subsides. Disease outbreaks are unpredictable. For example, the SARS virus disappeared just four months after it caused a global panic. In the event that COVID-19 has a similar disease cycle, we may be forced to abandon or delay the development of our COVID-related products due to a lack of patients or government funding. Successful development of our products is uncertain. Our development of current and future product candidates is subject to the risks of failure and delay inherent in the development of new pharmaceutical products, including: delays in product development, clinical testing, or manufacturing; unplanned expenditures in product development, clinical testing, or manufacturing; failure to receive regulatory approvals; emergence of superior or equivalent products; inability to manufacture on its own, or through any others, product candidates on a commercial scale; and failure to achieve market acceptance. Because of these risks, our research and development efforts may not result in any commercially viable products. If a significant portion of these development efforts are not successfully completed, required regulatory approvals are not obtained or any approved products are not commercially successfully, our business, financial condition, and results of operations may be materially harmed. Clinical studies required for our product candidates are expensive and time-consuming, and their outcome is uncertain. In order to obtain FDA approval to market a new pharmaceutical product, we must demonstrate proof of safety and effectiveness in humans. To meet these requirements, we must conduct “adequate and well controlled” clinical studies. Conducting clinical studies is a lengthy, time-consuming, and expensive process. The length of time may vary substantially according to the type, complexity, novelty, and intended use of the product candidate, and often can be several years or more per study. Delays associated with products for which we are directly conducting clinical studies may cause us to incur additional operating expenses. The commencement and rate of completion of clinical studies may be delayed by many factors, including, for example: inability to manufacture sufficient quantities of stable and qualified materials under cGMP, for use in clinical studies; slower than expected rates of patient recruitment; failure to recruit a sufficient number of patients; modification of clinical study protocols; changes in regulatory requirements for clinical studies; the lack of effectiveness during clinical studies; the emergence of unforeseen safety issues; delays, suspension, or termination of the clinical studies due to the IRB responsible for overseeing the study at a particular study site; and government or regulatory delays or “clinical holds” requiring suspension or termination of the studies. 40 The results from early clinical studies are not necessarily predictive of results obtained in later clinical studies. Accordingly, even if we obtain positive results from early clinical studies, we may not be able to confirm the results in future clinical studies. In addition, clinical studies may not demonstrate sufficient safety and effectiveness to obtain the requisite regulatory approvals for product candidates. Our clinical studies may be conducted in patients with CNS conditions, and in some cases, our product candidates are expected to be used in combination with approved therapies that themselves have significant adverse event profiles. During the course of treatment, these patients could suffer adverse medical events or die for reasons that may or may not be related to our product candidates. We cannot ensure that safety issues will not arise with respect to our product candidates in clinical development. The failure of clinical studies to demonstrate safety and effectiveness for the desired indications could harm the development of that product candidate and other product candidates. This failure could cause us to abandon a product candidate and could delay development of other product candidates. Any delay in, or termination of, our clinical studies would delay the filing of our NDAs with the FDA and, ultimately, our ability to commercialize our product candidates and generate product revenues. Any change in, or termination of, our clinical studies could materially harm our business, financial condition, and results of operations. We are subject to extensive and costly government regulation. Product candidates employing our technology are subject to extensive and rigorous domestic government regulation including regulation by the FDA, the Centers for Medicare and Medicaid Services, other divisions of the United States Department of Health and Human Services, the United States Department of Justice, state and local governments, and their respective foreign equivalents. The FDA regulates the research, development, preclinical and nonclinical testing and clinical studies, manufacture, safety, effectiveness, record-keeping, reporting, labeling, storage, approval, advertising, promotion, sale, distribution, import, and export of biopharmaceutical products. The FDA regulates small molecule chemical entities as drugs, subject to an NDA under the FDCA. The FDA applies the same standards for biologics, requiring an IND application, followed by a Biologic License Application, or BLA, prior to licensure. Other products, such as vaccines, are also regulated under the Public Health Service Act. FDA has conflated the standards for approval of NDAs and BLAs so that they require the same types of information on safety, effectiveness, and CMCs. If products employing our technologies are marketed abroad, they will also be subject to extensive regulation by foreign governments, whether or not they have obtained FDA approval for a given product and its uses. Such foreign regulation may be equally or more demanding than corresponding United States regulation. Government regulation substantially increases the cost and risk of researching, developing, manufacturing, and selling our products. The regulatory review and approval process, which includes preclinical and nonclinical testing and clinical studies of each product candidate, is lengthy, expensive, and uncertain. We or our collaborators must obtain and maintain regulatory authorization to conduct clinical studies. We or our collaborators must obtain regulatory approval for each product we intend to market, and the manufacturing facilities used for the products must be inspected and meet legal requirements. Securing regulatory approval requires the submission of extensive preclinical, nonclinical and clinical data and other supporting information for each proposed therapeutic indication in order to establish the product’s safety and efficacy, and in the case of biologics also potency and purity, for each intended use. The development and approval process takes many years, requires substantial resources, and may never lead to the approval of a product. Even if we are able to obtain regulatory approval for a particular product, the approval may limit the indicated medical uses for the product, may otherwise limit our ability to promote, sell, and distribute the product, may require that we conduct costly post-marketing surveillance, and/or may require that we conduct ongoing post-marketing studies. Material changes to an approved product, such as, for example, manufacturing changes or revised labeling, may require further regulatory review and approval. Once obtained, any approvals may be withdrawn, including, for example, if there is a later discovery of previously unknown problems with the product, such as a previously unknown safety issue. If we, our collaborators, or our CMOs fail to comply with applicable regulatory requirements at any stage during the regulatory process, such noncompliance could result in, among other things delays in the approval of applications or supplements to approved applications; refusal of a regulatory authority, including the FDA, to review pending market approval applications or supplements to approved applications; warning letters; fines; import and/or export restrictions; product recalls or seizures; injunctions; total or partial suspension of production; civil penalties; withdrawals of previously approved marketing applications or licenses; recommendations by the FDA or other regulatory authorities against governmental contracts; and/or criminal prosecutions. We do not have, and may never obtain, the regulatory approvals we need to market our product candidates. Following completion of clinical studies, the results are evaluated and, depending on the outcome, submitted to the FDA in the form of an NDA or BLA in order to obtain FDA approval of the product and authorization to commence commercial marketing. In responding to an NDA, the FDA may require additional testing or information, may require that the product labeling be modified, may impose post-approval study and other commitments or reporting requirements or other restrictions on product distribution, or may deny the application. The FDA has established performance goals for review of NDAs or BLAs: six months for priority applications and ten months for standard applications. However, the FDA is not required to complete its review within these time periods. The timing of final FDA review and action varies greatly but can take years in some cases and may involve the input of an FDA advisory committee of outside experts. Product sales in the United States may commence only when an NDA or BLA is approved. To date, we have not applied for or received the regulatory approvals required for the commercial sale of any of our products in the United States or in any foreign jurisdiction. None of our product candidates have been determined to be safe and effective, and we have not submitted an NDA or BLA to the FDA or an equivalent application to any foreign regulatory authorities for any of our product candidates. It is possible that none of our product candidates will be approved for marketing. Failure to obtain regulatory approvals, or delays in obtaining regulatory approvals, may adversely affect the successful commercialization of any drugs or biologics that we or our partners develop, may impose additional costs on us or our collaborators, may diminish any competitive advantages that we or our partners may attain, and/or may adversely affect our receipt of revenues or royalties. 41 We have never submitted an NDA before, and may be unable to do so for our product candidates we are developing. The conduct of pivotal clinical studies and the submission of a successful NDA is a complicated process. Although members of our management team have extensive industry experience, including in the development and clinical testing of drug candidates and the commercialization of drug, have limited experience in preparing, submitting and prosecuting regulatory filings, and have not submitted an NDA before. Consequently, we may be unable to successfully and efficiently execute and complete this planned clinical study in a way that leads to NDA submission and approval of our product candidates we are developing. We may require more time and incur greater costs than our competitors and may not succeed in obtaining regulatory approvals of product candidates that we develop. Failure to commence or complete, or delays in, our planned clinical studies would prevent or delay commercialization of TNX-102 SL and other product candidates we are developing. Our product candidates may cause serious adverse events, or SAEs, or undesirable side effects which may delay or prevent marketing approval, or, if approval is received, require them to be taken off the market, require them to include safety warnings or otherwise limit their sales. SAEs or undesirable side effects from any of our other product candidates could arise either during clinical development or, if approved, after the approved product has been marketed. The results of future clinical studies may show that our product candidates cause SAEs or undesirable side effects, which could interrupt, delay or halt clinical studies, resulting in delay of, or failure to obtain, marketing approval from the FDA and other regulatory authorities. If any of our other product candidates cause SAEs or undesirable side effects or suffer from quality control issues: ● regulatory authorities may impose a clinical hold or risk evaluation and mitigation strategies, or REMS, which could result in substantial delays, significantly increase the cost of development, and/or adversely impact our ability to continue development of the product; ● regulatory authorities may require the addition of statements, specific warnings, or contraindications to the product label, or restrict the product’s indication to a smaller potential treatment population; ● we may be required to change the way the product is administered or conduct additional clinical studies; ● we may be required to implement a risk minimization action plan, which could result in substantial cost increases and have a negative impact on our ability to commercialize the product; ● we may be required to limit the participants who can receive the product; ● we may be subject to limitations on how we promote the product; ● we may, voluntarily or involuntarily, initiate field alerts for product recall, which may result in shortages; ● sales of the product may decrease significantly; ● regulatory authorities may require us to take our approved product off the market; ● we may be subject to litigation or product liability claims; and ● our reputation may suffer. Any of these events could prevent us from achieving or maintaining market acceptance of the affected product or could substantially increase commercialization costs and expenses, which in turn could delay or prevent us from generating significant revenues from the sale of our products. If we are unable to file for approval of TNX-102 SL under Section 505(b)(2) of the FDCA or if we are required to generate additional data related to safety and efficacy in order to obtain approval under Section 505(b)(2), we may be unable to meet our anticipated development and commercialization timelines. Our current plans for filing NDAs for our most advanced product candidate, TNX-102 SL, include efforts to minimize the data we will be required to generate in order to obtain marketing approval and therefore reduce the development time. We intend to file Section 505(b)(2) NDAs for TNX-102 SL for FM, Long COVID and for other proposed indications, that might, if accepted by the FDA, save time and expense in the development and testing of TNX-102 SL. TNX-102 SL for FM and other CNS indications is our most advanced development product candidate which is in mid-Phase 3 for FM. The timeline for filing and review of our NDA for TNX-102 SL for FM is based on our plan to submit this NDA under Section 505(b)(2) of the FDCA, which would enable us to rely in part on data in the public domain or elsewhere. We have not yet filed an NDA under Section 505(b)(2) for any of our product candidates. Depending on the data that may be required by the FDA for approval, some of the data may be related to products already approved by the FDA. If the data relied upon is related to products already approved by the FDA and covered by third-party patents, we would be required to certify that we do not infringe the listed patents or that such patents are invalid or unenforceable. As a result of the certification, the third-party would have 45 days from notification of our certification to initiate an action against us. In the event that an action is brought in response to such a certification, the approval of our NDA could be subject to a stay of up to 30 months or more while we defend against such a suit. Approval of our product candidates under Section 505(b)(2) may therefore be delayed until patent exclusivity expires or until we successfully challenge the applicability of those patents to our product candidates. Alternatively, we may elect to generate sufficient additional clinical data so that we no longer rely on data which triggers a potential stay of the approval of our product candidates. Even if no exclusivity periods apply to our applications under Section 505(b)(2), the FDA has broad discretion to require us to generate additional data on the safety and efficacy of our product candidates to supplement third-party data on which we may be permitted to rely. In either event, we could be required, before obtaining marketing approval for any of our product candidates, to conduct substantial new research and development activities beyond those we currently plan to engage in order to obtain approval of our product candidates. Such additional new research and development activities would be costly and time-consuming. 