Tonix Pharmaceuticals Holding Corp.

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.

Forward-looking statements include, but are not necessarily limited to, those relating to:

Business Overview

Tonix Pharmaceuticals (“Tonix” or the “Company”) is a fully-integrated biopharmaceutical company developing and commercializing therapeutics to treat, and vaccines to prevent, disease and alleviate suffering. Tonix’s primary focus is to obtain U.S. marketing authorization for TNX-102 SL (cyclobenzaprine HCl sublingual tablet) 5.6 mg (2 x 2.8 mg tablets) for the management of fibromyalgia (“FM”) from the U.S. Food and Drug Administration (“FDA”). The FDA assigned a prescription drug user fee act (“PDUFA”) goal date of August 15, 2025, for a decision on marketing authorization for TNX-102 SL. In addition, we market two FDA-approved, prescription products for the treatment of acute migraine, and we are developing a robust pipeline of potential new products.

Our pipeline has been generated from internal discovery, as well as licenses, acquisitions and collaborations with academic institutions and non-profit organizations. Our development portfolio is focused on central nervous system (“CNS”), disorders, but also consists of immunology, infectious disease and rare disease, product candidates. The CNS portfolio includes small molecules and biologics to treat pain, neurologic, psychiatric and addiction conditions and includes TNX-1300 which is in Phase 2 clinical development to treat cocaine intoxication partially funded by the U.S. National Institute on Drug Abuse (NIDA). Our immunology portfolio includes TNX-1500 (anti-CD40L monoclonal antibody, or mAb), a biologic which has shown encouraging results in Phase 1, which we plan to study to prevent organ transplant rejection and treat autoimmune diseases. Our infectious disease portfolio includes TNX-801 (horsepox, live virus vaccine) a vaccine in development to prevent smallpox and mpox (formerly known as monkeypox) and TNX-4200, which is a discovery program for broad spectrum antiviral drugs funded by a U.S Department of Defense contract for up to $34 million over five years. TNX-4200 is being developed at our R&D facility located in Frederick, Maryland, (“RDC”), which has biosafety level 2 (BSL-2) with BSL-3 components. Tonix’s product development candidates are investigational new drugs or biologics and have not been approved for any indication.

Central Nervous System (CNS) Pipeline

In October 2024, Tonix submitted a New Drug Application (“NDA”) to the FDA for TNX-102 SL 5.6 mg for the management of FM, a proprietary sublingual tablet formulation of cyclobenzaprine (“CBP”) designed for bedtime administration, and in December 2024, the FDA assigned a PDUFA goal date of August 15, 2025, for a decision on marketing authorization for TNX-102 SL. FM is a chronic pain disorder characterized by widespread pain, non-restorative sleep, fatigue and impaired cognition. TNX-102 SL is a centrally-acting, non-opioid analgesic designed for long-term bedtime use and has been studied in three Phase 3 trials using TNX-102 SL 5.6 mg, two studies reported statistically significant results. The FDA granted TNX-102 SL Fast Track designation in July 2024. We are preparing for a commercial launch of TNX-102 SL in the fourth quarter of 2025, conditional on FDA approval.

In March 2024, Tonix announced it selected two contract manufacturing organizations (CMOs), one of which is Almac Pharma Services, a member of the privately owned Almac Group, as dual supply sources for the potential launch and commercialization of TNX-102 SL in the U.S.

TNX-102 SL also is being developed also as a treatment for acute stress reaction (“ASR”) and to prevent acute stress disorder (“ASD”) and posttraumatic stress disorder (“PTSD”) under a physician-initiated Investigational New Drug Application (“IND”) in partnership with the University of North Carolina (“UNC”) Institute for Trauma Recovery.

In addition, TNX-102 SL has active INDs for the treatment of PTSD, agitation in Alzheimer’s disease (“AAD”), alcohol use disorder (“AUD”) and the management of multi-site pain associated with Long COVID (also known as Post-Acute SARS-CoV-2 or PASC). TNX-102 SL for AAD has been granted Fast Track designation by the FDA. We are currently not actively studying TNX-102 SL in PTSD, AAD or AUD. Tonix is continuously evaluating further indications for which TNX-102 SL could potentially provide benefit.

Another CNS candidate in development is TNX-1300 (double-mutant cocaine esterase) which is in Phase 2 for the treatment of cocaine intoxication. TNX-1300 has been granted Breakthrough Therapy designation by the 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*(i.v.)*cocaine. In August of 2022, we received a Federal Grant from the U.S. National Institute on Drug Abuse (“NIDA”) a part of the U.S. National Institutes of Health (“NIH”) to advance the development of TNX-1300 as a treatment for cocaine intoxication.

Finally, we are developing TNX-1900 (intranasal potentiated oxytocin) for several CNS disorders through investigator-initiated studies. TNX-1900 is in development through investigator-initiated studies at Massachusetts General Hospital (“MGH”) for the treatment of binge eating disorder (“BED”), adolescent obesity, and bone health in pediatric autism. TNX-1900 is in development through an investigator-initiated study at the University of Washington for the treatment of social anxiety disorder.

Immunology Pipeline

Our lead candidate in the immunology pipeline is TNX-1500, an Fc-modified humanized monoclonal antibody (“mAb”), directed against CD40-ligand (CD40L, also known as CD154). TNX-1500 was engineered to modulate binding to Fc receptors with the goal of maintaining the activity of first-generation mAbs, yet with reduced risk of thrombotic complications. TNX-1500 is being developed to prevent organ transplant rejection as well as to treat autoimmune conditions. Topline results from a Phase 1 single ascending dose escalation study at 3 mg/kg, 10 mg/kg and 30 mg/kg of TNX-1500 in healthy volunteers was reported in the first quarter of 2025.

TNX-1500 has also been studied in combination with other immunosuppressive agents in allogeneic transplants in non-human primates at MGH. In experiments at MGH, 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. Results from 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.

TNX-1500 also is being studied in combination with other immunosuppressive agents in xenogeneic organ transplants in non-human primates at MGH. In some of these studies, genetically engineered (“GE”) pigs in baboon transplants were treated with cold perfused ischemia minimization and a novel co-stimulation-based immunosuppressive regimen including TNX-1500. The results of these preclinical studies were encouraging and demonstrated the potential of GE pig hearts in the context of a clinically applicable regimen. The multi-GE pigs were provided by eGenesis and Revivicor. Revivicor is a subsidiary of United Therapeutics. Some results from the collaboration with MGH and eGenesis were published in the peer-reviewed journal,Nature in 2023. In March of 2024, MGH announced the first GE pig kidney transplant into a living recipient supported in part by the pre-clinical work with TNX-1500. Subsequently, several other GE pig kidney transplants have been performed. TNX-1500 treatment has not been used in any human transplant recipient.

Our immunology pipeline also includes TNX-1700, a recombinant Trefoil Factor Family 2 (“hTFF2-HSA”) fusion protein that was licensed from Columbia University in 2019. TNX-1700 consists of TFF2 fused to human serum albumin 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 presented data that show a murine version of TNX-1700 consisting of a fusion protein with murine serum albumin 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. We plan to request an INTERACT meeting with the FDA in 2025 to seek early guidance on program development.

Infectious Disease Pipeline

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 minimally replicative vaccine based on synthesized horsepox, is in the pre-IND stage of development to protect against smallpox and mpox. In 2022 the WHO determined that the upsurge of mpox Clade IIb constituted a public health emergency of international concern (PHEIC). Mpox Clade IIB subsequently has become endemic in the U.S. mostly in populations of men who have sex with men. In August 2024, the WHO determined that the upsurge of mpox clade Ib in a growing number of countries in Africa constituted a PHEIC. The WHO reaffirmed the PHEIC status of mpox clade Ib in February of 2025. Mpox cases of the new clade Ib mpox have been detected in the United States and many other countries outside of Africa. Non-human primates vaccinated with TNX-801 were protected from mpox clade Ia in studies reported in the first quarter of 2020 and published in the peer-reviewed journalVaccines in 2023.

In September 2024, at the DoD’s MHSRS conference and in October 2024 at the World Vaccine Congress in Barcelona, Spain, Tonix presented new data on a potential mpox vaccine, TNX-801, demonstrating tolerability and no evidence of spreading to blood or tissues, even at high doses, in immunocompromised animals. After a single-dose vaccination, TNX-801 prevented clinical disease and lesions, and also decreased shedding in the mouth and lungs of animals after a lethal challenge with clade Ia monkeypox. These findings are consistent with TNX-801 inducing mucosal immunity and suggest TNX-801 may block forward transmission. In September 2024, the Company also announced that the WHO’s preferred target product profile (“TPP”) aligns with the characteristics of TNX-801. Key elements of the WHO draft TPP include single-dose, durable protection, administration without special equipment, and stability at ambient temperature. Other potential beneficial characteristics include the ability to limit forward transmission, use in case-contact vaccination strategies and suitability for use in immunocompromised individuals.

In October 2023, at the World Vaccine Congress - Europe, we reported that the TNX-801 vaccine was shown to be greater than 10 to 1,000-fold more minimally replicative than older vaccinia-based smallpox vaccines in both human primary cell lines and immunocompromised mice. In October 2024, at the World Vaccine Congress - Europe, we highlighted positive preclinical efficacy data of TNX-801, demonstrating tolerability in immunocompromised animals and showed that TNX-801 is unable to spread in blood or tissues in these animals, even at an approximately 100-fold higher dose than 20th century vaccinia vaccines in immune-comprised mice. These data were published in the peer-reviewed journalmSphere in 2024.

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. The company’s Good Manufacturing Practice (“GMP”)-capable advanced manufacturing facility in Dartmouth, MA was purpose-built to manufacture TNX-801. The GMP suites are currently decommissioned but are ready to be reactivated in case of a national or international emergency.