42 We may not be able to realize a shortened development timeline for TNX-102 SL for FM, Long COVID (or other proposed indications under TNX-102 SL), and the FDA may not approve our NDA based on their review of the submitted data. If cyclobenzaprine-containing products are withdrawn from the market by the FDA for any safety reason, we may not be able to reference such products to support a 505(b)(2) NDA for TNX-102 SL, and we may need to fulfill the more extensive requirements of Section 505(b)(1). If we are required to generate additional data to support approval, we may be unable to meet our anticipated development and commercialization timelines, may be unable to generate the additional data at a reasonable cost, or at all, and may be unable to obtain marketing approval of our lead product candidate. Any breakthrough, fast track or orphan drug designation or grant of priority review status by the FDA may not actually lead to a faster development or regulatory review or approval process, nor will it assure FDA approval of our product candidates. Additionally, our product candidates may treat indications that do not qualify for priority review vouchers. If a product candidate offers major advances in treatment, the FDA may designate it eligible for priority review. The FDA has broad discretion whether or not to grant these designations, so even if we believe a particular product candidate is eligible for these designations, we cannot assure you that the FDA would decide to grant them. Even if we do receive fast track designation or priority review, we may not experience a faster development process, review or approval compared to conventional FDA procedures. The FDA may withdraw fast track designation if it believes that the designation is no longer supported by data from our clinical development program. Even if approved, our products will be subject to extensive post-approval regulation. Once a product is approved, numerous post-approval requirements apply. Among other things, the holder of an approved NDA is subject to periodic and other FDA monitoring and reporting obligations, including obligations to monitor and report adverse events and instances of the failure of a product to meet the specifications in the NDA. Application holders must submit new or supplemental applications and obtain FDA approval for certain changes to the approved product, product labeling, or manufacturing process. Application holders must also submit advertising and other promotional material to the FDA and report on ongoing clinical studies. Depending on the circumstances, failure to meet these post-approval requirements can result in criminal prosecution, fines, injunctions, recall or seizure of products, total or partial suspension of production, denial or withdrawal of pre-marketing product approvals, or refusal to allow us to enter into supply contracts, including government contracts. In addition, even if we comply with FDA and other requirements, new information regarding the safety or effectiveness of a product could lead the FDA to modify or withdraw product approval. Even if we obtain regulatory approval to market our product candidates, our product candidates may not be accepted by the market. Even if the FDA approves one or more of our product candidates, physicians and patients may not accept it or use it. Even if physicians and patients would like to use our products, our products may not gain market acceptance among healthcare payors such as managed care formularies, insurance companies or government programs such as Medicare or Medicaid. Acceptance and use of our products will depend upon a number of factors including: perceptions by members of the health care community, including physicians, about the safety and effectiveness of our drug or device product; cost-effectiveness of our product relative to competing products; availability of reimbursement for our product from government or other healthcare payors; and effectiveness of marketing and distribution efforts by us and our licensees and distributors, if any. The degree of market acceptance of any pharmaceutical product that we develop will depend on a number of factors, including: ● cost-effectiveness; ● the safety and effectiveness of our products, including any significant potential side effects (including drowsiness and dry mouth), as compared to alternative products or treatment methods; ● the timing of market entry as compared to competitive products; ● the rate of adoption of our products by doctors and nurses; ● product labeling or product insert required by the FDA for each of our products; ● reimbursement policies of government and third-party payors; ● effectiveness of our sales, marketing and distribution capabilities and the effectiveness of such capabilities of our collaborative partners, if any; and ● unfavorable publicity concerning our products or any similar products. Because we expect sales of our current product candidates, if approved, to generate substantially all of our product revenues for the foreseeable future, the failure of these products to find market acceptance would harm our business and could require us to seek additional financing. We may use our financial and human resources to pursue a particular research program or product candidate and fail to capitalize on programs or product candidates that may be more profitable or for which there is a greater likelihood of success. Because we have limited financial and human resources, we are currently focusing on development of our lead product candidates. As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on existing and future product candidates for specific indications may not yield any commercially viable products. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through strategic alliance, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate, or we may allocate internal resources to a product candidate in a therapeutic area in which it would have been more advantageous to enter into a partnering arrangement. 43 RISKS RELATED TO OUR FINANCIAL CONDITION AND CAPITAL REQUIREMENTS; COMPETITION Our independent registered public accounting firm has included an explanatory paragraph relating to our ability to continue as a going concern in its report on our audited financial statements. We may be unable to continue to operate without the threat of liquidation for the foreseeable future. In connection with our management’s assessment, our report from our independent registered public accounting firm for the fiscal year ended December 31, 2022 includes an explanatory paragraph stating that our recurring losses from operations and net capital deficiency raise substantial doubt about our ability to continue as a going concern. If we are unable to obtain sufficient funding, our business, prospects, financial condition and results of operations will be materially and adversely affected and we may be unable to continue as a going concern. For example, we anticipate that our existing cash and cash equivalents will enable us to maintain our current operations into the fourth quarter of 2023, but not beyond. If we are unable to continue as a going concern, we may have to liquidate our assets and may receive less than the value at which those assets are carried on our consolidated financial statements, and investors will likely lose all or a part of their investment. Future reports from our independent registered public accounting firm may also contain statements expressing substantial doubt about our ability to continue as a going concern. If we seek additional financing to fund our business activities in the future and there remains substantial doubt about our ability to continue as a going concern, investors or other financing sources may be unwilling to provide additional funding on commercially reasonable terms or at all. We will need additional capital. If additional capital is not available or is available at unattractive terms, we may be forced to delay, reduce the scope of or eliminate our research and development programs, reduce our commercialization efforts or curtail our operations. In order to develop and bring our product candidates to market, we must commit substantial resources to costly and time-consuming research, preclinical and nonclinical testing, clinical studies and marketing activities and the buildout of our research and development and manufacturing facilities. We anticipate that our existing cash and cash equivalents will enable us to maintain our current operations into the fourth quarter of 2023, but not beyond. We anticipate using our cash and cash equivalents to fund further research and development with respect to our lead product candidate. We will, however, need to raise additional funding sooner if our business or operations change in a manner that consumes available resources more rapidly than we anticipate. Our requirements for additional capital will depend on many factors, including: ● successful commercialization of our product candidates; ● the time and costs involved in obtaining regulatory approval for our product candidates; ● costs associated with protecting our intellectual property rights; ● development of marketing and sales capabilities; ● payments received under future collaborative agreements, if any; and ● market acceptance of our products. To the extent we raise additional capital through the sale of equity securities, the issuance of those securities could result in dilution to our shareholders. In addition, if we obtain debt financing, a substantial portion of our operating cash flow may be dedicated to the payment of principal and interest on such indebtedness, thus limiting funds available for our business activities. If adequate funds are not available, we may be required to delay, reduce the scope of or eliminate our research and development programs, reduce our commercialization efforts or curtail our operations. In addition, we may be required to obtain funds through arrangements with collaborative partners or others that may require us to relinquish rights to technologies, product candidates or products that we would otherwise seek to develop or commercialize ourselves or license rights to technologies, product candidates or products on terms that are less favorable to us than might otherwise be available. We will require substantial additional funds to support our research and development activities, and the anticipated costs of preclinical and nonclinical testing and clinical studies, regulatory approvals and eventual commercialization. Such additional sources of financing may not be available on favorable terms, if at all. If we do not succeed in raising additional funds on acceptable terms, we may be unable to commence or complete clinical studies or obtain approval of any product candidates from the FDA and other regulatory authorities. In addition, we could be forced to discontinue product development, forego sales and marketing efforts and forego attractive business opportunities. Any additional sources of financing will likely involve the issuance of our equity securities, which will have a dilutive effect on our shareholders. There is no assurance that we will be successful in raising the additional funds needed to fund our business plan. If we are not able to raise sufficient capital in the near future, our continued operations will be in jeopardy and we may be forced to cease operations and sell or otherwise transfer all or substantially all of our remaining assets. Outbreaks of communicable diseases may materially and adversely affect our business, financial condition and results of operations. We may face risks related to health epidemics or outbreaks of communicable diseases. The outbreak of such communicable diseases, such as COVID-19, has and may result in future widespread health crisis that adversely affect general commercial activity and the economies and financial markets of many countries. An outbreak of communicable diseases, or the perception that such an outbreak could occur, and the measures taken by the governments of countries affected could adversely affect our business, financial condition or results of operations. For example, an outbreak could significantly disrupt our business by limiting our ability to travel or ship materials within or outside of an affected country and forcing temporary closure of facilities or service providers that we rely upon. An outbreak could also impact our ability to conduct our ongoing multicenter clinical trials if trial participant attendance at requisite study visits is substantially reduced and if a significant percentage of study participants and study staff are adversely affected by coronavirus or other infections and the resulting disease course. Moreover, government or community shutdowns such as those caused by the COVID-19 pandemic, may impair our ability to analyze and submit the results from our clinical and preclinical trials, leading to further delays in the development and approval of our product candidates. 44 Competition and technological change may make our product candidates and technologies less attractive or obsolete. We compete with established pharmaceutical and biotechnology companies that are pursuing other forms of treatment for the same or similar indications we are pursuing and that have greater financial and other resources. Other companies may succeed in developing products earlier than us, obtaining FDA approval for products more rapidly, or developing products that are more effective than our product candidates. Research and development by others may render our technology or product candidates obsolete or noncompetitive, or result in treatments or cures superior to any therapy we develop. We face competition from companies that internally develop competing technology or acquire competing technology from universities and other research institutions. As these companies develop their technologies, they may develop competitive positions that may prevent, make futile, or limit our product commercialization efforts, which would result in a decrease in the revenue we would be able to derive from the sale of any products. There can be no assurance that any of our product candidates will be accepted by the marketplace as readily as these or other competing treatments. Furthermore, if our competitors’ products are approved before ours, it could be more difficult for us to obtain approval from the FDA. For example, at least three vaccines for the prevention of COVID-19 have been approved to date, and we expect that other vaccines will be approved prior to the approval of our COVID-19 vaccine candidate, if it is approved at all. Even if our products are successfully developed and approved for use by all governing regulatory bodies, there can be no assurance that physicians and patients will accept our product(s) as a treatment of choice. Additionally, if a competitor receives FDA approval before we do for a drug that is similar to one of our product candidates, FDA approval for our product candidate may be precluded or delayed due to periods of non-patent exclusivity and/or the listing with the FDA by the competitor of patents covering its newly-approved drug product. Periods of non-patent exclusivity for new versions of existing drugs such as our current drug product candidate, TNX-102 SL, can extend up to three and one-half years. Furthermore, the pharmaceutical research industry is diverse, complex, and rapidly changing. By its nature, the business risks associated therewith are numerous and significant. The effects of competition, intellectual property disputes, market acceptance, and FDA regulations preclude us from forecasting revenues or income with certainty or even confidence. RISKS RELATED TO OUR INTELLECTUAL PROPERTY RIGHTS AND REGULATORY EXCLUSIVITY If we fail to protect our intellectual property rights, our ability to pursue the development of our technologies and products would be negatively affected. Our success will depend in part on our ability to obtain patents and maintain adequate protection of our technologies and products. If we do not adequately protect our intellectual property, competitors may be able to use our technologies to produce and market drugs using our technologies and patents in direct competition with us and erode our competitive advantage. Some foreign countries lack rules and methods for defending intellectual property rights and do not protect proprietary rights to the same extent as the United States. Many companies have had difficulty protecting their proprietary rights in these foreign countries. We may not be able to prevent misappropriation of our proprietary rights and intellectual property rights in these and other countries. We have received, and are currently seeking, patent protection for numerous compounds and methods of treating diseases. However, the patent process is subject to numerous risks and uncertainties, and there can be no assurance that we will be successful in protecting our products by obtaining and defending patents related to them. These risks and uncertainties include the following: patents that may be issued or licensed may be challenged, invalidated, or circumvented, or otherwise may not provide us any competitive advantage; our competitors, many of which have substantially greater resources than we and many of which have made significant investments in competing technologies, may seek, or may already have obtained, patents that will limit, interfere with, or eliminate our ability to make, use, and sell our potential products either in the United States or in international markets; there may be significant pressure on the United States government and other international governmental bodies to limit the scope of patent protection both inside and outside the United States for treatments that prove successful as a matter of public policy regarding worldwide health concerns; and countries other than the United States may have less robust patent laws than those upheld by United States courts, allowing foreign competitors the ability to exploit these laws to create, develop, and market competing products using our technologies and patents. Moreover, any patents issued to us may not provide us with meaningful protection, or others may challenge, circumvent or narrow our patents. Third parties may also independently develop products similar to our products, duplicate our unpatented products or design around any patents or propriety technologies on products we develop. Additionally, extensive time is required for development, testing and regulatory review of a potential product. While extensions of patent term due to regulatory delays may be available, it is possible that, before any of our product candidates can be commercialized, any related patent, even with an extension, may expire or remain in force for only a short period following commercialization, thereby reducing any advantages to us of the patent. In addition, the PTO and patent offices in other jurisdictions have often required that patent applications concerning pharmaceutical and/or biotechnology-related inventions be limited or narrowed substantially to cover only the innovations specifically exemplified in the patent application, thereby limiting the scope of protection against competitive challenges. Thus, even if we or our licensors are able to obtain patents, the patents may be substantially narrower than anticipated. Our success depends on our patents and patent applications that may be licensed exclusively to us and other patents and patent applications to which we may obtain assignment or licenses. We may not be aware, however, of all patents, published applications or published literature that may affect our business either by blocking our ability to commercialize our product candidates, by preventing the patentability of our product candidates to us or our licensors, or by covering the same or similar technologies. These patents, patent applications, and published literature may limit the scope of our future patent claims or adversely affect our ability to market our product candidates. In addition to patents, we rely on a combination of trade secrets, confidentiality, nondisclosure and other contractual provisions, and security measures to protect our confidential and proprietary information. These measures may not adequately protect our trade secrets or other proprietary information. If they do not adequately protect our rights, third parties could use our technology, and we could lose any competitive advantage we may have. In addition, others may independently develop similar proprietary information or techniques or otherwise gain access to our trade secrets, which could impair any competitive advantage we may have. Patent protection and other intellectual property protection is crucial to the success of our business and prospects, and there is a substantial risk that such protections will prove inadequate. 45 We may be involved in lawsuits to protect or enforce our patents, which could be expensive and time consuming. The pharmaceutical industry has been characterized by extensive litigation regarding patents and other intellectual property rights, and companies have employed intellectual property litigation to gain a competitive advantage. We may become subject to infringement claims or litigation arising out of present and future patents and other proceedings of our competitors. The defense and prosecution of intellectual property suits are costly and time-consuming to pursue, and their outcome is uncertain. Litigation may be necessary to determine the enforceability, scope, and validity of the proprietary rights of others. An adverse determination in litigation to which we may become a party could subject us to significant liabilities, require us to obtain licenses from third parties, or restrict or prevent us from selling our products in certain markets. Although patent and intellectual property disputes might be settled through licensing or similar arrangements, the costs associated with such arrangements may be substantial and could include our paying large fixed payments and ongoing royalties. Furthermore, the necessary licenses may not be available on satisfactory terms or at all. Competitors may infringe our patents, and we may file infringement claims to counter infringement or unauthorized use. Third parties may assert that our patents are invalid and/or unenforceable in these proceedings. Such litigation can be expensive, particularly for a company of our size, and time-consuming. In addition, in an infringement proceeding, a court may decide that a patent of ours is not valid or is unenforceable, or may refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover its technology. An adverse determination of any litigation or defense proceedings could put one or more of our patents at risk of being invalidated or interpreted narrowly. Third parties may also assert that our patents are invalid in patent office administrative proceedings. These proceedings include oppositions in the European Patent Office and inter partes review and post-grant review proceedings in the PTO. The success rate of these administrative challenges to patent validity in the United States is higher than it is for validity challenges in litigation. Interference or derivation proceedings brought before the PTO may be necessary to determine priority of invention with respect to innovations disclosed in our patents or patent applications. During these proceedings, it may be determined that we do not have priority of invention for one or more aspects in our patents or patent applications and could result in the invalidation in part or whole of a patent or could put a patent application at risk of not issuing. Even if successful, an interference or derivation proceeding may result in substantial costs and distraction to our management. Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation or interference or derivation proceedings, there is a risk that some of our confidential information could be compromised by disclosure. In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments. If investors perceive these results to be negative, the price of our common stock could be adversely affected. Except for the oppositions to European Patents 2501234, 2968992, and 2683245 (the Opposition Division in each of those oppositions maintained our claims in unamended form; Opponent has appealed that decision in the ‘234 Opposition and we expect the opponents to appeal the decisions in the ‘992 and ‘245 oppositions), there are no unresolved communications, allegations, complaints or threats of litigation related to the possibility that our patents are invalid or unenforceable. Any litigation or claims against us, whether or not merited, may result in substantial costs, place a significant strain on our financial resources, divert the attention of management and harm our reputation. An adverse decision in litigation or administrative proceedings could result in inadequate protection for our product candidates and/or reduce the value of any license agreements we have with third parties. If we infringe the rights of third parties we could be prevented from selling products, forced to pay damages, and defend against litigation. If our products, methods, processes and other technologies infringe the proprietary rights of other parties, we could incur substantial costs and we may have to: obtain licenses, which may not be available on commercially reasonable terms, if at all; abandon an infringing product candidate; redesign our products or processes to avoid infringement; stop using the subject matter claimed in the patents held by others; pay damages; and/or defend litigation or administrative proceedings which may be costly whether we win or lose, and which could result in a substantial diversion of our financial and management resources. There are risks to our intellectual property based on our international business initiatives. We may face risks to our technology and intellectual property as a result of our conducting strategic business discussions outside of the United States, and particularly in jurisdictions that do not have comparable levels of protection of corporate proprietary information and assets such as intellectual property, trademarks, trade secrets, know-how and customer information and records. While these risks are common to many companies, conducting business in certain foreign jurisdictions, housing technology, data and intellectual property abroad, or licensing technology to joint ventures with foreign partners may have more significant exposure. For example, we have shared intellectual properties with entities in China pursuant to confidentiality agreements in connection with discussions on potential strategic collaborations, which may expose us to material risks of theft of our proprietary information and other intellectual property, including technical data, manufacturing processes, data sets or other sensitive information. For example, our technology may be reverse engineered by the parties or other parties, which could result in our patents being infringed or our know-how or trade secrets stolen. The risk can be by direct intrusion wherein technology and intellectual property is stolen or compromised through cyber intrusions or physical theft through corporate espionage, including with the assistance of insiders, or via more indirect routes. GENERAL COMPANY-RELATED RISKS If preclinical and nonclinical testing or clinical studies for our product candidates are unsuccessful or delayed, we will be unable to meet our anticipated development and commercialization timelines. We rely and expect to continue to rely on third parties, including contract research organizations, or CROs, and outside consultants, to conduct, supervise or monitor some or all aspects of preclinical and nonclinical testing and clinical studies involving our product candidates. We have less control over the timing and other aspects of these preclinical and nonclinical testing activities and clinical studies than if we performed the monitoring and supervision entirely on our own. Third parties may not perform their responsibilities for our preclinical and nonclinical testing and clinical studies on our anticipated schedule or, for clinical studies, consistent with a clinical study protocol. Delays in preclinical and nonclinical testing, and clinical studies could significantly increase our product development costs and delay product commercialization. In addition, many of the factors that may cause, or lead to, a delay in the clinical studies may also ultimately lead to denial of regulatory approval of a product candidate. 46 The commencement of clinical studies can be delayed for a variety of reasons, including delays in: ● demonstrating sufficient safety and efficacy to obtain regulatory approval to commence a clinical study; ● reaching agreement on acceptable terms with prospective CROs and study sites; ● developing a stable formulation of a product candidate; ● manufacturing sufficient quantities of a product candidate; and ● obtaining institutional review board, or IRB, approval to conduct a clinical study at a prospective site. Once a clinical study has begun, it may be delayed, suspended or terminated by us or the FDA or other regulatory authorities due to a number of factors, including: ● ongoing discussions with the FDA or other regulatory authorities regarding the scope or design of our clinical studies; ● failure to conduct clinical studies in accordance with regulatory requirements; ● lower than anticipated recruitment or retention rate of patients in clinical studies; ● inspection of the clinical study operations or study sites by the FDA or other regulatory authorities resulting in the imposition of a clinical hold; ● lack of adequate funding to continue clinical studies; ● negative results of clinical studies; ● investigational drug product out-of-specification; or ● nonclinical or clinical safety observations, including adverse events and SAEs. If clinical studies are unsuccessful, and we are not able to obtain regulatory approvals for our product candidates under development, we will not be able to commercialize these products, and therefore may not be able to generate sufficient revenues to support our business. We rely on third parties to conduct, supervise and monitor our clinical studies, and if those third parties perform in an unsatisfactory manner, it may harm our business. We rely on CROs and clinical study sites to ensure the proper and timely conduct of our clinical studies. While we have agreements governing their activities, we will have limited influence over their actual performance. We will control only certain aspects of our CROs’ activities. Nevertheless, we will be responsible for ensuring that our clinical studies are conducted in accordance with the applicable protocol, legal, regulatory and scientific standards and our reliance on the CROs does not relieve us of our regulatory responsibilities. We and our CROs are required to comply with the FDA’s cGCP for conducting, recording and reporting the results of clinical studies to assure that data and reported results are credible and accurate and that the rights, integrity and confidentiality of clinical study participants are protected. The FDA enforces these cGCPs through periodic inspections of study sponsors, principal investigators and clinical study sites. If we or our CROs fail to comply with applicable cGCPs, the clinical data generated in our clinical studies may be deemed unreliable and the FDA may require us to perform additional clinical studies before approving any marketing applications. Upon inspection, the FDA may determine that our clinical studies did not comply with cGCPs. In addition, our clinical studies, including our ongoing Phase 3 RESILIENT study, will require a sufficiently large number of fibromyalgia participants to evaluate the effectiveness and safety of TNX-102 SL in FM. Accordingly, if our CROs fail to comply with these regulations or fail to recruit a sufficient number of participants, our clinical studies may be delayed or we may be required to repeat such clinical studies, which would delay the regulatory approval process. Our CROs are not our employees, and we are not able to control whether or not they devote sufficient time and resources to our clinical studies. These CROs may also have relationships with other commercial entities, including our competitors, for whom they may also be conducting clinical studies, or other drug development activities which could harm our competitive position. If our CROs do not successfully carry out their contractual duties or obligations, fail to meet expected deadlines, or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols or regulatory requirements, or for any other reasons, our clinical studies may be extended, delayed