TNX-1800 is a live virus vaccine on the RPV platform that expresses the SARS-CoV-2 spike protein from the ancestral Wuhan strain, which has shown encouraging results in non-human primates. In June 2024, the Company announced preclinical data, demonstrating immunity and tolerability, during an oral keynote talk at the Vaccine Congress 2024. Like TNX-801, TNX-1800 is a live minimally replicative vaccine based on horsepox that is believed to provide immune protection with better tolerability than modern vaccinia viruses. TNX-1800 was selected by the NIH’s Project NextGen for inclusion in clinical trials as part of a select group of next generation COVID-19 vaccine candidates with the intent to identify promising vaccine platforms. If Tonix is able to provide TNX-1800 to NIH, they would conduct a Phase 1 trial and cover the full cost. However, Tonix has not prioritized the production of TNX-1800, so it is uncertain whether or how quickly this project will progress. The COVID-19 vaccines approved for use 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. These data were published in the peer-reviewed journalVaccines in 2023. 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.

Tonix is developing potential broad-spectrum antiviral drugs in three programs: CD45-targeted therapeutics (TNX-4200), cathepsin inhibitors (TNX-3900) and viral glycan-targeted engineered biologics (TNX-4000). The DoD announced in December 2022 a plan to move beyond a ‘one bug, one drug’ approach and are seeking broad-spectrum drugs since it may be hard to predict which or how many viruses may be deployed on the battlefield.

In July 2024 Tonix was awarded a contract with a potential for up to $34 million over five years by the Defense Threat Reduction Agency (DTRA), an agency within the DoD. The objective of the contract is to develop small molecule broad-spectrum antiviral agents for the prevention or treatment of infections to improve the medical readiness of military personnel in biological threat environments. Tonix’s program will focus on optimization and development of its TNX-4200 program, to develop an orally available CD45 antagonist with broad-spectrum efficacy against a range of viral families through preclinical evaluation. The program is expected to establish physicochemical properties, pharmacokinetics, and safety attributes to support an IND submission and to fund a first-in-human Phase 1 clinical study. Tonix plans to leverage previous research on phosphatase inhibitors, specifically compounds that target CD45, to optimize lead compounds for therapeutic intervention of biothreat agents and provide the government with a complete and cost-effective solution for a broad-spectrum medical countermeasure. Tonix’s premise is that partial inhibition of CD45 will provide optimal antiviral protection while requiring lower plasma drug concentrations, a lower dose, and a better safety profile.

Tonix will utilize its state-of-the-art research laboratory capabilities, including a Biosafety Level 3 (BSL-3) lab and an Animal Biosafety Level 3 (ABSL-3) facility at the RDC, as well as experienced personnel in-house.

Rare Disease Pipeline

Our rare disease portfolio consists of TNX-2900 (intranasal potentiated oxytocin) for Prader-Willi syndrome (“PWS”), a genetic disorder characterized by complex symptoms. The formulation technology for TNX-2900 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. The therapeutic technology was licensed from Inserm, the French National Institute of Health and Medical Research. TNX-2900 was granted Orphan-Drug Designation by the FDA in the second half of 2023 and the IND was cleared by the FDA in the fourth quarter of 2023 and received Rare Pediatric Disease Designation on March 21, 2024. 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 PWS gene mutations.

Marketed Medicines

Our commercial portfolio consists of two FDA-approved prescription products for the treatment of migraine: Zembrace SymTouch (sumatriptan injection) 3 mg and Tosymra (sumatriptan nasal spray) 10 mg. Zembrace SymTouch and Tosymra are both indicated for the treatment of acute migraine with or without aura in adults. Zembrace SymTouch is the only branded sumatriptan autoinjector professionally promoted in the United States and is designed for ease of use and favorable tolerability with a low 3 mg dose. Tosymra is a novel intranasal sumatriptan product formulated with a permeation enhancer that provides rapid and efficient absorption of sumatriptan. Tosymra was approved on the basis of bioequivalence to subcutaneous (s.c.) sumatriptan. Tonix Medicines is the only manufacturer with both a branded injectable and nasal spray indicated for the acute treatment of migraine with or without aura in adults.

In September 2024, Tonix announced that the United States Patent and Trademark Office (USPTO) issued U.S. Patent No. 12,097,183 to the Company, claiming use of a pre-filled autoinjector comprising a composition of Zembrace® SymTouch® for treating migraines via subcutaneous administration. This patent, excluding possible patent term extensions, is expected to fortify protection and market exclusivity into 2036. Additionally, Tonix announced that the USPTO issued U.S. Patent No. 12,090,139 to the Company, claiming a pharmaceutical composition, a method of treating migraine via intranasal administration, and an intranasal delivery system for Tosymra®. This patent is expected to fortify protection and market exclusivity into 2030.

In June 2024, the Company presented data at the 66th Annual Scientific Meeting of the American Headache Society (AHS) comparing real-world data with real-world usage of non-oral migraine products with the most recent AHS consensus statement. This data stressed the need for customizing treatment of migraine headaches to the needs of patients. Thus far, real world data show that conformity with the guidelines and the consensus statement have yet to be achieved but has the potential to be increased. The data show the use of non-oral drugs for treating an acute migraine attack was only 7% in 2012 and has decreased to below 4% in 2023, when the potential need for such drugs is anticipated to be a more substantial percentage of migraineurs based on epidemiological data. In 2024, Tonix Medicines launched a national educational campaign focusing on the link between migraine, gastroparesis, and the need for non-oral acute migraine therapies.

Facilities

Relating to our development programs, we own and operate the RDC in Frederick, Maryland consisting of one building totaling approximately 48,000 square feet. The RDC conducts research on CNS, immunology, and infectious disease candidates. The RDC facility is mostly biosafety level 2 (BSL-2), with some components designated BSL-3. We also own an Advanced Development Center (“ADC”) located in the New Bedford business park in Dartmouth, Massachusetts. This approximately 45,000 square foot BSL-2 facility is intended to accelerate development, clinical and commercial scale manufacturing of live-virus vaccines and biologics to support clinical trials. This facility was decommissioned in 2024 but Tonix has the ability to reactivate it should we choose to do so.

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

Our Strategy

Our strategy is to use our integrated development and marketing capabilities to advance innovative programs across multiple therapeutic areas through the drug development process, with the ultimate objectives of FDA approval and commercialization. The principal components of our strategy are to:

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 of development is set forth below.

Central Nervous System

Fibromyalgia (FM)

Fibromyalgia is a common chronic pain disorder that is understood to result from amplified sensory and pain signaling within the central nervous system, called central sensitization. Brain imaging studies have localized the functional disorder to the brain’s insular and anterior cingulate cortex. Fibromyalgia afflicts more than 10 million adults in the U.S., the majority of whom are women. Symptoms of fibromyalgia include chronic widespread pain, non-restorative sleep, fatigue, and brain fog (or cognitive dysfunction). Other associated symptoms include mood disturbances, including depression, anxiety, headaches, and abdominal pain or cramps. Individuals suffering from fibromyalgia often struggle with their daily activities, have impaired quality of life, and frequently are disabled. Physicians and patients report common dissatisfaction with currently marketed products. Fibromyalgia is now recognized as the prototypic nociplastic syndrome. Nociplastic pain is the third primary type of pain in addition to nociceptive pain and neuropathic pain. Many patients present with pain syndromes that are combinations of the three primary types of pain. Nociplastic syndromes can involve components of both central and peripheral sensitization. Fibromyalgia can occur without any identifiable precipitating event. However, many fibromyalgia cases follow one or more precipitating event(s) including: chronic nociceptive or neuropathic pain states; recovery from an infectious illness; a cancer diagnosis or cancer treatment; a metabolic or endocrine stress; or a traumatic event. In the cases of recovery from an infectious illness, fibromyalgia is considered an Infection-Associated Chronic Condition. In addition to fibromyalgia cases associated with other conditions or stressors, the U.S. National Academies of Sciences, Engineering, and Medicine, has concluded that fibromyalgia is a diagnosable condition that occurs after recovery from COVID-19 in the context of Long COVID. Fibromyalgia is also recognized as a Chronic Overlapping Pain Condition, due to shared symptoms with chronic fatigue syndrome/myalgic encephalomyelitis, irritable bowel syndrome, endometriosis, low back pain, post-concussive syndrome (also known as mild traumatic brain injury), chronic Lyme disease, chronic diabetic neuropathy and chronic post-herpetic neuralgia.

We believe that diagnosing fibromyalgia in Long COVID patients will increase the potential market for TNX-102 SL as compared to market estimates from before the COVID-19 pandemic. Tonix has previously presented its analysis of real-world evidence from the TriNetX claims database suggesting that over 40% of Long COVID patients present with a constellation of symptoms that overlap with fibromyalgia.

According to reports by Frost and Sullivan and Eversana 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, based on U.S. claims data, approximately 50% of patients diagnosed with FM are prescribed opioids within 18 months of diagnosis, despite the lack of evidence for their effectiveness and the risk of addiction and toxicity, including overdose.

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.

Acute Stress Disorder (ASD)

ASD is a mental health condition that can occur within the first month of experiencing a traumatic event. The symptoms are similar to those of PTSD and can affect both civilian and military populations. According to the National Center for PTSD, in the U.S. about 60% of men and 50% of women experience at least one trauma in their lives. In the U.S. alone, one-third of emergency department visits (40-50 million patients per year) involve evaluation after trauma exposures, and in a 2014 study involving U.S. veterans, 87% reported exposure to at least one potentially traumatic event during their service. No medications are currently available at or near the point of care to treat patients suffering from acute traumatic events and to support long-term health.

Immunology

Organ Transplant Rejection

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

Gastric and Colorectal cancers

Gastric or stomach cancer is a disease in which malignant cancer cells line the inner lumen of the stomach. Development of this form of cancer is often influenced by age, diet and other stomach 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 36.4%. According to 2018-2021 data, approximately 0.8 percent of men and women will be diagnosed with stomach cancer during their lifetime. In 2021, there were an estimated 130,263 people living with stomach cancer in the U.S. As of 2024, there were approximately 26,890 new cases with 10,880 deaths.

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, malignancy begins in the mucosal layer and spreads outwards.