or terminated, and we may not be able to obtain regulatory approval for, or successfully commercialize our product candidates. As a result, our financial results and the commercial prospects for such product candidates would be harmed, our costs could increase, and our ability to generate revenues could be delayed. We also rely on other third parties to store and distribute drug products for our clinical studies. Any performance failure on the part of our distributors could delay clinical development or marketing approval of our product candidates or commercialization of our products, if approved, producing additional losses and depriving us of potential product revenue. We will need to expand our operations and increase the size of our company, and we may experience difficulties in managing growth. As we advance our product candidates through preclinical and nonclinical testing and clinical studies, and develop new product candidates and buildout of our research and development and manufacturing facilities, we will need to increase our product development, scientific, regulatory and compliance and administrative headcount to manage these programs. In addition, to meet our obligations as a public company, we will need to increase our general and administrative capabilities. Our management, personnel and systems currently in place may not be adequate to support this future growth. Our need to effectively manage our operations, growth and various projects requires that we: ● successfully attract and recruit new employees with the expertise and experience we will require; 47 ● manage our clinical programs effectively, which we anticipate being conducted at numerous clinical sites; ● develop a marketing, distribution and sales infrastructure in addition to a post-marketing surveillance program if we seek to market our products directly; and ● continue to improve our operational, manufacturing, quality assurance, financial and management controls, reporting systems and procedures. If we are unable to successfully manage this growth and increased complexity of operations, our business may be adversely affected. Our executive officers and other key personnel are critical to our business, and our future success depends on our ability to retain them. Our success depends to a significant extent upon the continued services of Dr. Seth Lederman, our President and Chief Executive Officer and Dr. Gregory M. Sullivan, our Chief Medical Officer. Dr. Lederman has overseen Tonix Pharmaceuticals, Inc., a wholly-owned subsidiary, since inception and provides leadership for our growth and operations strategy as well as being an inventor on many of our patents. Dr. Sullivan has served as our Chief Medical Officer since 2014 and directed the Phase 2 AtEase study, Phase 3 HONOR study, the Phase 3 RECOVERY study, Phase 3 RELIEF study, the Phase 3 RALLY study and the Phase 3 RESILIENCE study. Loss of the services of Drs. Lederman or Sullivan would have a material adverse effect on our growth, revenues, and prospective business. The loss of any of our key personnel, or the inability to attract and retain qualified personnel, may significantly delay or prevent the achievement of our research, development or business objectives and could materially adversely affect our business, financial condition and results of operations. Any employment agreement we enter into will not ensure the retention of the employee who is a party to the agreement. In addition, we have only limited ability to prevent former employees from competing with us. Furthermore, our future success will also depend in part on the continued service of our key scientific and management personnel and our ability to identify, hire, and retain additional personnel. We experience intense competition for qualified personnel and may be unable to attract and retain the personnel necessary for the development of our business. Moreover, competition for personnel with the scientific and technical skills that we seek is extremely high and is likely to remain high. Because of this competition, our compensation costs may increase significantly. If we are unable to hire additional qualified personnel, our ability to grow our business may be harmed. Over time we will need to hire additional qualified personnel with expertise in drug development, product registration, clinical, preclinical and nonclinical research, quality compliance, government regulation, formulation and manufacturing, financial matters and sales and marketing. We compete for qualified individuals with numerous biopharmaceutical companies, universities and other research institutions. Competition for such individuals is intense, and we cannot be certain that our search for such personnel will be successful. Attracting and retaining qualified personnel will be critical to our success. We rely on third parties to manufacture the compounds used in our studies, and we intend to rely on them for the manufacture of any approved products for commercial sale. If these third parties do not manufacture our product candidates in sufficient quantities and at an acceptable cost, clinical development and commercialization of our product candidates could be delayed, prevented or impaired. We have no experience in the clinical or commercial-scale manufacture of drugs or in designing drug manufacturing processes. We intend to rely on CMOs to manufacture some or all of our product candidates in clinical studies and our products that reach commercialization. Completion of our clinical studies and commercialization of our product candidates requires the manufacture of a sufficient supply of our product candidates. We have contracted with outside sources to manufacture our development compounds. If, for any reason, we become unable to rely on our current sources for the manufacture of our product candidates, either for clinical studies or, at some future date, for commercial quantities, then we would need to identify and contract with additional or replacement third-party manufacturers to manufacture compounds for nonclinical, preclinical, clinical, and commercial purposes. Although we are in discussions with other manufacturers we have identified as potential alternative CMOs of TNX-102 SL, we may not be successful in negotiating acceptable terms with any of them. We believe that there are a variety of manufacturers that we may be able to retain to produce these products. However, once we retain a manufacturing source, if our manufacturers do not perform in a satisfactory manner, we may not be able to develop or commercialize potential products as planned. Certain specialized manufacturers are expected to provide us with modified and unmodified pharmaceutical compounds, including finished products, for use in our preclinical and nonclinical testing and clinical studies. Some of these materials are available from only one supplier or vendor. Any interruption in or termination of service by such sole source suppliers could result in a delay or interruption in manufacturing until we locate an alternative source of supply. Any delay or interruption in manufacturing operations (or failure to locate a suitable replacement for such suppliers) could materially adversely affect our business, prospects, or results of operations. We do not have any short-term or long-term manufacturing agreements with many of these manufacturers. If we fail to contract for manufacturing on acceptable terms or if third-party manufacturers do not perform as we expect, our development programs could be materially adversely affected. This may result in delays in filing for and receiving FDA approval for one or more of our products. Any such delays could cause our prospects to suffer significantly. Failure by our third-party manufacturers to comply with the regulatory guidelines set forth by the FDA with respect to our product candidates could delay or prevent the completion of clinical studies, the approval of any product candidates or the commercialization of our products. Such third-party manufacturers must be inspected by FDA for cGMP compliance before they can produce commercial product. We may be in competition with other companies for access to these manufacturers’ facilities and may be subject to delays in manufacture if the manufacturers give other clients higher priority than they give to us. If we are unable to secure and maintain third-party manufacturing capacity, the development and sales of our products and our financial performance may be materially affected. 48 Manufacturers are obligated to operate in accordance with FDA-mandated requirements. A failure of any of our third-party manufacturers to establish and follow cGMP requirements and to document their adherence to such practices may lead to significant delays in the availability of material for clinical studies, may delay or prevent filing or approval of marketing applications for our products, and may cause delays or interruptions in the availability of our products for commercial distribution following FDA approval. This could result in higher costs to us or deprive us of potential product revenues. Drug manufacturers are subject to ongoing periodic unannounced inspections by the FDA, the Drug Enforcement Administration, or DEA, and corresponding state and foreign agencies to ensure strict compliance with cGMP requirements and other requirements under Federal drug laws, other government regulations and corresponding foreign standards. If we or our third-party manufacturers fail to comply with applicable regulations, sanctions could be imposed on us, including fines, injunctions, civil penalties, failure by the government to grant marketing approval of drugs, delays, suspension or withdrawal of approvals, seizures or recalls of product, operating restrictions and criminal prosecutions. Adverse global conditions, including economic uncertainty, may negatively impact our financial results. Global conditions, dislocations in the financial markets, or inflation could adversely impact our business. In addition, the global macroeconomic environment has been and may continue to be negatively affected by, among other things, instability in global economic markets, increased U.S. trade tariffs and trade disputes with other countries, instability in the global credit markets, supply chain weaknesses, instability in the geopolitical environment as a result of the Russian invasion of the Ukraine, the withdrawal of the United Kingdom from the European Union, and other political tensions, and foreign governmental debt concerns. Such challenges have caused, and may continue to cause, uncertainty and instability in local economies and in global financial markets, which may adversely affect our business. Our internal computer systems, or those of our CROs or other contractors or consultants, may fail or suffer security breaches, which could result in a material disruption of our product development programs. Despite the implementation of security measures, our internal computer systems and those of our CROs and other contractors and consultants are vulnerable to damage or disruption from computer viruses, software bugs, unauthorized access, natural disasters, terrorism, war, and telecommunication, equipment and electrical failures. While we have not, to our knowledge, experienced any significant system failure, accident or security breach to date, if such an event were to occur and cause interruptions in our operations, it could result in a material disruption of our programs. For example, the loss of clinical trial data from completed or ongoing clinical trials for any of our product candidates could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. Moreover, our information security systems and those of our CROs are also subject to laws and regulations requiring that we take measures to protect the privacy and security of certain information gathered and used in our business. For example, HIPAA and its implementing regulations impose, among other requirements, certain regulatory and contractual requirements regarding the privacy and security of personal health information. In the European Union the General Data Protection Regulation, or GDPR, is even more restrictive with respect to all personal information, including information masked by a coding system. In addition to HIPAA and GDPR, numerous other federal and state laws, including, without limitation, state security breach notification laws, state health information privacy laws and federal and state consumer protection laws, govern the collection, use, disclosure and storage of personal information. To the extent that any disruption or security breach results in a loss of or damage to our data or applications, or inappropriate disclosure or theft of confidential or proprietary information, we could incur liability, the further development of our product candidates could be delayed, our competitive position could be compromised, or our business reputation could be harmed. Corporate and academic collaborators may take actions to delay, prevent, or undermine the success of our products. Our operating and financial strategy for the development, clinical testing, manufacture, and commercialization of drug candidates is heavily dependent on our entering into collaborations with corporations, academic institutions, licensors, licensees, and other parties. Our current strategy assumes that we will successfully establish these collaborations, or similar relationships; however, there can be no assurance that we will be successful establishing such collaborations. Some of our existing collaborations are, and future collaborations may be, terminable at the sole discretion of the collaborator. Replacement collaborators might not be available on attractive terms, or at all. The activities of any collaborator will not be within our control and may not be within our power to influence. There can be no assurance that any collaborator will perform its obligations to our satisfaction or at all, that we will derive any revenue or profits from such collaborations, or that any collaborator will not compete with us. If any collaboration is not pursued, we may require substantially greater capital to undertake development and marketing of our proposed products and may not be able to develop and market such products effectively, if at all. In addition, a lack of development and marketing collaborations may lead to significant delays in introducing proposed products into certain markets and/or reduced sales of proposed products in such markets. Data provided by collaborators and others upon which we rely that has not been independently verified could turn out to be false, misleading, or incomplete. We rely on third-party vendors, scientists, and collaborators to provide us with significant data and other information related to our projects, clinical studies, and our business. If such third parties provide inaccurate, misleading, or incomplete data, our business, prospects, and results of operations could be materially adversely affected. Our product candidates may face competition sooner than expected. We intend to seek data exclusivity or market exclusivity for our product candidates provided under the FDCA and similar laws in other countries. We believe that TNX-801 could qualify for 12 years of data exclusivity under the Biologics Price Competition and Innovation Act of 2009, or BPCIA, which was enacted as part of the Patient Protection and Affordable Care Act. Under the BPCIA, an application for a biosimilar product or BLA cannot be submitted to the FDA until four years, or if approved by the FDA, until 12 years, after the original brand product identified as the reference product is approved under a BLA. The BPCIA provides an abbreviated pathway for the approval of biosimilar and interchangeable biological products. The new abbreviated regulatory pathway establishes legal authority for the FDA to review and approve biosimilar biologics, including the possible designation of a biosimilar as “interchangeable” based on its similarity to an existing brand product. The new law is complex and is only beginning to be interpreted and implemented by the FDA. While it is uncertain when any such processes may be fully adopted by the FDA, any such processes could have a material adverse effect on the future commercial prospects for any of our product candidates that are biologics. There is also a risk that BPCIA could be repealed or amended to shorten this exclusivity period, potentially creating the opportunity for biosimilar competition sooner than anticipated after the expiration of our patent protection. Although there is no current discussion of repeal or modification of the BPCIA, the future remains uncertain. Moreover, the extent to which a biosimilar, once approved, will be substituted for any reference product in a way that is similar to traditional generic substitution for non-biological products is not yet clear, and will depend on a number of marketplace and regulatory factors that are still developing. 49 Our product candidates that are not, or are not considered, biologics that would qualify for exclusivity under the BPCIA may be eligible for market exclusivity as drugs under the FDCA. The FDCA provides a five-year period of non-patent marketing exclusivity within the U.S. to the first applicant to gain approval of an NDA for an NCE. A drug is an NCE if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not accept for review an abbreviated new drug application, or ANDA, or a 505(b)(2) NDA, submitted by another company for another version of such drug where the applicant does not own or have a legal right of reference to all the data required for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement. The FDCA also provides three years of marketing exclusivity for an NDA, 505(b)(2) NDA or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example, for new indications, dosages, or strengths of an existing drug. This three-year exclusivity covers only the conditions associated with the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the original active agent. Even if, as we expect, our product candidates are considered to be reference products eligible for 12 years of exclusivity under the BPCIA or five years of exclusivity under the FDCA, another company could market competing products if the FDA approves a full BLA or full NDA for such product containing the sponsor’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of the products. Moreover, an amendment or repeal of the BPCIA could result in a shorter exclusivity period for our product candidates, which could have a material adverse effect on our business. If we fail to establish marketing, sales and distribution capabilities, or fail to enter into arrangements with third parties, we will not be able to create a market for our product candidates. Our strategy with our product candidates is to control, directly or through contracted third parties, all or most aspects of the product development process, including marketing, sales and distribution. Currently, we do not have any sales, marketing or distribution capabilities. In order to generate sales of any product candidates that receive regulatory approval, we must either acquire or develop an internal marketing and sales force with technical expertise and with supporting distribution capabilities or make arrangements with third parties to perform these services for us. The acquisition or development of a sales and distribution infrastructure would require substantial resources, which may divert the attention of our management and key personnel and defer our product development efforts. To the extent that we enter into marketing and sales arrangements with other companies, our revenues will depend on the efforts of others. These efforts may not be successful. If we fail to develop sales, marketing and distribution channels, or enter into arrangements with third parties, we will experience delays in product sales and incur increased costs. Sales of pharmaceutical products largely depend on the reimbursement of patients’ medical expenses by government health care programs and private health insurers. Without the financial support of the government or third-party payors, the market for our products will be limited. These third-party payors are increasingly challenging the price and examining the cost effectiveness of medical products and services. Recent proposals to change the health care system in the United States have included measures that would limit or eliminate payments for medical products and services or subject the pricing of medical treatment products to government control. Significant uncertainty exists as to the reimbursement status of newly approved health care products. Third-party payors may not reimburse sales of our products or enable our collaborators to sell them at profitable prices. Our business strategy might involve out-licensing product candidates to or collaborating with larger firms with experience in marketing and selling pharmaceutical products. There can be no assurance that we will be able to successfully establish marketing, sales, or distribution relationships; that such relationships, if established, will be successful; or that we will be successful in gaining market acceptance for our products. To the extent that we enter into any marketing, sales, or distribution arrangements with third parties, our product revenues will be lower than if we marketed and sold our products directly, and any revenues we receive will depend upon the efforts of such third-parties. If we are unable to establish such third-party sales and marketing relationships, or choose not to do so, we will have to establish and rely on our own in-house capabilities. We, as a company, have no experience in marketing or selling pharmaceutical products and currently have no sales, marketing, or distribution infrastructure. To market any of our products directly, we would need to develop a marketing, sales, and distribution force that both has technical expertise and the ability to support a distribution capability. The establishment of a marketing, sales, and distribution capability would significantly increase our costs, possibly requiring substantial additional capital. In addition, there is intense competition for proficient sales and marketing personnel, and we may not be able to attract individuals who have the qualifications necessary to market, sell, and distribute our products. There can be no assurance that we will be able to establish internal marketing, sales, or distribution capabilities. If we are unable to, or choose not to establish these capabilities, or if the capabilities we establish are not sufficient to meet our needs, we will be required to establish collaborative marketing, sales, or distribution relationships with third parties. Our relationships with customers, physicians, and third-party payors will be subject, directly or indirectly, to federal and state healthcare fraud and abuse laws, false claims laws, health information privacy and security laws, and other healthcare laws and regulations. If we are unable to comply, or have not fully complied, with such laws, we could face substantial penalties. Healthcare providers, physicians and third-party payors in the United States and elsewhere will play a primary role in the recommendation and prescription of any drug candidates for which we obtain marketing approval. Our current and future arrangements with healthcare professionals, principal investigators, consultants, customers and third-party payors may subject us to various federal and state fraud and abuse laws and other health care laws, including, without limitation, the federal Anti-Kickback Statute, the federal civil and criminal false claims laws and the law commonly referred to as the Physician Payments Sunshine Act and regulations. These laws will impact, among other things, our clinical research, proposed sales, marketing and educational programs. In addition, we may be subject to patient privacy laws by both the federal government and the states in which we conduct or may conduct our business. The laws that will affect our operations include, but are not limited to: ● the federal Anti-Kickback Statute, which prohibits, among other things, persons or entities from knowingly and willfully soliciting, receiving, offering or paying any remuneration (including any kickback, bribe or rebate), directly or indirectly, overtly or covertly, in cash or in kind, in return for the purchase, recommendation, leasing or furnishing of an item or service reimbursable under a federal healthcare program, such as the Medicare and Medicaid programs; 50 ● federal civil and criminal false claims laws, including, without limitation, the False Claims Act, and civil monetary penalty laws which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment or approval from Medicare, Medicaid or other government payors that are false or fraudulent or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government; ● the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created new federal criminal statutes that prohibit a person from knowingly and willfully executing a scheme or making false or fraudulent statements to defraud any healthcare benefit program, regardless of the payor (e.g., public or private); ● HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and its implementing regulations, and as amended again by the final HIPAA omnibus rule, Modifications to the HIPAA Privacy, Security, Enforcement, and Breach Notification Rules Under HITECH and the Genetic Information Nondiscrimination Act; Other Modifications to HIPAA, published in January 2013, which imposes certain requirements relating to the privacy, security and transmission of individually identifiable health information without appropriate authorization by entities subject to the rule, such as health plans, health care clearinghouses and health care providers, and their respective business associates; ● federal transparency laws, including the federal Physician Payments Sunshine Act, which is part of PPACA, that require certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to report annually to the Centers for Medicare & Medicaid Services, or CMS, information related to: (i) payments or other “transfers of value’’ made to physicians and teaching hospitals; and (ii) ownership and investment interests held by physicians and their immediate family members; ● state and foreign law equivalents of each of the above federal laws, state laws that require manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures, and state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government or to adopt compliance programs as prescribed by state laws and regulations, or that otherwise restrict payments that may be made to healthcare providers; and ● state and foreign laws that govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts. Because of the breadth of these laws and the narrowness of the statutory exceptions and safe harbors available, it is possible that some of our business activities could be subject to challenge under one or more of such laws. It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, disgorgement, imprisonment, exclusion of drugs from government funded healthcare programs, such as Medicare and Medicaid, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws and the curtailment or restructuring of our operations. The risk of our being found in violation of these laws is increased by the fact that many of them have not been fully interpreted by the regulatory authorities or the courts, and their provisions are open to a variety of interpretations. Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs. Any action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business. The shifting compliance environment and the need to build and maintain robust and expandable systems to comply with multiple jurisdictions with different compliance and/or reporting requirements increases the possibility that a healthcare company may run afoul of one or more of the requirements. Coverage and adequate reimbursement may not be available for our current or any future drug candidates, which could make it difficult for us to sell profitably, if approved. Market acceptance and sales of any drug candidates that we commercialize, if approved, will depend in part on the extent to which reimbursement for these drugs and related treatments will be available from third-party payors, including government health administration authorities, managed care organizations and other private health insurers. Third-party payors decide which therapies they will pay for and establish reimbursement levels. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own coverage and reimbursement policies. However, decisions regarding the extent of coverage and amount of reimbursement to be provided for any drug candidates that we develop will be made on a payor-by-payor basis. One payor’s determination to provide coverage for a drug does not assure that other payors will also provide coverage, and adequate reimbursement, for the drug. Additionally, a third-party payor’s decision to provide coverage for a therapy does not imply that an adequate reimbursement rate will be approved. Each payor determines whether or not it will provide coverage for a therapy, what amount it will pay the manufacturer for the therapy, and on what tier of its formulary it will be placed. The position on a payor’s list of covered drugs, or formulary, generally determines the co-payment that a patient will need to make to obtain the therapy and can strongly influence the adoption of such therapy by patients and physicians. Patients who are prescribed treatments for their conditions and providers prescribing such services generally rely on third-party payors to reimburse all or part of the associated healthcare costs. Patients are unlikely to use our drugs unless coverage is provided and reimbursement is adequate to cover a significant portion of the cost of our drugs. A primary trend in the U.S. healthcare industry and elsewhere is cost containment. Third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications. We cannot be sure that coverage and reimbursement will be available for any drug that we commercialize and, if reimbursement is available, what the level of reimbursement will be. Inadequate coverage and reimbursement may impact the demand for, or the price of, any drug for which we obtain marketing approval. If coverage and adequate reimbursement are not available, or are available only to limited levels, we may not be able to successfully commercialize our current and any future drug candidates that we develop. 51 Healthcare legislative or regulatory reform measures, including government restrictions on pricing and reimbursement, may have a negative impact on our business and results of operations. In the United States and some foreign jurisdictions, there have been, and continue to be, several legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of product candidates, restrict or regulate post-approval activities, and affect our ability to profitably sell any product candidates for which we obtain marketing approval. Among policy makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access. In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives. For example, in the United States, the Patient Protection and Affordable Care Act of 2010 (“ACA”) substantially changed the way healthcare is financed by both the government and private insurers , and significantly affects the pharmaceutical industry. Many provisions of the ACA impact the biopharmaceutical industry, including that in order for a biopharmaceutical product to receive federal reimbursement under the Medicare Part B and Medicaid programs or to be sold directly to U.S. government agencies, the manufacturer must extend discounts to entities eligible to participate in the drug pricing program under the Public Health Services Act, or PHS. Additionally, the Inflation Reduction Act of 2022, which took in 2023, includes policies that are designed to have a direct impact on drug prices and reduce drug spending by the federal government. This legislation contains substantial drug pricing reforms, including the establishment of a drug price negotiation program within the U.S. Department of Health and Human Services that would require manufacturers to charge a negotiated “maximum fair price” for certain selected drugs covered by Medicare or pay an excise tax for noncompliance, the establishment of rebate payment requirements on manufacturers of certain drugs payable under Medicare Parts B and D to penalize price increases that outpace inflation, and requires manufacturers to provide discounts on Part D drugs. Legislative, administrative, and private payor efforts to control drug costs span a range of proposals, including drug price negotiation, Medicare Part D redesign, drug price inflation rebates, international mechanisms, generic drug promotion and anticompetitive behavior, manufacturer reporting, and reforms that could impact therapies utilizing the accelerated approval pathway. We cannot predict the ultimate content, timing or effect of any changes to the ACA, the Inflation Reduction Act, or other federal and state healthcare policy reform efforts including those aimed at drug pricing. There is no assurance that federal or state health care reform will not adversely affect our future business and financial results, and we cannot predict how future federal or state legislative, judicial or administrative changes relating to healthcare policy will affect our business. At the federal level, the now-departed Trump administration proposed numerous prescription drug cost control measures. Similarly, the new Biden administration has made lowering prescription drug prices one of its priorities. The Biden administration has not yet proposed any specific plans, but we expect that these will be forthcoming in the near term. At the state level, legislatures are increasingly passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. Other examples of proposed changes include, but are not limited to, expanding post-approval requirements, changing the Orphan Drug Act, and restricting sales and promotional activities for pharmaceutical products. We cannot be sure whether additional legislative changes will be enacted, or whether government regulations, guidance or interpretations will be changed, or what the impact of such changes would be on the marketing approvals, sales, pricing, or reimbursement of our drug candidates or products, if any, may be. We expect that these and other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we receive for any approved drug. Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our drugs. In addition, FDA regulations and guidance may be revised or reinterpreted by the FDA in ways that may significantly affect our business and our products. Any new regulations or guidance, or revisions or reinterpretations of existing regulations or guidance, may impose additional costs or lengthen FDA review times for our product candidates. We cannot determine how changes in regulations, statutes, policies, or interpretations when and if issued, enacted or adopted, may affect our business in the future. Such changes could, among other things, require: ● additional clinical trials to be conducted prior to obtaining approval; ● changes to manufacturing methods; ● recalls, replacements, or discontinuance of one or more of our products; and ● additional recordkeeping. Such changes would likely require substantial time and impose significant costs, or could reduce the potential commercial value of our product candidates. In addition, delays in receipt of or failure to receive regulatory clearances or approvals for any other products would harm our business, financial condition, and results of operations. If we obtain approval to commercialize any approved products outside of the United States, a variety of risks associated with international operations could materially adversely affect our business. If TNX-102 SL or any of our other product candidates are approved for commercialization outside of the United States, we intend to enter into agreements with third parties to market them on a worldwide basis or in more limited geographical regions. We expect that we will be subject to additional risks related to entering into international business relationships, including: ● different regulatory requirements for drug approvals; ● reduced protection for intellectual property rights, including trade secret and patent rights; ● unexpected changes in tariffs, trade barriers and regulatory requirements; ● economic weakness, including inflation, or political instability in particular foreign economies and markets; ● compliance with tax, employment, immigration and labor laws for employees living or traveling abroad; ● foreign taxes, including withholding of payroll taxes; ● foreign currency fluctuations, which could result in increased operating expenses and reduced revenues, and other obligations incident to doing business in another country; ● workforce uncertainty in countries where labor unrest is more common than in the United States; ● production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad; 52 ● business interruptions resulting from geopolitical actions, including war and terrorism, or natural disasters including earthquakes, hurricanes, floods and fires; and ● difficulty in importing and exporting clinical study materials and study samples. We face the risk of product liability claims and may not be able to obtain insurance. Our business exposes us to the risk of product liability claims that are inherent in the development of drugs. If the use of one or more of our or our collaborators’ drugs harms people, we may be subject to costly and damaging product liability claims brought against us by clinical study participants, consumers, health care providers, pharmaceutical companies or others selling our products. Our inability to obtain sufficient product liability insurance at an acceptable cost to protect against potential product liability claims could prevent or inhibit the commercialization of pharmaceutical products we develop, alone or with collaborators. While we currently carry clinical study insurance and product liability insurance, we cannot predict all of the possible harms or side effects that may result and, therefore, the amount of insurance coverage we hold now or in the future may not be adequate to cover all liabilities we might incur. We intend to expand our insurance coverage to include the sale of commercial products if we obtain marketing approval for our drug candidates in development, but we may be unable to obtain commercially reasonable product liability insurance for any products approved for marketing. If we are unable to obtain insurance at an acceptable cost or otherwise protect against potential product liability claims, we will be exposed to significant liabilities, which may materially and adversely affect our business and financial position. If we are sued for any injury allegedly caused by our or our collaborators’ products, our liability could exceed our total assets and our ability to pay the liability. A product liability claim or series of claims brought against us would decrease our cash and could cause our stock price to fall. We use hazardous chemicals in our business. Potential claims relating to improper handling, storage or disposal of these chemicals could affect us and be time-consuming and costly. Our research and development processes and/or those of our third party contractors may involve the controlled use of hazardous materials and chemicals. These hazardous chemicals are reagents and solvents typically found in a chemistry laboratory. Our operations also produce hazardous waste products. Federal, state and local laws and regulations govern the use, manufacture, storage, handling and disposal of hazardous materials. While we attempt to comply with all environmental laws and regulations, including those relating to the outsourcing of the disposal of all hazardous chemicals and waste products, we cannot eliminate the risk of contamination from or discharge of hazardous materials and any resultant injury. In the event of such an accident, we could be held liable for any resulting damages and any liability could materially adversely affect our business, financial condition and results of operations. Compliance with environmental laws and regulations may be expensive. Current or future environmental regulations may impair our research, development or production efforts. We might have to pay civil damages in the event of an improper or unauthorized release of, or exposure of individuals to, hazardous materials. We are not insured against these environmental risks. If we enter into collaborations with third parties, they might also work with hazardous materials in connection with our collaborations. We may agree to indemnify our collaborators in some circumstances against damages and other liabilities arising out of development activities or products produced in connection with these collaborations. In addition, the federal, state and local laws and regulations governing the use, manufacture, storage, handling and disposal of hazardous or radioactive materials and waste products may require us to incur substantial compliance costs that could materially adversely affect our business, financial condition and results of operations. Our insurance policies are expensive and protect us only from some business risks, which will leave us exposed to significant uninsured liabilities. We carry insurance for most categories of risk that our business may encounter, however, we may not have adequate levels of coverage. We currently maintain general liability, clinical study, property, workers’ compensation, products liability and directors’ and officers’ insurance, along with an umbrella policy, which collectively costs approximately $2,000,000 per annum. We cannot provide any assurances that we will be able to maintain existing insurance at current or adequate levels of coverage. Any significant uninsured liability may require us to pay substantial amounts, which would adversely affect our cash position and results of operations. If we retain collaborative partners and our partners do not satisfy their obligations, we will be unable to develop our partnered product candidates. In the event we enter into any collaborative agreements, we may not have day-to-day control over the activities of our collaborative partners with respect to any of these product candidates. Any collaborative partner may not fulfill its obligations under these agreements. If a collaborative partner fails to fulfill its obligations under an agreement with us, we may be unable to assume the development of the products covered by that agreement or enter into alternative arrangements with a third party. In addition, we may encounter delays in the commercialization of the product candidate that is the subject of the agreement. Accordingly, our ability to receive any revenue from the product candidates covered by these agreements will be dependent on the efforts of our collaborative partner. We could also become involved in disputes with a collaborative partner, which could lead to delays in or termination of our development and commercialization programs and time-consuming and expensive litigation or arbitration. In addition, any such dispute could diminish our collaborators’ commitment to us and reduce the resources they devote to developing and commercializing our products. Conflicts or disputes with our collaborators, and competition from them, could harm our relationships with our other collaborators, restrict our ability to enter future collaboration agreements and delay the research, development or commercialization of our product candidates. If any collaborative partner terminates or breaches its agreement, or otherwise fails to complete its obligations in a timely manner, our chances of successfully developing or commercializing these product candidates would be materially and adversely affected. We may not be able to enter into collaborative agreements with partners on terms favorable to us, or at all. Our inability to enter into collaborative arrangements with collaborative partners, or our failure to maintain such arrangements, would limit the number of product candidates that we could develop and ultimately, decrease our sources of any future revenues. We may be unsuccessful in obtaining a priority review voucher for material threat medical countermeasures. In 2016, the 21 st Century Cures Act, or the Act, was signed into law to support ongoing biomedical innovation. One part of the Act, Section 3086, is aimed at “Encouraging Treatments for Agents that Present a National Security Threat.” The Act created a new priority review voucher program for approved “material threat medical countermeasures.” The Act defines such countermeasures as drug or biologic products, including vaccines, intended to treat biological, chemical, radiological, or nuclear agents that present a national security threat or to treat harm from a condition that may be caused by administering a drug or biological product against such an agent. The Department of Homeland Security has identified 13 such threats, including anthrax, smallpox, Ebola/Marburg, tularemia, botulinum toxin, and pandemic influenza, which includes the SARS coronavirus 2 known as SARS-CoV-2. A priority review voucher can be applied to any other product; it shortens the FDA review timeline for a new application from 10 to 12 months to 6 months. The recipient of a priority review voucher may transfer it. 53 There may not be market interest in TNX-801. The government is the only market for most medical countermeasures. This is because unlike other drugs and vaccines, these products are not sold to doctors, hospitals, or pharmacies. The BioShield Special Reserve Fund, or SRF, has been the sole medical countermeasures market for the last decade. The SRF is now appropriated annually and has not kept pace with the need for purchasing products ready for stockpiling. During 2020, $735 million was appropriated to SRF. As such, even if TNX-801 were to receive FDA licensure, the commercial success of TNX-801 remains uncertain. Government entities may take actions that directly or indirectly have the effect of limiting opportunities for our vaccine candidates for COVID-19. Various government entities, including the U.S. government, are offering incentives, grants and contracts to encourage additional investment by commercial organizations into preventative and therapeutic agents against COVID-19, which may have the effect of increasing the number of competitors and/or providing advantages to competitors. Accordingly, there can be no assurance that we will be able to successfully establish a competitive market share if we ultimately receive regulatory approval for our vaccines as a vaccine for COVID-19. COVID-19 vaccines may also be subject to government pricing controls, which could adversely affect the profitability of any COVID-19 vaccine we are able to develop and commercialize. If technology developed for the purposes of developing new medicines or vaccines can be applied to the creation or development of biological weapons, then our technology may be considered “dual use” technology and be subject to limitations on public disclosure or export. Our research and development of synthetic poxviruses is dedicated not only to creating tools that better protect public health but also to safeguarding any information with broad, dual-use potential that could be inappropriately applied. “Dual use research” is research conducted for legitimate purposes that generates knowledge, information, technologies, and/or products that can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat to public health, agricultural crops, or national security. Because variola, the agent that causes smallpox, is a pox virus, the technology we created could be considered dual use and could be subject to export control, for example under the Wassenaar Arrangement. Further, if federal authorities determine that our research is subject to institutional oversight, we will need to implement a risk-management plan developed in collaboration with the institutional review entity. Failure to comply with the plan may result in suspension, limitation, or termination of federal funding or loss of future federal funding opportunities for any of our research. We face risks in connection with existing and future collaborations with respect to the development, manufacture, and commercialization of our product candidates. We face a number of risks in connection with our current collaborations. Our collaboration agreements are subject to termination under various circumstances. Our collaborators may change the focus of their development and commercialization efforts or may have insufficient resources to effectively assist in the development of our products. Any future collaboration agreements may have the effect of limiting the areas of research and development that we may pursue, either alone or in collaboration with third parties. Further, disagreements with collaborators, including disagreements over proprietary rights, contract interpretation, or the preferred course of development, might cause delays, might result in litigation or arbitration, or might result in termination of the research, development or commercialization of our products. Any such disagreements would divert management attention and resources and be time-consuming and costly. We face risks in connection with the testing, production and storage of our vaccine product candidates. Developing our TNX-1850 and TNX-801 vaccine candidates each require testing of challenges with monkeypox or SARS-CoV-2 viruses under controlled experimental conditions. The testing of TNX-1850 and TNX-801 may carry risk of infection and harm to individuals. In addition, our TNX-1850 and TNX-801 vaccine candidates are both live forms of the horsepox. We have initiated vaccine-manufacturing activities to support further nonclinical testing of TNX-801. The production and storage of the synthesized horsepox virus stock and, once initiated, TNX-1850 virus stock, may carry risk of infection and harm to individuals. Any such infection could expose us to product and general liability claims, and may carry risk of infection and harm to individuals. RISKS RELATED TO OUR STOCK Sales of additional shares of our common stock could cause the price of our common stock to decline. Sales of substantial amounts of our common stock in the public market, or the availability of such shares for sale, by us or others, including the issuance of common stock upon exercise of outstanding options and warrants, could adversely affect the price of our common stock. We and our directors and officers may sell shares into the market, which could adversely affect the market price of shares of our common stock. 