The 5-year relative survival rate with colorectal cancer is 65.0%, per the National Cancer Institute. Based on 2018-2021 data, approximately 4.0 percent of men and women will be diagnosed with colorectal cancer during their lifetime. In 2021, there were an estimated 1,392,445 people living with colorectal cancer in the United States. As of 2024, there were approximately 152,810 new cases with 53,010 deaths. It is the 3 rd leading cause of cancer death in women, and 2 nd in men.

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 clade II cases spread rapidly in the U.S. and other countries. The Clade II mpox affects mostly men who have sex with men in the U.S., where it has become endemic. In August 2024, the World Health Organization (“WHO”) declared mpox Clade Ib to be a public health emergency of international concern (PHEIC) due to an outbreak in the Democratic Republic of the Congo that spread globally, including to the United States. Clade Ib affects children as well as adults. The WHO reaffirmed the PHEIC status of mpox clade Ib in February of 2025.

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. The U.S. National Academy of Sciences has recently issued a consensus report raising concerns about the state of new mpox vaccines in development.

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. New variants continue to sweep across the world in successive 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.

Rare Disease

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.

Tonix’s Marketed Migraine Products

Zembrace SymTouch and Tosymra – Acute Migraine in Adults

In June 2023, we acquired two FDA-approved, marketed products from Upsher-Smith: Zembrace SymTouch (sumatriptan injection) 3 mg and Tosymra (sumatriptan nasal spray) 10 mg. Zembrace SymTouch and Tosymra are both indicated for the treatment of acute migraine with or without aura in adults.

Zembrace SymTouch is the only actively promoted brand of sumatriptan autoinjector in the United States. It has a unique low dose and has demonstrated onset of migraine pain relief in as few as 10 minutes (17% of patients vs. 5% for placebo). Zembrace SymTouch also demonstrated migraine pain freedom for 46% of patients (vs 27% for placebo) at 2 hours in a single-attack, double-blind study (N=230). Zembrace SymTouch currently has patent protection to 2036. Tosymra employs Intravail® permeation enhancer technology and is pharmacokinetically equivalent to 4 mg subcutaneous sumatriptan. Tosymra delivers migraine pain relief in as little as 10 minutes with just one spray for some patients (13% vs. 5% for placebo). Tosymra® currently has patent protection to 2031.

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:

*Investigator Initiated Studies

TNX-102 SL

Overview

TNX-102 SL is a proprietary sublingual tablet formulation of cyclobenzaprine (“CBP”) that efficiently delivers CBP across the oral mucosal membrane into the systemic circulation. We have active IND’s for TNX-102 SL as a bedtime treatment for fibromyalgia, PTSD, of multi-site pain associated with Long COVID, AAD and AUD. The University of North Carolina has an investigator-initiated IND for ASD that references our INDs. 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 transmucosal absorption of CBP.

The current TNX-102 SL sublingual tablets each contain 2.8 mg of CBP. 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 multi-functional drug that blocks the serotonin-2A, alpha-1 adrenergic, muscarinic M1 and histaminergic H1 receptors.

CBP is a tertiary amine tricyclic, that is the listed 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 or ER 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 (ER) CBP capsules taken once a day mimic, and flatten, the pharmacokinetic profile of three times per day CBP IR tablets.

Both the IR and ER tablet formulations of CBP result in accumulation of the persistent metabolite norcyclobenzaprine (“norCBP”) to blood levels that exceed the levels of CBP. NorCBP is a secondary amine tricyclic with a relatively stronger inhibitory activity of the norepinephrine transporter (NET) than the parent CBP. We believe that the accumulation of norCBP is undesirable in a medicine to be taken chronically at bedtime because norCBP accumulates over weeks, potentially interfering with the dynamic receptor effects of CBP and also may interrupt sleep quality by inhibiting the NET.

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 pharmacokinetic 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 bypasses the “first pass” hepatic metabolism that swallowed medications undergo, results in a higher plasma level of CBP relative to norcyclobenzaprine during sleeping hours when taken at bedtime. We believe the dynamic changes in CBP after TNX-102 SL administration at steady state during chronic use contribute to its activity in treating fibromyalgia. We believe this is the first drug designed to increase the activity of the tertiary amine tricyclic parent and decrease the activity of the secondary amine tricyclic metabolite. 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. The most common adverse event was transient numbness in the mouth after TNX-102 SL administration.

In September 2024, at the 11th Global Conference on Pharmaceutics and Novel Drug Delivery Systems (PDDS 2024), the Company announced data highlighting the proprietary formulation technology and pharmacokinetic properties of TNX-102 SL, including composition and methods patents based on the proprietary eutectic formulation of TNX-102 SL that are expected to provide market exclusivity until at least 2034 in the U.S., EU, Japan, China and other jurisdictions. The eutectic protects cyclobenzaprine HCl from interacting with the basifying agent that is also part of the formulation and required for efficient transmucosal absorption. The formulation of TNX-102 SL was designed specifically for sublingual administration and transmucosal absorption for bedtime dosing to target disturbed sleep, improve pain and other fibromyalgia symptoms, while reducing the risk of daytime somnolence.

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 (“FDCA”) with Amrix as the listed drug. We believe that TNX-102 SL has the potential to provide clinical benefit in fibromyalgia and PTSD and possibly other CNS indications that are underserved by currently marketed products or have no approved treatment.

We have also successfully completed a bridging pharmacokinetic study in ethnic Japanese and Chinese volunteers that shows similar characteristics to our historical data in Caucasian volunteers. We believe this will satisfy one of the criteria for approval in Japan and China and will allow us to reference the U.S. efficacy data to support marketing applications in those countries.

TNX-102 SL (cyclobenzaprine HCl sublingual tablets) – FM program

We are developing TNX-102 SL as a bedtime treatment for FM.

Clinical Development Plan

NDA Acceptance and PDUFA Goal Date

In October 2024, Tonix submitted its NDA to the FDA for TNX-102 SL 5.6 mg for the management of fibromyalgia and in December 2024, the FDA assigned a PDUFA goal date of August 15, 2025, for a decision on marketing authorization for TNX-102 SL. We are preparing for a commercial launch of TNX-102 SL in the fourth quarter of 2025, conditional on FDA approval.

Pre-NDA Meetings and Fast Track Designation

In July 2024, Tonix was granted Fast Track designation by the FDA for TNX-102 SL for FM. The designation validates that FM is a serious condition and that TNX-102 SL has the potential to address this unmet medical need. Tonix previously announced alignment with the FDA regarding the content of its proposed NDA submission, following completion of the Company’s pre-NDA meetings.

During the second quarter of 2024, Tonix successfully completed two positive pre-NDA meetings with the FDA for TNX-102 SL for the management of fibromyalgia. The first, with minutes announced in June 2024, was a Type B Chemistry, Manufacturing, and Controls (CMC) meeting to seek alignment and agreement with the FDA on key CMC topics to support the planned NDA submission for TNX-102 SL. Based on formal meeting minutes, the Company believes it is aligned with the FDA on proposed drug substance and drug product commercial specifications, shelf life assignment, manufacturing and commercial drug packaging. At the second pre-NDA meeting announced in July 2024, the Company and the FDA aligned on nonclinical, clinical pharmacology and clinical matters and agreed that the proposed data package is sufficient to support the NDA submission.

Completed Phase 3 RESILIENT Study (F307) with Statistically Significant Improvement in Primary Endpoint of Pain Reduction

The first patient was enrolled in the pivotal Phase 3 RESILIENT study in April 2022. The RESILIENT study was 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 enrolled 457 participants in the U.S. 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 RESILIENT study achieved statistical significance on the pre-specified 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]: -1.8 [0.12] units) versus placebo (-1.2 [0.12] units), analyzed by mixed model repeated measures with multiple imputation (LS mean [SE] difference: -0.7 [0.16] units, p=0.00005). In addition, all pre-specified sensitivity analyses of the primary endpoint were statistically significant (p≤0.001). We observed reduction in pain across all weeks of the 14-week study, with nominal p<0.01 for every week. The rapid onset of action with separation from placebo at Week 1 was sustained throughout all weeks of dosing. TNX-102 SL was well tolerated and consistent with prior trials, with no new safety signals observed. Among participants randomized to the TNX-102 SL and placebo arms, 81.0% and 79.2%, respectively, completed the 14-week dosing period. As expected, based on prior TNX-102 SL studies, administration site reactions were the most commonly reported adverse events and were higher in the TNX-102 SL treatment group. Hypoaesthesia oral and paraesthesia oral, or tongue and mouth numbness or tingling, product taste abnormal (typically a bitter aftertaste upon dosing), and tongue discomfort were local effects nearly always temporally related to dose administration and transiently expressed (<60 minutes) in most occurrences. The only treatment-emergent adverse events that occurred at a rate of 3.0% or greater in either arm were these four oral adverse events, along with COVID-19, somnolence, and headache. Adverse events resulted in premature study discontinuation in 6.1% of those who received TNX-102 SL compared with 3.5% of placebo recipients. There were a total of seven serious adverse events in five patients, five of which were experienced by three patients in the placebo arm, and two of which were in the TNX-102 SL arm. Of the two in the TNX-102 SL arm, one was renal cancer, deemed unrelated to study drug, and the other was acute pancreatitis with onset 14 days after dosing was completed, reported as possibly related to study drug, and was resolved before the final study visit.

Completed Phase 3 RALLY Study (F306)

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 designed 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. 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. 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 (~80% higher in each), which we believe may have been impacted by conducting the study in the period of highest mortality across the U.S. from the COVID-19 pandemic (September 2020 through March 2021 for the interim analysis sample).