54 An active trading market for our common stock may not be sustained. Although our common stock is listed on the NASDAQ Capital Market, the market for our shares has demonstrated varying levels of trading activity. Furthermore, the current level of trading may not be sustained in the future. The lack of an active market for our common stock may impair investors’ ability to sell their shares at the time they wish to sell them or at a price that they consider reasonable, may reduce the fair market value of their shares and may impair our ability to raise capital to continue to fund operations by selling shares and may impair our ability to acquire additional intellectual property assets by using our shares as consideration. The market price of our common stock has been extremely volatile and may continue to be volatile due to numerous circumstances beyond our control. The market price of our common stock has fluctuated, and may continue to fluctuate, widely, due to many factors, some of which may be beyond our control. These factors include, without limitation: ● “short squeezes”; ● comments by securities analysts or other third parties, including blogs, articles, message boards and social and other media; ● large stockholders exiting their position in our common stock or an increase or decrease in the short interest in our common stock; ● actual or anticipated fluctuations in our financial and operating results; ● risks and uncertainties associated with the ongoing COVID-19 pandemic; ● the timing and allocations of new product candidates; ● public perception of our product candidates and competitive products; ● changes in financial estimates or recommendations by securities analysts; ● changes in the reimbursement policies of third party insurance companies or government agencies; and ● overall general market fluctuations. Stock markets in general and our stock price in particular have experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of those companies and our company. Broad market fluctuations may adversely affect the trading price of our common stock. In particular, a proportion of our common stock has been and may continue to be traded by short sellers which may put pressure on the supply and demand for our common stock, further influencing volatility in its market price. Additionally, these and other external factors have caused and may continue to cause the market price and demand for our common stock to fluctuate, which may limit or prevent investors from readily selling their shares of common stock and may otherwise negatively affect the liquidity of our common stock. A “short squeeze” due to a sudden increase in demand for shares of our common stock that largely could lead to extreme price volatility in shares of our common stock. Investors may purchase shares of our common stock to hedge existing exposure or to speculate on the price of our common stock. Speculation on the price of our common stock may involve long and short exposures. To the extent aggregate short exposure exceeds the number of shares of our common stock available for purchase on the open market, investors with short exposure may have to pay a premium to repurchase shares of our common stock for delivery to lenders of our common stock. Those repurchases may in turn, dramatically increase the price of our common stock until additional shares of our common stock are available for trading or borrowing. This is often referred to as a “short squeeze.” A proportion of our common stock has been and may continue to be traded by short sellers which may increase the likelihood that our common stock will be the target of a short squeeze. A short squeeze could lead to volatile price movements in shares of our common stock that are unrelated or disproportionate to our operating performance or prospectus and, once investors purchase the shares of our common stock necessary to cover their short positions, the price of our common stock may rapidly decline. Investors that purchase shares of our common stock during a short squeeze may lose a significant portion of their investment. We could be delisted from Nasdaq, which could seriously harm the liquidity of our stock and our ability to raise capital. We have had in the past, and may in the future, have difficulty satisfying Nasdaq listing requirements for our common stock. If we are unable to satisfy Nasdaq listing requirements, we will cease to be eligible to trade on Nasdaq. In such event: ● We may have to pursue trading on a less recognized or accepted market, such as the OTC Bulletin Board or the “pink sheets.” ● Shares of our common stock could be less liquid and marketable, thereby reducing the ability of stockholders to purchase or sell our shares as quickly and as inexpensively as they have done historically. If our stock is traded as a “penny stock,” transactions in our stock would be more difficult and cumbersome. ● We may be unable to access capital on favorable terms or at all, as companies trading on alternative markets may be viewed as less attractive investments with higher associated risks, such that existing or prospective institutional investors may be less interested in, or prohibited from, investing in our common stock. This may also cause the market price of our common stock to decline. We do not anticipate paying dividends on our common stock and, accordingly, shareholders must rely on stock appreciation for any return on their investment. We have never declared or paid cash dividends on our common stock and do not expect to do so in the foreseeable future. The declaration of dividends is subject to the discretion of our board of directors and will depend on various factors, including our operating results, financial condition, future prospects and any other factors deemed relevant by our board of directors. You should not rely on an investment in our company if you require dividend income from your investment in our company. The success of your investment will likely depend entirely upon any future appreciation of the market price of our common stock, which is uncertain and unpredictable. There is no guarantee that our common stock will appreciate in value. We expect that our quarterly results of operations will fluctuate, and this fluctuation could cause our stock price to decline. Our quarterly operating results are likely to fluctuate in the future. These fluctuations could cause our stock price to decline. The nature of our business involves variable factors, such as the timing of the research, development and regulatory pathways of our product candidates, which could cause our operating results to fluctuate. 55 Due to the possibility of fluctuations in our revenues and expenses, we believe that quarter-to-quarter comparisons of our operating results are not a good indication of our future performance. The rights of the holders of common stock may be impaired by the potential issuance of preferred stock. Our articles of incorporation give our board of directors the right to create new series of preferred stock. As a result, the board of directors may, without stockholder approval, issue preferred stock with voting, dividend, conversion, liquidation or other rights which could adversely affect the voting power and equity interest of the holders of common stock. Preferred stock, which could be issued with the right to more than one vote per share, could be utilized as a method of discouraging, delaying or preventing a change of control. The possible impact on takeover attempts could adversely affect the price of our common stock. Although we have no present intention to issue any shares of preferred stock or to create a series of preferred stock, we may issue such shares in the future. If we fail to comply with the rules under the Sarbanes-Oxley Act of 2002 related to accounting controls and procedures, or if we discover material weaknesses and deficiencies in our internal control and accounting procedures, our stock price could decline significantly and raising capital could be more difficult. If we fail to comply with the rules under the Sarbanes-Oxley Act of 2002 related to disclosure controls and procedures, or, if we discover material weaknesses and other deficiencies in our internal control and accounting procedures, our stock price could decline significantly and raising capital could be more difficult. Section 404 of the Sarbanes-Oxley Act requires annual management assessments of the effectiveness of our internal control over financial reporting. If material weaknesses or significant deficiencies are discovered or if we otherwise fail to achieve and maintain the adequacy of our internal control, we may not be able to ensure that we can conclude on an ongoing basis that we have effective internal controls over financial reporting in accordance with Section 404 of the Sarbanes-Oxley Act. Moreover, effective internal controls are necessary for us to produce reliable financial reports and are important to helping prevent financial fraud. If we cannot provide reliable financial reports or prevent fraud, our business and operating results could be harmed, investors could lose confidence in our reported financial information, and the trading price of our common stock could drop significantly. If securities or industry analysts do not publish research or reports about our business, or if they change their recommendations regarding our stock adversely, our stock price and trading volume could decline. The trading market for our common stock will be influenced by the research and reports that industry or securities analysts publish about us or our business. Our research coverage by industry and financial analysts is currently limited. Even if our analyst coverage increases, if one or more of the analysts who cover us downgrade our stock, our stock price would likely decline. If one or more of these analysts cease coverage of our company or fail to regularly publish reports on us, we could lose visibility in the financial markets, which in turn could cause our stock price or trading volume to decline. Other companies may have difficulty acquiring us, even if doing so would benefit our stockholders, due to provisions under our corporate charter and bylaws, as well as Nevada law. Provisions in our articles of incorporation, our bylaws, and under Nevada law could make it more difficult for other companies to acquire us, even if doing so would benefit our stockholders. Our articles of incorporation and bylaws contain the following provisions, among others, which may inhibit an acquisition of our company by a third party: ● advance notification procedures for matters to be brought before stockholder meetings ● a limitation on who may call stockholder meetings ● a limitation on the removal of directors ● the ability of our board of directors to issue up to 5,000,000 shares of preferred stock without a stockholder vote We are also subject to provisions of Nevada law that prohibit us from engaging in any business combination with any “interested stockholder,” meaning generally that a stockholder who beneficially owns 10 percent or more of our stock cannot acquire us for a period of time after the date this person became an interested stockholder, unless various conditions are met, such as approval of the transaction by our board of directors and stockholders. Our bylaws designate the Eighth Judicial District Court of Clark County, Nevada as the sole and exclusive forum for certain types of actions and proceedings that may be initiated by our stockholders, which could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, officers, employees or agents. Our bylaws require that, to the fullest extent permitted by law, and unless the Company consents in writing to the selection of an alternative forum, the Eighth Judicial District Court of Clark County, Nevada, will, to the fullest extent permitted by law, be the sole and exclusive forum for each of the following: ● any derivative action or proceeding brought in the name or right of the Company or on its behalf, ● any action asserting a claim for breach of any fiduciary duty owed by any director, officer, employee or agent of the Company to the Company or the Company’s stockholders, ● any action arising or asserting a claim arising pursuant to any provision of NRS Chapters 78 or 92A or any provision of our articles of incorporation or bylaws, or ● any action asserting a claim governed by the internal affairs doctrine, including, without limitation, any action to interpret, apply, enforce or determine the validity of our articles of incorporation or bylaws. Because the applicability of the exclusive forum provision is limited to the extent permitted by law, we believe that the exclusive forum provision would not apply to suits brought to enforce any duty or liability created by the Securities Exchange Act of 1934, as amended (Exchange Act), or any other claim for which the federal courts have exclusive jurisdiction, and that federal courts have concurrent jurisdiction over all suits brought to enforce any duty or liability created by the Securities Act of 1933, as amended (Securities Act). We note that there is uncertainty as to whether a court would enforce the provision and that investors cannot waive compliance with the federal securities laws and the rules and regulations thereunder. Although we believe this provision benefits us by providing increased consistency in the application of Nevada law in the types of lawsuits to which it applies, the provision may have the effect of discouraging lawsuits against our directors and officers. 56 ITEM 1B – UNRESOLVED STAFF COMMENTS There are no unresolved staff comments at December 31, 2022. ITEM 2 – PROPERTIES We maintain our principal office at 26 Main Street, Suite 101, Chatham, New Jersey 07928. Our telephone number at that office is (862) 799-8599 and our fax number is (212) 923-5700. On August 28, 2020, we entered into a lease, whereby we agreed to lease new office space, commencing September 2020 and expiring December 2025. In connection therewith, we maintain a letter of credit, which has a remaining balance of $140,201 as of December 31, 2022, and such amount is deposited into the restricted cash account maintained at the bank that issued the letter of credit. On December 6, 2018, we entered into a lease amendment, whereby we agreed to lease new office space in New York, New York, commencing January 15, 2019, and expiring on November 30, 2020. In August 2020, we signed a one-year extension, expiring in November 2021. In September 2021, we signed a one-year extension, expiring in November 2022. In May 2022, we signed a one-year extension, expiring in November 2023. In connection therewith, we maintain a letter of credit, which has a remaining balance of $100,653 as of December 31, 2022, and such amount is deposited into the restricted cash account maintained at the bank that issued the letter of credit. On October 1, 2021, we completed the purchase of a research and development facility in Maryland totaling $17.5 million, to process development activities. As of December 31, 2022, the asset was operational and the asset was ready for its intended use. On December 23, 2020, we completed the purchase of our approximately 44-acre site in Hamilton, Montana for $4.5 million, for the construction of a vaccine development and commercial scale manufacturing facility. As of December 31, 2022, the facility was not ready for its intended use. On September 28, 2020, we completed the purchase of our 45,000 square foot facility in Massachusetts for $4.0 million, to house our new Advanced Development Center for accelerated development and manufacturing of vaccines. As of December 31, 2022, the facility was operational and ready for its intended use. Future minimum lease payments are as follows (in thousands): Year Ending December 31, 2023 $ 441 2024 164 2025 159 2026 9 2027 2 775 Included interest (15 ) $ 760 We believe that our existing facilities are suitable and adequate to meet our current business requirements. ITEM 3 – LEGAL PROCEEDINGS From time to time, we may become involved in various lawsuits and legal proceedings which arise in the ordinary course of business. However, litigation is subject to inherent uncertainties, and an adverse result in these or other matters may arise from time to time that may harm our business. We are currently not aware of any such legal proceedings or claims that we believe will have, individually or in the aggregate, a material adverse effect on our business, financial condition, operating results or cash flows. ITEM 4 – MINE SAFETY DISCLOSURES Not applicable. 57 PART II ITEM 5 – MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES Market Information Our common stock is listed on The NASDAQ Capital Market under the symbol “TNXP”. Holders On March 10, 2023, the closing sale price of our common stock, as reported by The NASDAQ Stock Market, was $0.62 per share. On March 10, 2023, there were 231 holders of record of our common stock. Because many of our shares of common stock are held by brokers and other institutions on behalf of stockholders, we are unable to estimate the total number of stockholders represented by these record holders. Dividend Policy We have never paid any cash dividends on our capital stock and do not anticipate paying any cash dividends on our common stock in the foreseeable future. We intend to retain future earnings to fund ongoing operations and future capital requirements of our business. Any future determination to pay cash dividends will be at the discretion of the Board and will be dependent upon our financial condition, results of operations, capital requirements and such other factors as the Board deems relevant. Recent Sales of Unregistered Securities None. Repurchases of Equity Securities by the Issuer and Affiliated Purchasers We did not purchase any of our registered securities during the period covered by this Annual Report. ITEM 6 – RESERVED 58 ITEM 7 – MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS This Management’s Discussion and Analysis of Financial Condition and Results of Operations includes a number of forward-looking statements that reflect Management’s current views with respect to future events and financial performance. You can identify these statements by forward-looking words such as “may” “will,” “expect,” “anticipate,” “believe,” “estimate” and “continue,” or similar words. Those statements include statements regarding the intent, belief or current expectations of us and members of its management team as well as the assumptions on which such statements are based and should be read together with the “Risk Factors” section of this Annual Report on Form 10-K for a discussion of important factors that could cause actual results to differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis. Our actual results could differ materially from those anticipated in these forward-looking statements as a result of various factors, including those discussed below and elsewhere in this Annual Report and in other reports we file with the Securities and Exchange Commission, particularly those under “Risk Factors.”. Business Overview We are a clinical-stage biopharmaceutical company focused on developing therapeutics and vaccines to treat and prevent human disease and alleviate suffering. We have a rich pipeline of products in development that has been curated from internal discovery, as well as licenses, acquisitions and collaborations with academic institutions and contract research organizations. We continue to build capabilities in synthetic biology, precision medicine, protein engineering, medicinal chemistry, molecular biology, pharmacogenomics and clinical-scale manufacturing. Our therapeutics under development include both small molecules and biologics. Our portfolio consists of central nervous system, or CNS, rare disease, immunology, and infectious disease product candidates. The CNS portfolio includes small molecules and biologics to treat pain, neurologic, psychiatric and addiction conditions. Our rare disease portfolio focuses on developing novel therapies for patients with rare diseases, including those caused by genetic disorders which are characterized by complex symptoms and for which no drug is approved. Our immunology portfolio includes biologics to address organ transplant rejection, autoimmune diseases and cancer. Our infectious disease portfolio includes a vaccine in development to prevent smallpox and mpox (formerly known as monkeypox), next-generation vaccines to prevent COVID-19, a platform to make fully human mAbs to treat COVID-19 and humanized anti-SARS-CoV-2 mAbs. Our vaccine in development to prevent smallpox and mpox also serves as the live virus vaccine platform or recombinant pox vaccine (RPV) platform for other infectious diseases. Our latest stage CNS product candidate is TNX-102 SL*, a proprietary sublingual tablet formulation of cyclobenzaprine (CBP) designed for bedtime administration. TNX-102 SL has active INDs for fibromyalgia, or FM, FM-type Long COVID or PASC (post-acute sequelae of SARS-CoV-2 infection), posttraumatic stress disorder, or PTSD, agitation in Alzheimer’s disease, or AAD, and alcohol use disorder, or AUD. 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 reported topline data from the completed study in March of 2022. As expected, based on interim analysis results, TNX-102 SL did not achieve statistical significance over placebo on the primary endpoint of reduction in daily pain, and relative to the previous positive Phase 3 Study (RELIEF), RALLY had an unexpected increase in study participant adverse event-related discontinuations in both drug and placebo groups. In April 2022, we started a new potentially confirmatory Phase 3 study of TNX-102 SL in FM, RESILIENT. Interim analysis results are expected in the second quarter of 2023 and topline results are expected in the fourth quarter of 2023. Following a positive outcome of the RESILIENT study, we believe we would be positioned to file a New Drug Application (NDA) for TNX-102 SL for the management of FM. TNX-102 SL is also being developed as a potential treatment for a type of Long COVID, the symptoms of which overlap with FM, that we term FM-type Long COVID. We initiated enrollment in the Phase 2 study PREVAIL, in August 2022. The primary endpoint is a change in daily pain scores from baseline. 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. Future studies will employ the one month look-back CAPS-5 as the primary endpoint rather than the one week look-back used in prior studies. 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. We do 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. We do not have any near-term plans to start a Phase 2 study in AUD. TNX-1900* (intranasal potentiated oxytocin) is in development for the treatment of chronic migraine and obesity-associated 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 animal studies to potentiate binding of oxytocin to the oxytocin receptor. We received IND clearance from the FDA in the fourth quarter of 2021 to study TNX-1900 in chronic migraine and we initiated a Phase 2 study in migraine in the first quarter of 2023. We expect interim analysis results from the first 50 percent of patients enrolled in the fourth quarter of 2023. In March 2022, we announced an agreement with Massachusetts General Hospital, a teaching hospital of Harvard Medical School, to conduct an investigator-initiated Phase 2 clinical trial to study TNX-1900 in BED. The Phase 2 clinical trial is expected to start in the second quarter of 2023. We do not own an IND for BED. We also licensed technology to use TNX-1900 for the treatment of insulin resistance from the University of Geneva and also have rights to develop it as a treatment for craniofacial pain, but we are not imminently pursuing clinical trials in either of these indications at this time. 59 TNX-601 ER* (tianeptine hemioxalate extended-release tablets) is a CNS product candidate in development as a treatment for major depressive disorder, or depression, and with possible additional indications of PTSD, and neurocognitive dysfunction associated with corticosteroid use. TNX-601 ER represents a novel approach to treating depression in the U.S., since the active ingredient tianeptine induces a neuroprotective and resilient phenotype in both neurons and microglia under conditions of stress in animals. The dramatic and unique effects of tianeptine are illustrated in animal models by the restoration of dendritic arborization of pyramidal neurons of CA3 region of hippocampus and the dentate gyrus region new neuron formation and integration into hippocampal networks. In contrast, antidepressants that are marketed in the U.S. act by modulating the levels or receptor binding of neurotransmitters in the synapse. We have completed a Phase 1 trial for formulation development outside of the U.S. We expect to initiate a potentially pivotal Phase 2 study in the first quarter of 2023 for the treatment of major depressive disorder and we expect interim analysis results from the first 50 percent of patients enrolled in the fourth quarter of 2023. Another CNS candidate 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. In August of 2022, we received a Federal Grant from the National Institute on Drug Abuse (NIDA) to advance the development of TNX-1300 as a treatment for cocaine intoxication. We expect to initiate a potentially pivotal Phase 2 study of TNX-1300 in emergency rooms in the second quarter of 2023. 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 expected to be developed as a treatment for PTSD, depression and attention-deficit/hyperactivity disorder, or ADHD. TNX-1600 is in the preclinical stage of development. Our rare disease portfolio consists of TNX-2900*, another magnesium-potentiated, 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 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, and is in the pre-IND stage of development. Our lead candidate in the immunology pipeline is TNX-1500*, a humanized mAb, directed against CD40-ligand, or CD40L (also known as CD154), 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 or MGH, 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 allogeneic organ transplants in non-human primates. Preliminary results from ongoing experiments in kidney and 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 therapies were associated with an increased risk of blood clots or thrombosis. In the non-human primate studies with TNX-1500 for allogeneic kidney or heart transplantation, no evidence of thrombosis has been observed so far. We expect to start a Phase 1 study of TNX-1500 in the second quarter of 2023. TNX-1500 also is being studied in combination with other immunosuppressive agents in xenogeneic organ transplants in non-human primates at MGH and at the University of Maryland at Baltimore or UMB. In experiments at UMB, TNX-1500 is being studied to prevent rejection of xenogeneic hearts from genetically engineered pigs developed by the Revivicor division of United Therapeutics Corporation. Our immunology pipeline also includes TNX-1700*, a recombinant Trefoil Factor Family 2, or rTFF2, fusion protein that was licensed from Columbia University in 2019. TNX-1700 consists of TFF2 fused to human serum albumin or I and is a biologic being developed to treat gastric and colorectal cancers by an immune-oncology mechanism, in combination with PD1 blockers, and is in the preclinical stage of development. We recently presented data that show a murine version of TNX-1700 consisting of a fusion protein with murine serum albumin or MSA was able to evoke anti-tumor immunity in the MC38 mouse model of colorectal cancer as monotherapy and that TNX-1700 augmented the efficacy of anti-PD1 therapy in both the MC38 mouse model and the CT26.wt models of colorectal cancer. Our infectious disease portfolio includes vaccines based on our live virus vaccine or recombinant pox vaccine, “RPV” platform. Live virus vaccines are believed to protect against poor clinical outcomes of infectious diseases by eliciting T cell responses in addition to antibody responses. TNX-801*, a live attenuated vaccine based on synthesized horsepox is in the pre-IND stage of development to protect against smallpox and mpox. Non-human primates vaccinated with TNX-801 were protected from monkeypox in studies reported in the first quarter of 2020. A Phase 1 study of TNX-801 in humans is expected to start in the second half of 2023. TNX-801 also serves as the live virus vaccine platform for other infectious diseases for which subsequent products will be designed by expressing other viral antigens in the horsepox vector. TNX-1850* is a live virus vaccine that expresses the SARS-CoV-2 spike protein from the BA.2 strain that has not yet been tested in animals. 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 out-competed the ancestral Wuhan strain, we began work on 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. Of those, based on the trajectory of COVID-19, the focus is now on TNX-1850. 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 have shown 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. TNX-2300* is a live virus vaccine based on bovine parainfluenza virus in development to protect against COVID-19. In April 2022, we extended a sponsored research agreement with Kansas State University to develop a vaccine candidate, TNX-2300, for the prevention of COVID-19 that utilizes a novel live virus vaccine vector platform based on bovine parainfluenza virus. The efficacy of co-expression of the CD40-ligand, also known as CD154, to stimulate T cell immunity will also be tested. Attenuated bovine parainfluenza virus has previously been shown to be an effective antigen delivery vector in humans. Previous work by others has shown that attenuated BPI3V is tolerated and immunogenic in non-human primates and human infants and children. We believe the vector is well suited for mucosal immunization using a nasal atomizer, and can also be delivered parenterally. TNX-2300 is in the preclinical stage of development. TNX-3600* and TNX-3800* are mAbs directed against SARS-CoV-2 which are in development as potential therapeutic or preventative agents for COVID-19. Given the unpredictable trajectory of the SARS-CoV-2 virus and new variants, we seek to contribute a broad set of anti-SARS-CoV-2 mAbs, 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 refers to a series of fully human mAbs generated by human-human hybridomas from COVID-19 convalescent volunteers. We are collaborating with Columbia University to produce these fully human mAbs to SARS-CoV-2 spike proteins from variants such as delta, omicron and XBB1.5 and to other viral targets. TNX-3800 refers to three humanized murine mAbs which we licensed exclusively in December 2022 from Curia Global, Inc. for the treatment or prophylaxis of SARS-CoV-2 infection. The initial focus is to develop COVID-19 therapeutic mAbs. We plan to seek indications similar to previously EUA-approved therapeutic mAbs for treating individuals with mild-to-moderate COVID-19 who are at high risk for progression to severe disease or for prophylaxis in individuals with compromised immune systems who are at high risk for severe COVID-19 disease. None of the previously EUA-approved therapeutic or preventative mAbs are still available, because each has become obsolete since the SARS-CoV-2 virus has mutated to evade their binding. TNX-3600 and TNX-3800 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. TNX-3600 and TNX-3800 are in the preclinical stage of development. 60 TNX-3700* is a COVID-19 mRNA vaccine candidate employing a zinc nanoparticle (ZNP) formulation. In collaboration with Kansas State University,