Completed Phase 3 RELIEF Study (F304) with Statistically Significant Improvement in Primary Endpoint of Pain Reduction

In the fourth quarter of 2020, we announced the results of a randomized, double-blind, placebo-controlled, 12-week Phase 3 study of TNX-102 SL in 503 participants with FM, which we refer to as the RELIEF study. The primary objective of this study was to evaluate the potential clinical benefit of using TNX-102 SL to treat FM at a dose of 5.6 mg, administered sublingually once daily at bedtime for 12 weeks. The primary endpoint of the RELIEF trial was the daily diary pain severity score change from baseline to Week 14 (using the weekly averages of the daily numerical rating scale scores), analyzed by mixed model repeated measures with multiple imputation. The RELIEF study achieved statistical significance on the primary efficacy endpoint: change from baseline in the weekly average of daily diary pain severity numerical rating scale (NRS) scores for TNX-102 SL 5.6 mg (LS mean [SE]: -1.9 [0.12] units) versus placebo (-1.5 [0.12] units), analyzed by mixed model repeated measures with multiple imputation (LS mean [SE] difference: -0.4 [0.16] units, p=0.010).

The statistically significant improvement in pain is further substantiated when diary pain was analyzed by another standard statistical approach, a 30 percent responder analysis, with 46.8% on active and 34.9% on placebo having a 30 percent or greater reduction in pain (logistic regression; odds ratio [95% CI]: 1.67 [1.16, 2.40]; p=0.006, uncorrected). 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 quality 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 prior 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 studies, administration site reactions are the most commonly reported adverse events and were higher in the TNX-102 SL treatment group, including rates of hypoaesthesia oral (17.3% vs. 0.8%), oral pain/discomfort (11.7% v. 2.0%), product taste abnormal (6.5% vs. 0.4%), and paraesthesia oral (5.6% v. 0.4%). Hypoaesthesia or paraesthesia oral and product taste abnormal were local administration site effects nearly always temporally related to dose administration and transiently expressed (<60 minutes) in most 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 case of pneumonia secondary to an infection.

Global NDA Requirements

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 new chemical entity (NCE). 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.

The F108 Phase 1 study was initiated in March 2022 and the clinical phase was completed in May 2022. Since the similarity in PK profile between people of Japanese and Chinese descent was confirmed, the PK data from the two ethnic groups were pooled as for Asian data (n=20) and compared retrospectively with the Caucasian study data from Study TNX-CY-F110 (n=16). The Asian/Caucasian geometric mean ratios of cyclobenzaprine Cmax, AUC 0-T and AUC 0-∞ were between 0.9 and 1.11 after both the 5.6 mg dose and the 2.8 mg dose. The 90% CI of Asian/Caucasian geometric mean ratios for Cmax, AUC 0-T and AUC 0-∞, were all within the formal narrow equivalence limit of 0.8 to 1.25 after both the 5.6 mg dose and 2.8 mg dose, respectively. These results support similarity in cyclobenzaprine PK between Asian (pooled Japanese and Chinese) and Caucasian samples.

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 open-label extension studies of the PTSD program. Based on the FDA’s guidance, the long-term safety exposure studies in PTSD was used to support the NDA for the management of fibromyalgia.

Manufacturing of TNX-102 SL

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 fibromyalgia market. During the second quarter of 2024, Tonix successfully completed a pre-NDA meeting with the FDA for TNX-102 SL for a Type B Chemistry, Manufacturing, and Controls (CMC) meeting to seek alignment and agreement with the FDA on key CMC topics to support the planned NDA submission for TNX-102 SL. Based on formal meeting minutes, the Company believes it is aligned with the FDA on proposed drug substance and drug product commercial specifications, shelf life assignment, manufacturing and commercial drug packaging. In March 2024, Tonix announced it selected two contract manufacturing organizations (CMOs), one of which is Almac Pharma Services, a member of the privately owned Almac Group, as dual supply sources for the potential launch and commercialization of TNX-102 SL in the U.S.

TNX-102 SL – Acute Stress Disorder Program

TNX-102 SL is being developed as a bedtime treatment for ASR in collaboration with the University of North Carolina under an investigator-initiated IND.

Phase 2 OASIS Study

This investigator-initiated study will be conducted by the University of North Carolina Institute for Trauma Recovery. The University of North Carolina has been awarded a $3 million grant from the DoD to investigate the potential of Tonix’s TNX-102 SL to reduce the frequency and severity of adverse effects of acute trauma. The proposed Optimizing Acute Stress reaction Interventions with TNX-102 SL (OASIS) trial will examine the safety and efficacy of TNX-102 SL to reduce adverse posttraumatic neuropsychiatric sequelae among patients presenting to the emergency department (“ED”) after a motor vehicle collision. The trial will enroll approximately 180 individuals who acutely experienced trauma at ED study sites across the U.S. and participants will be randomized in the ED to receive a two-week course of either TNX-102 SL or placebo. We expect enrollment in the OASIS study to begin in the first half of 2025. The OASIS trial will examine the safety and efficacy of TNX-102 SL to reduce adverse posttraumatic neuropsychiatric sequelae among patients in the ED after a motor vehicle collision. A fourteen day course of bedtime TNX-102 SL will be tested in the immediate aftermath of motor vehicle collision trauma. The study will test the potential for TNX-102 SL to target trauma-related sleep disturbance and its ability to facilitate recovery from ASR and to prevent PTSD. The results may ultimately provide military personnel with a new treatment option that, when administered in the early aftermath of a traumatic event to individuals with ASR symptoms, improves warfighter function.

The OASIS trial will build upon a foundation of knowledge and infrastructure developed through the University of North Carolina-led, $40 million AURORA initiative. The AURORA study is a major national research initiative to improve the understanding, prevention, and recovery of individuals who have experienced a traumatic event. AURORA is supported by funding from the NIH, leading brain health nonprofit One Mind, private foundations, and partnerships with leading tech companies such as Mindstrong Health and Verily Life Sciences, the health care arm of Google’s parent company Alphabet.

Initiation of patient enrollment in the proposed investigator sponsored OASIS trial is anticipated in the first half of 2025. The FDA granted IND clearance in the first quarter of 2024.

In August 2024 at the DoD’s MHSRS conference, the Company presented clinical data and rationale supporting the potential for TNX-102 SL to be studied for the treatment of ASR and prevention of PTSD. Prior studies showed that treatment with TNX-102 SL showed effects on sleep and PTSD symptoms in PTSD patients at two and four weeks. This supportive data on the effects of TNX-102 SL on reducing PTSD symptoms suggest early intervention immediately after trauma using TNX-102 SL has the potential to reduce ASR/ASD symptoms which are similar to those of PTSD. Data from these trials support testing of TNX-102 SL within 24 hours of index trauma for effects on ASR symptoms and the subsequent incidence of newly developed PTSD.

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 mgi.v. doses was well tolerated and interrupted cocaine effects after cocaine 50 mgi.v. challenge.

In August 2022, we announced that we received a Cooperative Agreement grant from NIDA, part of NIH, to support development of TNX-1300. 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 manufactured Phase 2 drug product clinical supply.

We initiated a Phase 2 clinical trial, CATALYST, of TNX-1300 in the third quarter of 2024. The Phase 2 trial is a single-blind, placebo-controlled, proof-of-concept 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. Because of the challenges of recruiting eligible patients into this study, we are not guiding to a timeline for completion of enrollment or topline data.

TNX-1900 –Adolescent Obesity, Binge Eating Disorder. Social Anxiety and Bone Health in Autism

TNX-1900 (intranasal potentiated oxytocin) is a proprietary formulation of oxytocin primarily in development under investigator-initiated INDs for the treatment of adolescent obesity, binge eating disorder, bone health in pediatric autism, and social anxiety disorder. 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.

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.

There are three ongoing Phase 2 investigator-initiated studies enrolling at MGH: the POWER study for the treatment of adolescent obesity, the STROBE study for the treatment of BED, and the BOX study for the treatment of bone health in pediatric autism. In addition to the studies at MGH, University of Washington is conducting an investigator-initiated study of TNX-1900 in SAD using functional MRI, in which the clinical phase has been completed, and data analyses are in progress.

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.

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.

TNX-1500 was engineered to modulate binding to Fc receptors with the goal of maintaining the activity of first-generation monoclonal antibodies (mAbs), yet with reduced risk of thrombotic complications. TNX-1500 is being developed as a prophylaxis against organ transplant rejection as well as to treat autoimmune conditions. The IND was cleared for the prevention of kidney transplant, and a Phase 1 single ascending dose escalation study at 3 mg/kg, 10 mg/kg and 30 mg/kg of TNX-1500 in healthy volunteers was initiated in the second quarter of 2023. The objectives of the Phase 1 trial were to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenous TNX-1500, as well as to support dosing in a planned Phase 2 trial in kidney transplant recipients. We reported positive topline data related to the Phase 1 in February of 2025. TNX-1500 showed suppression of the primary and secondary antibody responses to KLH antigen challenges for the 10 and 30 mg/kg doses. Additionally, preliminary pharmacokinetic results showed mean half-life (t 1/2) for the 10 mg/kg and 30 mg/kg dose groups of 34-38 days, consistent with monthly dosing. In healthy volunteers, TNX-1500 was generally well-tolerated with a favorable safety profile. Anti-CD40L has multiple potential indications in addition to solid organ and bone marrow transplantation including autoimmune diseases: potential pipeline in a product. Tonix plans to discuss these results with the FDA in an End-of-Phase 1 meeting. Pending alignment with the FDA, a Phase 2 study of TNX-1500 in kidney transplant recipients will be pursued.

TNX-1500 has also been studied in combination with other immunosuppressive agents in allogeneic transplants in non-human primates at MGH. In experiments at MGH, 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. Results from 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. Some results from this collaboration were published in the peer-reviewed journal,American Journal of Transplantationin 2023. In June 2024, at the American Transplant Congress 2024, Tonix announced data demonstrating the combined use of TNX-1500 and anti-CD28 monoclonal antibody, VEL-101 is associated with durable protection and graft survival and function in a nonhuman primate model. Further data demonstrated that TNX-1500 has promise to prevent rejection of 9-, or 10-gene-edited (GE) pig hearts. All research has been directed by the faculty of the Center for Transplantation Sciences at Massachusetts General Hospital.

TNX-1500 also is being studied in combination with other immunosuppressive agents in xenogeneic organ transplants in non-human primates at MGH. In some of these studies, genetically engineered (“GE”) pigs in baboon transplants were treated with cold perfused ischemia minimization and a novel costimulation-based immunosuppressive regimen including TNX-1500. The results of these preclinical studies were encouraging and demonstrated the potential of genetically engineered pig hearts in the context of a clinically applicable regimen. The multi-GE pigs were provided by eGenesis and Revivicor. Revivicor is a subsidiary of United Therapeutics. Some results from the collaboration with MGH and eGenesis were published in the peer-reviewed journal,Nature in 2023. In March of 2024, MGH announced the first GE pig kidney transplant into a living recipient supported in part by the pre-clinical work with TNX-1500. TNX-1500 therapy was not used in the human transplant recipient.

In pre-clinical experiments at MGH, TNX-1500 is being studied as monotherapy or in combination with immunosuppressive drugs in heart and kidney organ transplants in animals. The data demonstrates that TNX-1500 showed activity in preventing organ rejection and was well tolerated in animals. Blockade of CD40L with TNX-1500 monotherapy consistently prevented pathologic alloimmunity in animal models of cardiac and kidney allograft model without evidence of clinical thrombosis.

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.

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-1700 — Gastric and Colorectal Cancers

TNX-1700 is a recombinant Trefoil Family Factor 2 (hTFF2-HSA) fusion protein in development to treat gastric and colorectal 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 colorectal 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.

Preclinical data has shown that mTFF2-CTP augmented the efficacy of mAb anti-PD-1 therapy. Anti-PD-1 in combination with mTFF2-CTP showed greater anti-tumor activity in PD-L1-overexpressing mice. The mechanism of action is to suppress myeloid-derived suppressor cells and activate anti-cancer CD8+ T cells, which is different from checkpoint inhibitors. There is potential synergy with anti-PD-1 or anti-PD-L1 mAbs.

TNX-801 –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 and mpox. 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®, the only non-replicating virus vaccine, is currently approved by the FDA to protect against smallpox and mpox. Jynneos® requires two-doses, with an efficacy of approximately 35% after one dose. During the most recent mpox outbreak in the United States, dropout between doses was 24%. 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. We also believe that TNX-801 would require only one dose.

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. The Bipartisan Commission on Biodefense (2024) noted that “Smallpox and other orthopoxviruses pose significant threats to the United States and the world due to their potential for weaponization, accidental release, and vulnerability of populations who stopped routinely vaccinating against smallpox in the 1970s” (Bipartisan Commission on Biodefense).

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 has become endemic in the U.S. since it spread in the U.S. and other countries outside of Africa, mostly in populations of gay men. In August 2024, the WHO determined that the upsurge of mpox in a growing number of countries in Africa constitutes a public health emergency of international concern (PHEIC), the second such declaration in the past two years in response to transmission of the virus. Mpox cases of the new clade Ib mpox have since also been detected in multiple countries outside of Africa, including the U.S.. Animals vaccinated with TNX-801 were protected from mpox in studies reported in the first quarter of 2020. These data were published in the peer-reviewed journalVaccines in 2023.

In November 2024, Tonix announced that it has entered into a sponsored research agreement with the Kenya Medical Research Institute (KEMRI) to design, plan and seek regulatory approval for a Phase 1 clinical study in Kenya to test the safety, tolerability, and immunogenicity of TNX-801 as a vaccine to prevent mpox and smallpox. Tonix will be the sponsor and KEMRI will lead the execution of the proposed clinical trial.

In September 2024, at the DoD’s MHSRS conference and in October 2024 at the World Vaccine Congress in Barcelona, Spain, Tonix presented new data on potential mpox vaccine, TNX-801, demonstrating tolerability and no evidence of spreading to blood or tissues, even at high doses, in immunocompromised animals. After a single-dose vaccination, TNX-801 prevented clinical disease and lesions, and also decreased shedding in the mouth and lungs of animals after a lethal challenge with clade Ia monkeypox. These findings are consistent with TNX-801 inducing mucosal immunity and suggest TNX-801 has the ability to block forward transmission. In September 2024, the Company also announced that the WHO’s preferred TPP aligns with the characteristics of TNX-801. Key elements of the WHO draft TPP include single-dose, durable protection, administration without special equipment, and stability at ambient temperature. Other potential beneficial characteristics include the ability to limit forward transmission, use in case-contact vaccination strategies and suitability for use in immunocompromised individuals.

In August 2024, Tonix and Bilthoven Biologicals, part of the world’s largest vaccine manufacturer the Cyrus Poonawalla Group, which includes the Serum Institute of India, announced a collaboration to advance TNX-801.

In October 2023, at the World Vaccine Congress - Europe, we reported that the TNX-801 vaccine was shown to be greater than 10 to 1,000-fold more minimally replicative than older vaccinia-based smallpox vaccines in both human primary cell lines and immunocompromised mice. Similar data was also published in the peer-reviewed journalmSphere which presented data demonstrating that TNX-801 is less virulent than 20th Century vaccinia vaccines in immune-compromised mice.

In August 2023 we received pre-IND meeting written responses from the FDA. Tonix believes the FDA feedback provides a path to agreement on the design of a Phase 1/2 study and the overall clinical development plan. The Phase 1/2 clinical trial will assess the safety, tolerability, and immunogenicity of TNX-801, following the submission and clearance of an IND. We are actively working to develop a vaccine meeting cGMP quality to support a clinical study.

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. These results were published in the peer-reviewed journalViruses 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.

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. The company’s Good Manufacturing Practice (GMP)-capable advanced manufacturing facility in Dartmouth, MA was purpose-built to manufacture TNX-801 and the GMP suites are ready to be reactivated in case of a national or international emergency.

TNX-1800 – COVID-19 Vaccine

TNX-1800 is a minimally replicative, live virus vaccine based on our RPV platform that expresses the SARS-CoV-2 spike protein from the ancestral Wuhan strain. TNX-1800 is being further developed to rapidly address new variants as they emerge. The vaccine platform itself can carry a payload of genes. The vaccine protects against COVID-19 by eliciting a durable T cell, humoral and mucosal immune response. It is delivered in only one dose. In November 2023, Tonix announced that the NIAID, a part of the NIH, will conduct a Phase 1 clinical trial with TNX-1800 as part of the Project NextGen Covid-19 Vaccine initiative. This NIAID/NIH program is funded to take selected NextGen vaccine candidates into Phase 1 and Phase 2 trials. Because of extensive reviews of NIH programs, the future of this program is uncertain.

The COVID-19 vaccines that are approved for use 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 limited ability to block the spread of infection (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 (e.g. smallpox). The TNX-1800 vaccine development plan is wholly consistent with priority vaccine attributes advanced by the White House Office of Science and Technology Policy’s Pandemic Preparedness Plan from September 2021, the National Biodefense Science Board report from August 2023, and the BARDA Strategic Plan 2022-2026. Tonix believes its RPV platform can address a wide variety of disease targets of public health interest.

The results of an animal study data showing the protective effect of TNX-1800 vaccine was published in the peer-reviewed journalVaccines in 2023 and show that TNX-1800 induces complete protection against SARS-CoV-2 infection as well as evidence that indicates an impact on spread of infection. These data also 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 has also began undertaking studies to show attenuation of the RPV platform itself in order to evaluate the potential use of the live vaccine platform in the immunocompromised host by the use of mouse model system. These data (detailed below) demonstrate that the RPV vaccine platform that is used for TNX-1800 is >10- to 1,000-fold more minimally replicative than older VACV-based smallpox vaccines in human primary cell lines and immunocompromised mice.

We received pre-IND meeting written responses from the FDA in 2021 regarding our investigational plan to establish the safety and effectiveness evidence in support of the licensure of TNX-1800. We believe that the FDA feedback provides a clear pathway forward towards utilizing its underlying RPV platform for a COVID-19 vaccine.

We announced the issuance of U.S. Patent for TNX-801 smallpox and mpox vaccine and 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.

At the World Vaccine Congress in October 2023, Tonix presented its positive, published non-human primate data for the TNX-1800 (spike from Wuhan strain) from animal challenge studies using live SARS-CoV- 2. 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. Further, as an expected additional outcome, all 16 animals vaccinated with either dose of TNX-1800 or the control TNX-801 manifested a “take”, or cutaneous response, signaling that the horsepox vector elicits a strong T cell immune response. These results support the expectation that TNX-1800 at the low dose of 1 x 106 PFU is an appropriate dose for a one-dose vaccine in humans. These data were published in the peer-reviewed journalVaccines in 2023.

Additional studies have been undertaken to show attenuation of the RPV platform alone (TNX-801) in order to evaluate the potential use of this live vaccine in the immunocompromised host. These data demonstrate that the RPV platform used with TNX-1800 is >10- to 1,000-fold more minimally replicative than older VACV-based smallpox vaccines in human primary cell lines and immunocompromised mice.

TNX-4200 – Broad-Spectrum Antiviral

Tonix is developing CD45-targeted therapeutics (TNX-4200). In July 2024 Tonix was awarded a contract with a potential for up to $34 million over five years by DTRA. The objective of the contract is to develop small molecule broad-spectrum antiviral agents for the prevention or treatment of infections to improve the medical readiness of military personnel in biological threat environments.

Tonix’s program will focus on optimization and development of its TNX-4200 program, to develop an orally available CD45 antagonist, with broad-spectrum efficacy against a range of viral families through preclinical evaluation. The program is expected to establish physicochemical properties, pharmacokinetics, and safety attributes to support an IND submission and to fund a first-in-human Phase 1 clinical study. Tonix plans to leverage previous research on phosphatase inhibitors, specifically compounds that target CD45, to optimize lead compounds for therapeutic intervention of biothreat agents and provide the government with a complete and cost-effective solution for a broad-spectrum medical countermeasure. Tonix’s hypothesis is that partial inhibition of CD45 will provide optimal antiviral protection while requiring lower plasma drug concentrations, a lower dose, and a better safety profile.

TNX-2900 – Prader-Willi Syndrome (PWS)

TNX-2900 is based on our patented intranasal potentiated oxytocin formulation, or TNX-1900, but being developed for PWS. Tonix licensed technology using oxytocin-based therapeutics for the treatment of PWS and non-organic failure to thrive disease from Inserm. The licensing agreement has been negotiated and signed by Inserm Transfert, the private subsidiary of Inserm, on behalf of Inserm, Aix-Marseille Université and Centre Hospitalier Universitaire of Toulouse. 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. There is currently no approved treatment for either the suckling deficit in infants or the obesity and hyperphagia in older children associated with PWS. Since PWS is an orphan disease that occurs in approximately one in 15,000 births, TNX-2900 for PWS has been granted Orphan Drug Designation and Rare Pediatric Disease Designation 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, and Tonix has received IND clearance.

In 2022, Tonix entered into a research collaboration with Inserm involvingin vitro andin 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 PWS 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.

Tonix’s Facilities Overview

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 is the principal site for the research on TNX-4200, a broad-spectrum antiviral targeting CD45 funded by the U.S. Department of Defense, Defense Threat Agency contract. The RDC also conducts research on CNS and immunology drugs. The RDC facility is biosafety level 2 (BSL-2) with BSL-3 components.

The Advanced Development Center (ADC)

The ADC located in the New Bedford business park in Dartmouth, Massachusetts is intended to accelerate development, clinical and commercial scale manufacturing of live-virus vaccines and biologics. ADC includes single-use bioreactors and purification suites with equipment for Good Manufacturing Practice (GMP) production of vaccines and biologics for clinical trials, including the capability of producing sterile vaccines in glass vials.

The ADC is an approximately 45,000 square foot BSL-2 facility which can employ up to 70 researchers, scientists, manufacturing, and technical support staff. This facility was decommissioned in May 2024 but Tonix has the ability to reactivate it should we choose to do so.

Marketing, Sales and Distribution

Marketing activity for Zembrace Symtouch and Tosymra in the United States is conducted by our wholly-owned subsidiary, Tonix Medicines, Inc. We focus our sales and marketing efforts on physicians in private practice and in public treatment systems. We employ standard pharmaceutical marketing practices to promote our products, encompassing advertisements, professional symposia, sales initiatives, and educational outreach aimed at physicians, nurses, social workers, counselors, and other stakeholders involved in treating acute migraine in adults. We have established contracts with third-party vendors to handle logistics, offer customer services, and manage other related aspects for our products. These services include managing product-specific websites, conducting insurance research, processing orders, and handling delivery and fulfillment services. Zembrace Symtouch and Tosymra are primarily sold to pharmaceutical wholesalers, pharmacies, and specialty distributors. We intend to implement patient access programs and expand distribution channels in our marketing efforts for our migraine drugs.

In 2024, Tonix engaged EVERSANA to support the launch strategy and commercial planning of TNX-102 SL for the management of fibromyalgia. Specifically, EVERSANA worked with Tonix to assess the fibromyalgia landscape and help plan an efficient go-to-market strategy.

In 2024, Tonix hired a new head of Commercial Operations as well as Vice Presidents to run Medical Affairs and Marketing, each with decades of experience successfully launching and commercializing new CNS products. In January 2025, Tonix announced the appointment of a vice president to oversee Market Access. In 2025, we will continue to build out our commercial team and capabilities as we look forward to a targeted launch of TNX-102 SL in the fourth quarter of 2025, contingent on FDA approval.

Competition

Our sector faces intense competition and experiences rapid, substantial technological advancements both domestically and internationally. Our potential competitors encompass major pharmaceutical and biotechnology firms, specialty pharmaceutical and generic drug manufacturers, academic institutions, government agencies, and research organizations. We consider efficacy, safety, tolerability, reliability, pricing, and reimbursement levels as crucial competitive factors influencing the development and commercial success of our product candidates. Numerous potential competitors, including some of the organizations listed below, possess considerably larger financial, technical, and human resources, as well as extensive experience in discovering and developing product candidates, securing FDA and other regulatory approvals, and commercializing those products, far surpassing our own capabilities. Hence, our competitors might achieve greater success in securing FDA approval for drugs and gaining widespread market acceptance compared to us. The drugs offered by our competitors may prove to be more effective or better marketed and sold than any product we bring to market, potentially rendering our product candidates obsolete or non-competitive before we can recoup the expenses incurred in their development and commercialization. We expect to encounter heightened competition as the market sees the introduction of new drugs and the emergence of advanced technologies. Additionally, the evolution of novel treatment approaches for the conditions we are focusing on may potentially diminish the competitiveness or relevance of our drugs. Below, we provide an overview of the competitive landscape for the indications where Tonix has product candidates either in or nearing the clinical stages of development.

Migraine

Zembrace Symtouch and Tosymra are indicated for the treatment of acute migraine and compete with generic versions of sumatriptan. Zembrace is an autoinjector formulation of sumatriptan and competes with generic subcutaneous products. Tosymra is an intranasal formulation of sumatriptan and competes with generic intranasal products. Zembrace and Tosymra also compete with the new molecular entities including oral migraine therapies such as Nurtec® (Rimegepant) from Pfizer Inc. and Ubrelvy® (Ubrogepant) and QULIPTA® (atogepant) from AbbVie Inc. and intranasal migraine therapies such as Zavzpret™ (vazegepant) by Pfizer, Inc. Most recently, Axsome Therapeutics announced FDA approval of SYMBRAVO® (meloxicam and rizatriptan) for the acute treatment of migraine with or without aura in adults. We also note that the PDUFA goal date for Shin Nippon Biomedical Laboratories, Ltd and Satsuma Pharmaceuticals is April 30, 2025 for their intranasal asset STS101 (dihydroergotamine) for the treatment of migraine headaches.

Fibromyalgia

We are currently awaiting an FDA decision on marketing authorization for TNX-102 SL for the management of fibromyalgia. There are 3 products approved for the treatment of fibromyalgia which include Lyrica® (pregabalin), developed by Pfizer, Inc., Cymbalta® (duloxetine), developed by Eli Lilly and Company, and Savella® (milnacipran) marketed by AbbVie. Pregabalin and duloxetine are available as generics, while Savella is still on patent. There has not been a new product approved for this indication in 15 years.

Tonix is aware of multiple companies actively developing treatments for fibromyalgia. Axsome Therapeutics Inc. expects to submit an NDA for AXS-14 (esreboxetine) for the management of fibromyalgia to the FDA for AXS-14 in Q1 2025. Virios Therapeutics, Inc. announced the initiation of a Phase 3 trial in the U.S. for IMC-1 for the treatment of fibromyalgia. IMC-1 is a fixed dose combination of famciclovir + celecoxib, is a 505(b)(2) and has been granted Fast Track Designation by the FDA. Tonix is also focused on developments for fibromyalgia outside of the U.S. and keeps abreast of the progress made by Australian company Tryptamine Therapeutics Ltd who announced positive data from a Phase IIa clinical trial of TRP-8802 for fibromyalgia which was presented in an abstract at the International Association for the Study of Pain (IASP) 2024 World Congress on August 9, 2024.

Long COVID (Post-Acute Sequelae of SARS-CoV-2 Infection or PASC)

As of now, there are no specific drugs approved by the FDA solely for the treatment of Long COVID (formerly known as Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)). Tonix is aware of several companies developing therapeutics for the treatment of Long COVID including, but not limited to, Direct Biologics, LLC (Phase III for DB-001 was completed in the fourth quarter of 2024 and American CryoStem Corporation. Other developments include Organicell Regenerative Medicine, Inc. is conducting a Phase 2 for Zofin as a potential therapeutic for Long COVID. PaxMedica, Inc. is developing PAX-101 for the treatment of Long COVID and currently conducting a Phase1b in South Africa. In October 2024, Resolve Therapeutics, LLC, announced the results from its Phase II Long COVID study of RSLV-132. Furthermore, GeNeuro announced the data from Phase II GNC-501 clinical trial in patients suffering from Long COVID, testing temelimab against placebo. Finally, in June 2024, Berlin Cures Holding AG announced that it is preparing for a Phase III study in Long COVID and Statera BioPharma, Inc. is comparing STAT-205 with placebo for reducing fatigue in Long COVID.

Acute Stress Reaction/Acute Stress Disorder (ASR/ASD)

There are no approved drugs for treating ASR or for the prevention of ASD or PTSD. In October 2024, BioXcel Therapeutics announced a Phase IIa efficacy and safety trial of BXCL501 in patients experiencing ASD resulting from motor vehicle collisions to begin in the first half of 2025. BXCL501 is an orally dissolvable film formulation of the α2A adrenergic receptor agonist dexmedetomidine that is FDA approved as IGALMI® for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults.

Cocaine Intoxication

There are no approved antidotes for the treatment of cocaine intoxication. Patients generally receive supportive care. We are not aware of any drugs in development for the treatment of cocaine intoxication. We are aware of companies that are targeting cocaine use disorder and we monitor their progress. Embera NeuroTherapeutics currently lists EMB-001 in Phase II development for the treatment of cocaine use disorder in its pipeline.

Transplantation Rejection and Autoimmune Treatments with Anti-CD40-ligand Monoclonal Antibodies

We are aware of multiple companies advancing the development of biologics targeting the CD40L molecule including Sanofi, UCB, Eledon Pharmaceuticals, and Amgen Inc. Eledon Pharmaceuticals revealed promising results from the Phase I/II trial of tegoprubart, aimed at preventing islet transplant rejection in individuals with type 1 diabetes. The trial showed that the first human cases of insulin independence were achieved using an anti-CD40L monoclonal antibody therapy, without relying on tacrolimus, the current standard treatment for preventing transplant rejection. Sanofi’s SAR441344 (Frexalimab), a second-generation anti-CD40L monoclonal antibody, is being tested in multiple sclerosis. In a Phase II trial involving participants with relapsing multiple sclerosis (NCT04879628), frexalimab demonstrated effectiveness in quickly reducing the number of new gadolinium-enhancing T1-lesions at week 12. Amgen Inc. is currently conducting a Phase III trial to test Dazodalibep for Sjogren’s Syndrome (NCT06104124) with an estimated completion date for the first half of 2026. H. Lundbeck is testing Lu AG22515 for Thyroid Eye Disease (TED) and plans to report results from the Phase Ib TED study in the second half of 2026. In 2024, UCB and Biogen announced positive results from a Phase III trial testing Dapirolizumab Pegol for Systemic Lupus Erythematosus. In November 2024, UCB and Biogen announced the initiation of their potentially confirmatory Phase III trial to test Dapirolizumab Pegol for Systemic Lupus Erythematosus (NCT06617325). These are a few key highlights that underscore the focus of major pharmaceutical companies in this area and we monitor the activity of other companies in the process of developing antagonistic anti-CD40 mAbs, including Novartis, Boehringer Ingelheim GmbH, Kiniska Pharmaceuticals, Boston Immune Therapies, and NapaJen Pharma Inc.

Prader Willi Syndrome

Somatropin, which targets the Growth Hormone Receptor is approved in the U.S. and marketed by Pfizer Inc. and Novo Nordisk. Novartis AG markets Omnitrope® in Europe. There are no approved products for the treatment of hyperphagia or over-eating in PWS. Patients generally receive care to best manage individual symptom presentation. ACADIA Pharmaceuticals Inc. currently have ACP-101 (intranasal carbetocin) (acquired Levo Therapeutics in June 2022) in a Phase 3, randomized, double-blind, placebo-controlled, 8-week clinical study to assess the efficacy, safety, and tolerability, of ACP-101 in PWS with long term follow-up. Acadia anticipates the enrollment of the final patient in by the fourth quarter of 2025, with top-line results expected to be announced in the first half of 2026. Soleno is developing diazoxide chloride controlled release (DCCR) which had positive results in a randomized withdrawal study of PWS. The PDUFA goal date for a decision on marketing authorization is in March 2025.

Carmot Therapeutics Inc. announced that they plan to release Phase I single ascending dose (SAD)/MAD data for CT-PYY in 2025 for the treatment of PWS. Harmony Biosciences Holdings, Inc. received Orphan Drug Designation for their asset Wakix (pitolisant hydrochloride) for the treatment of PWS. Harmony Biosciences announced initial topline results from its Phase II proof-of-concept study in patients with PWS, which showed a signal on improvement in the primary outcome related to excessive daytime sleepiness in November 2022. At the end of 2024, Neuren Pharmaceuticals Limited announced the suspension of its Phase II open-label study of the safety, tolerability, and pharmacokinetics of oral NNZ-2591 in Prader-Willi syndrome (PWS-001) due to a revised development strategy.

Tonix is knowledgeable about several companies dedicated to developing a therapy for the treatment of PWS including, but not limited to, Aardvark Therapeutics, ConSynance Therapeutics, Lipidio Pharma, Helsinn, Inversago Pharma, Saniona, 9 Meters Biopharma, Neuracle Science, Harmony Biosciences Holding Inc., and Notitia Biotechnologies.

Gastric and Colorectal Cancer

TNX-1700 asset is a recombinant TFF2 (albumin fusion peptide) and has demonstrated that by targeting myeloid derived suppressor cells (MDSCs) using TFF2-MSA fusion protein synergizes well with PD-1 blockade therapy in advanced and metastatic syngeneic mouse models of colorectal cancer. Tonix is aware of several companies that are focused on MDSCs to treat Gastric and Colorectal Cancer. Anbogen announced a drug supply collaboration to evaluate the combination of Anbogen’s ABT-301, with BeiGene’s tislelizumab, in patients with mismatch repair–proficient or microsatellite stable metastatic colorectal cancer (“mCRC”) in a global Phase II trial. Gilead Sciences and Arcus Biosciences announced new data from Cohort B of ARC-9, a Phase Ib/II study evaluating the safety and efficacy of etrumadenant, a dual A2a/b adenosine receptor antagonist, plus anti-PD-1 monoclonal antibody zimberelimab, FOLFOX chemotherapy and bevacizumab (EZFB) in third-line mCRC. In 2023, TriSalus Life Sciences announced it plans to initiate a Phase II trial of SD-101 (Nelitolimod) for colorectal cancer. NextCure, Inc. have NC410 in the clinic for Colorectal Cancer. Faron Pharmaceuticals Oy have Bexmarilimab in the clinic for Colorectal Cancer. Merck & Co., Inc. and Agenus are collaborating on MK-4830 for Colorectal Cancer.

Smallpox / Mpox

BioNTech SE is conducting a Phase I/II study in the U.S. evaluating the safety, tolerability, reactogenicity and immunogenicity of the investigational RNA-based multivalent vaccine candidate BNT166a for active immunization against mpox. The study is expected to complete in the first quarter of 2026. In 2023, Moderna announced it has mRNA-1769 in preclinical development for the treatment of Mpox. Moderna is conducting a P1/2 study of mpox vaccine in the U.K. Emergent BioSolutions, Inc. has enabled the enrolment of the first patients for the MOSA, a pan-African randomized platform adaptive trial to test Tembexa to treat mpox at Mbandaka Hospital in Equateur Province, Democratic Republic of Congo. A first interim analysis is expected by the end of the first quarter of 2025. Other companies we monitor include GeoVax Labs, Inc., NanoViricides, Inc., EpiVax, Inc., Gylden Pharma Limited.

Covid-19

There are many vaccine products in development for the treatment or prevention of Covid-19 globally. Approved products include Pfizer-BioNTech’s (BNT162b2), Moderna’s (mRNA-1273) and Novavax’s (NVX-CoV2373) which are routinely updated to address new variants. CSL and Arcturus announced that the European Commission has granted marketing authorization for KOSTAIVE (ARCT-154), an mRNA COVID-19 vaccine, KOSTAIVE is currently marketed in Japan against COVID-19. Codagenix is developing CoviLiv™ as an intranasal vaccine candidate and in Phase 3 for COVID-19. Other companies working in the area include: Vaxart Inc. which is developing a potentially orally administered vaccine based on the adenovirus serotype 5 (Ad-5) vector to express the spike protein of SARS-CoV-2; CastleVax USA which is developing a potential nasally administered vaccine based on a Newcastle disease virus (NDV) vector to express the Spike protein of SARS-CoV-2.

Intellectual Property

We believe that we have an extensive patent portfolio and substantial know-how relating to TNX-102 SL, Zembrace®, Tosymra®, TNX-1300, TNX-1500, TNX-2900, TNX-1900, TNX-801, TNX-1800 and TNX-1700, 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 10, 2025, the patents we are either the owner of record of or own the contractual right to include 42 issued U.S. patents and 432 issued non-U.S. patents. We are actively pursuing an additional 23 U.S. non-provisional patent applications, 3 international patent applications, and 244 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 February 10, 2025 are summarized below.

TNX-102 SL — Central Nervous System Conditions

Our patent portfolio for TNX-102 SL includes patents and 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 pain, fatigue and sleep disturbances in fibromyalgia, for treating or managing fibromyalgia (early onset response, favorable tolerability, or side effect profile), for alcohol abuse, for disordered sleep, for sexual dysfunction, for depression in fibromyalgia, for fatigue and disordered sleep (e.g., CAP rates), for post-acute sequelae of SARS-CoV-2 infection, for acute stress reaction/acute stress disorder, and for agitation in neurodegenerative conditions, e.g., AD.

Certain eutectic compositions were discovered by development partners and are termed the “Eutectic Technology.” The patent portfolio for CBP compositions (e.g., TNX-102 SL) relating to the Eutectic Technology includes patents and 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, U.S. Patent No. 11,026,898, and U.S. Patent No. 11,839,594. These U.S. patents and counterpart non-U.S. patents, and any U.S. and non-U.S. patents that issue in the future from this portfolio 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. On January 11, 2024, the European Patent Office Technical Board of Appeal reversed the October 2019 decision of the Opposition Division of the European Patent Office maintaining the patent in unamended form and held the patent to be invalid. No appeal may be taken from that decision.

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 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 August 4, 2023, Chinese Patent No. ZL201910263541.6, entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride,” issued. The claims recite a eutectics of cyclobenzaprine hydrochloride and beta-mannitol and methods of making those eutectics.

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

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 after the January 2022 oral proceedings. Hexal AG did not appeal that decision.

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 after the February 2022 oral proceedings. Hexal AG did not appeal that decision.

On June 4, 2024, U.S. Patent No. 11,998,516, entitled “Methods and Compositions for Treating Depression Using Cyclobenzaprine,” issued. The claims recite methods for treating major depressive disorder in a fibromyalgia patient using a composition comprising cyclobenzaprine or its salts.

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

On December 12, 2023, U.S. Patent No. 11,839,594 entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The claims recite a method of manufacturing a eutectic comprising cyclobenzaprine hydrochloride and beta-mannitol comprising mixing or milling.

On February 14, 2024, European Patent No. 3,650,081, entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The claims recite a eutectic of mannitol and cyclobenzaprine hydrochloride and methods of manufacturing a eutectic.

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, Japan, and Hong Kong. On October 5, 2022, International Patent Application No. PCT/US2022/045791, entitled “Cyclobenzaprine Treatment for Sexual Dysfunction,” was filed and is now nationalized in European Patent Office and U.S. (U.S. Patent Application No. 18/698,483). 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, International Patent Application No. PCT/IB2018/001509, entitled “Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions,” was 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 November 28, 2023, U.S. Patent No. 11,826,321, entitled “Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions,” issued. The claims are directed to a method for treating or preventing one or more agitation associated symptoms comprising administering a eutectic of cyclobenzaprine HCl and mannitol.

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 PCT application is now nationalized in 13 countries. 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 PCT is now nationalized in 15 countries. 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 of cyclobenzaprine hydrochloride and mannitol in dosage units with a basifying agent.

On June 21, 2023, U.S. non-provisional Patent Application No. 18/212,500 and International Patent Application No. PCT/US2023/025895, entitled “Cyclobenzaprine Treatment for Post-Acute Sequelae of (SARS)-CoV-2 Infection (PASC),” were filed. The PCT is now nationalized in 9 countries. The claims are directed to methods of treating PASC or one or more associated symptoms comprising administering cyclobenzaprine or a pharmaceutically acceptable salts of cyclobenzaprine.

On December 19, 2024, U.S. non-provisional Patent Application No. 18/988,194 and International Patent Application No. PCT/US2024/061125, entitled “Early Onset Response, Favorable Tolerability, and Side Effect Profile in the Treatment of Fibromyalgia,” were filed. The claims are directed to methods for treating or managing fibromyalgia and its associated symptoms in subjects characterized by an early onset of one or more of: (1) a reduction in widespread pain; (2) a reduction in sleep disturbance; (3) a reduction in fatigue; or (4) an improved sleep quality. The claims are also directed to methods for preventing or avoiding clinically meaningful changes in mean weight, in mean systolic blood pressure or mean diastolic blood pressure, or a decline in sexual functioning.

On January 23, 2025, International Patent Application No. PCT/US2025/012803, entitled Cyclobenzaprine Treatment for Acute Stress Reaction or Acute Stress Disorder,” was filed. The claims are directed to methods for treating or preventing acute stress reaction (ASR) or acute stress disorder (ASD) and associated symptoms thereof using a composition with cyclobenzaprine or its salts in.

TNX-1900 — Oxytocin-Based Treatments for Obesity, Eating Disorders, Pain, Insulin Resistance, and Diabetes

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. On October 4, 2023, European Patent No. 3242676, entitled “Magnesium-Containing Oxytocin Formulations and Methods of Use,” issued.

We also acquired International Patent Application No. PCT/US2017/027265, filed April 12, 2017, entitled “Magnesium-Containing Oxytocin Formulations and Methods of Use” (nationalized in 9 countries). On December 3, 2024, U.S. Patent No. 12,156,897, entitled “Magnesium-Containing Oxytocin Formulations and Methods of Use,” issued. The patent, which claims methods for treating autism spectrum disorder, social anxiety disorder, or a social communication disorder, will expire in April 2037, 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). On April 30, 2024, U.S. Patent No. 11,970,554, entitled “Labeled Oxytocin and Method of Manufacture and Use,” issued.

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 (PWS)

We have licensed technology using oxytocin-based therapeutics for the treatment of PWS 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-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 (nationalized in 14 countries).

On August 28, 2024, European Patent No. 3993876, entitled “Anti-CD154 Antibodies and Uses Thereof,” issued (validated in 37 countries). The claims recite an isolated antibody that binds CD154, compositions comprising the antibody, and use of the compositions for treating or preventing a transplant rejection.

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-1800 and TNX-1850 — Live Modified Horsepox Vaccine for Prevention of COVID-19

We are developing TNX-1800 and TNX-1850, live minimally replicative modified HPXVs, as a COVID-19 preventing vaccine against different strains of SARS-CoV-2. 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 now nationalized in 19 countries. These applications are directed to synthetic poxviruses comprising a SARS-CoV-2 virus protein, poxvirus delivery vectors for SARS-CoV-2 virus 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 Colorectal 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 colorectal cancers. The licensed patents are directed to rTFF2 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-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 6 countries) and U.S. Patent Application No. 18/055,596, both entitled “Compositions and Methods for Increasing Efficacy of a Drug.”

TNX-4300 — Estianeptine for Psychiatric and Neurodegenerative Diseases

We are developing TNX-4300, the (S)-isomer of tianeptine, for psychiatric and neurodegenerative diseases. On March 27, 2024, we filed International Patent Application No. PCT/US2024/021799, entitled “(S)-Tianeptine and Use in Treating Disorders and Conditions Associated with Peroxisome Proliferator-Activated Receptor.”

Zembrace and Tosymra — Sumatriptan

We have acquired the intellectual property rights of Zembrace SymTouch and Tosymra and their uses in treating migraine from Upsher-Smith Laboratories, LLC. These rights include U.S. Patent No. 9,211, 282, U.S. Patent No. 9,610,280, U.S. Patent No. 9,974,770, U.S. Patent No. 10,603,305, U.S. Patent No. 11,337,962, U.S. Patent No. 10,537,554, and U.S. Patent No. 11,364, 224. These rights also include International Patent Application No. PCT/US2016/015961, entitled “Pharmaceutical Composition Comprising Sumatriptan for Treating Migraine,” (nationalized in 7 countries, excluding rights in Brazil and China) and International Patent Application No. PCT/IB2010/001708, entitled “Formulations Comprising Triptan Compounds,” (nationalized in 11 countries, excluding rights in Brazil, Russia, India, and China).

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

Sublingual CBP/Amitriptyline

CBP – Depression

CBP – PTSD

CBP Fatigue

CBP – Agitation in Neurodegenerative Condition

CBP/Amitriptyline Eutectic Formulations

Analogs of CBP

Oxytocin therapeutics

Nociceptin/Orphanin FQ therapeutics

Tianeptine – Neurocognitive Dysfunction

TFF2 therapeutics

Synthetic Chimeric Poxviruses

Triptan Compound – Formulations

Triptan Compound – Migraine

CD40 and anti-CD154 Therapeutics

CBP - ASD and PTSD

Pending Patent Applications

Our current pending patent applications are as follows:

CD40 and anti-CD154 Therapeutics

CBP/Amitriptyline Eutectic Formulations

Sublingual CBP/Amitriptyline

CBP – Agitation in Neurodegenerative Condition

Analogs of CBP

CBP – ASD and PTSD

CBP – Fibromyalgia

CBP – Fibromyalgia (Early Onset Response, Favorable Tolerability, and Side Effect Profile)

CBP – Acute Stress Reaction or Acute Stress Disorder

CBP – Alcohol Use Disorder

CBP – Sexual dysfunction

CBP – Post-Acute Sequelae of SARS-CoV-2 (PASC)

Oxytocin therapeutics

Nociceptin/Orphanin FQ therapeutics

Synthetic Chimeric Poxviruses

Synthetic Vaccinia Virus

Poxvirus vaccine against COVID-19

TFF2 therapeutics

Antiviral Drugs – Cathepsin Inhibitors

Triptan Compound – Formulations

Triptan Compound – Migraine

Tianeptine – Conditions Associated with Peroxisome Proliferator-Activated Receptor

Trademarks and Service Marks

Tonix Pharmaceuticals, Inc.

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 mark: 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. 98/327953, filed December 22, 2023), 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. 98/577945, filed May 31, 2024), ANGSTRO-TECHNOLOGY (Serial No. 98/006538, filed May 22, 2023) and TNX-102 SL (Serial No. 97/185424, filed December 22, 2021).

Tonix Medicines, Inc.

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: NOTIME4MIGRAINES (Reg. No. 5392512, issued January 30, 2018); SYMTOUCH (Reg. No. 5186988, issued April 18, 2017); TOSYMRA (Reg. No. 5981221, issued February 11, 2020); TOSYMRA & DROPLET Design (Reg. No. 6142333, issued August 11, 2020); ZEMBRACE (Reg. No. 5186989, issued April 18, 2017); ZEMBRACE SYMTOUCH (Reg. No.5478282, issued May 29, 2018); DROPLET Design (Reg. No. 6117797, issued August 4, 2020); TONIX ONE LOGO Design (Serial No. 99/057051, filed February 26, 2025). We are the owner of the following International Registrations under the Madrid Protocol: TOSYMRA (Reg. No. 1501060, issued October 16, 2019 – Extensions of Protection to: Canada, European Union, Japan, Republic of Korea, United Kingdom); ZEMBRACE (Reg. No. 1683288, issued August 17, 2022 – Extensions of Protection to: Canada (still pending), China, European Union, Israel, Mexico, United Kingdom); DROPLET Design (Reg. No. 1545038, issued June 29, 2020 – Extensions of Protection to: Canada, European Union, Israel, Japan, Norway, Republic of Korea, Switzerland, Turkey, United Kingdom); European Union: TONIX ONE LOGO Design (Application No. 19151272, filed March 4, 2025).

Research and Development

We have approximately 45 employees dedicated to research and development. Our research and development operations are located in Chatham, NJ, 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.

Marketing

We have nine employees supporting sales administration and marketing initiatives. We also have three sales employees who are focused on customer service requests and top-tier headache specialists. We utilize third party vendors to support trade, managed markets, marketing initiatives, and promotional compliance programs.

Manufacturing

We have contracted with third-party cGMP-compliant contract manufacturer organizations(“CMOs”), for the manufacture of TNX-102 SL drug substance and drug products for clinical and commercial supply. Our manufacturing operations are managed and controlled out of our Dublin, Ireland offices.

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.

We own a 45,000 square foot facility in Massachusetts, to house our new Advanced Development Center for accelerated development and manufacturing of vaccines and biologics. This facility is currently decommissioned. It was designed for the manufacture of nonclinical and clinical investigational products for our Infectious Disease portfolio. The current focus of which is TNX-801 a Smallpox and Mpox Preventing Vaccine and TNX-1800 a COVID vaccine selected by NIH/NIAID Project NextGen for Inclusion in Clinical Trials. This facility was decommissioned in 2024 but Tonix has the ability to reactivate it should we choose to do so.

Our two marketed products, Zembrace and Tosymra, are manufactured at cGMP compliant, FDA audited, U.S. based CMOs with expertise in pre-filled syringe and inhalation expertise.

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:

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.

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. 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. We submitted NDA under Section 505(b)(2) for TNX-102 SL for FM, and plan to submit an 505(b)(2)for 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.

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 exclusivities 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:

Fast Track Designation

A Fast Track is a designation by the FDA of an investigational drug which:

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.

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 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:

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.

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 17, 2025, we had 81 full-time employees, of whom 12 hold M.D. or Ph.D. degrees. We have 45 employees dedicated to research and development. We have two employees supporting sales administration and marketing initiatives and three sales employees who are focused on customer service requests and top-tier headache specialists. 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, New Jersey, Dartmouth, Massachusetts, 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.

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.** **