UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
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DOCUMENTS INCORPORATED BY REFERENCE
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TABLE OF CONTENTS
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PART I
ITEM 1 - BUSINESS
This Annual Report on Form 10-K (including the section regarding Management’s Discussion and Analysis of Financial Condition and Results of Operations) contains forward-looking statements regarding our business, financial condition, results of operations and prospects. Words such as “expects,” “anticipates,” “intends,” “plans,” “believes,” “seeks,” “estimates” and similar expressions or variations of such words are intended to identify forward-looking statements, but are not deemed to represent an all-inclusive means of identifying forward-looking statements as denoted in this Annual Report on Form 10-K. Additionally, statements concerning future matters are forward-looking statements.
Although forward-looking statements in this Annual Report on Form 10-K reflect the good faith judgment of our Management, such statements can only be based on facts and factors currently known by us. Consequently, forward-looking statements are inherently subject to risks and uncertainties and actual results and outcomes may differ materially from the results and outcomes discussed in or anticipated by the forward-looking statements. Factors that could cause or contribute to such differences in results and outcomes include, without limitation, those specifically addressed under the heading “Risks Factors” below, as well as those discussed elsewhere in this Annual Report on Form 10-K. Readers are urged not to place undue reliance on these forward-looking statements, which speak only as of the date of this Annual Report on Form 10-K. We file reports with the Securities and Exchange Commission (“SEC”). You can read and copy any materials we file or will file with the SEC, which, among other places, can be found on the SEC’s website at http://www.sec.gov, as well as on our corporate website at www.tonixpharma.com).
We undertake no obligation to revise or update any forward-looking statements in order to reflect any event or circumstance that may arise after the date of this Annual Report on Form 10-K. Readers are urged to carefully review and consider the various disclosures made throughout the entirety of this Annual Report, which attempt to advise interested parties of the risks and factors that may affect our business, financial condition, results of operations and prospects.
Tonix Pharmaceuticals®, Tonmya®, Protectic™, Angstro-Technology™ and other trademarks and intellectual property of ours appearing in this report are our property. This report contains additional trade names and trademarks of other companies. We do not intend our use or display of other companies’ trade names or trademarks to imply an endorsement or sponsorship of us by such companies, or any relationship with any of these companies.
Business Overview
We are a clinical-stage biopharmaceutical company focused on developing therapeutics and vaccines to treat and prevent human disease and alleviate suffering. We have a rich pipeline of products in development that has been curated from internal discovery, as well as licenses, acquisitions and collaborations with academic institutions and contract research organizations. We continue to build capabilities in synthetic biology, precision medicine, protein engineering, medicinal chemistry, molecular biology, pharmacogenomics and clinical-scale manufacturing. Our therapeutics under development include both small molecules and biologics.
Our portfolio consists of central nervous system, or CNS, rare disease, immunology, and infectious disease product candidates. The CNS portfolio includes small molecules and biologics to treat pain, neurologic, psychiatric and addiction conditions. Our rare disease portfolio focuses on developing novel therapies for patients with rare diseases, including those caused by genetic disorders which are characterized by complex symptoms and for which no drug is approved. Our immunology portfolio includes biologics to address organ transplant rejection, autoimmune diseases and cancer. Our infectious disease portfolio includes a vaccine in development to prevent smallpox and mpox (formerly known as monkeypox), next-generation vaccines to prevent COVID-19, a platform to make fully human monoclonal antibodies, or mAbs, to treat COVID-19 and humanized anti-SARS-CoV-2 mAbs. Our vaccine in development to prevent smallpox and mpox also serves as the live virus vaccine platform or recombinant pox vaccine (RPV) platform for other infectious diseases.
Our latest stage CNS product candidate is TNX-102 SL*, a proprietary sublingual tablet formulation of cyclobenzaprine (CBP) designed for bedtime administration. TNX-102 SL has active INDs for fibromyalgia, or FM, FM-type Long COVID or PASC (post-acute sequelae of SARS-CoV-2 infection), posttraumatic stress disorder, or PTSD, agitation in Alzheimer’s disease, or AAD, and alcohol use disorder, or AUD.
TNX-102 SL is in mid-Phase 3 development for the management of FM, a pain disorder characterized by chronic widespread pain, non-restorative sleep, fatigue and impaired cognition. In December 2020, we reported positive results from the Phase 3 RELIEF study of TNX-102 SL 5.6 mg for the management of FM. In July 2021, we reported pre-planned interim analysis results from a second Phase 3 study, RALLY. Based on the recommendation from the independent data monitoring committee (IDMC) that the RALLY trial was unlikely to demonstrate a statistically significant improvement in the primary endpoint, we stopped enrollment of new participants but allowed those participants who were already enrolled to complete the study. We reported topline data from the completed study in March of 2022. As expected, based on interim analysis results, TNX-102 SL did not achieve statistical significance over placebo on the primary endpoint of reduction in daily pain, and relative to the previous positive Phase 3 Study (RELIEF), RALLY had an unexpected increase in study participant adverse event-related discontinuations in both drug and placebo groups. In April 2022, we started a new potentially confirmatory Phase 3 study of TNX-102 SL in FM, RESILIENT. Interim analysis results are expected in the second quarter of 2023 and topline results are expected in the fourth quarter of 2023. Following a positive outcome of the RESILIENT study, Tonix believes we would be positioned to file a New Drug Application (NDA) for TNX-102 SL for the management of FM.
TNX-102 SL is also being developed as a potential treatment for a type of Long COVID, the symptoms of which overlap with FM, that we term FM-type Long COVID. We initiated enrollment in the Phase 2 study PREVAIL, in August 2022. The primary endpoint is a change in daily pain scores from baseline.
For TNX-102 SL in PTSD, we completed the Phase 3 RECOVERY trial and reported topline results in the fourth quarter of 2020 in which TNX-102 SL did not meet the primary efficacy endpoint. PTSD is a serious psychiatric condition that develops in response to experiencing a traumatic event. We subsequently completed a meeting with the FDA to discuss potential new endpoints going forward for the indication of treatment of PTSD. Future studies will employ the one month look-back CAPS-5 as the primary endpoint rather than the one week look-back as used in prior studies.
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The AAD program is Phase 2 ready with an active IND and FDA Fast Track designation. AAD, which includes emotional lability, restlessness, irritability, and aggression, is one of the most distressing and debilitating of the behavioral complications of Alzheimer’s disease. Tonix does not have any near-term plans to start a Phase 2 study in AAD.
The AUD program is also Phase 2 ready with an active IND. AUD is a chronic relapsing brain disease characterized by compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using alcohol. Tonix does not have any near-term plans to start a Phase 2 study in AUD.
TNX-1900* (intranasal potentiated oxytocin) is in development for the treatment of chronic migraine and obesity-associated binge eating disorder, or BED. TNX-1900 was acquired from Trigemina, Inc. and licensed from Stanford University in 2020. The potentiated formulation includes magnesium, which has been shown in animal studies to potentiate binding of oxytocin to the oxytocin receptor. We received IND clearance from the FDA in the fourth quarter of 2021 to study TNX-1900 in chronic migraine and we initiated a Phase 2 study in migraine in the first quarter of 2023. We expect interim analysis results from the first 50 percent of patients enrolled in the fourth quarter of 2023. In March 2022, we announced an agreement with Massachusetts General Hospital, a teaching hospital of Harvard Medical School, to conduct an investigator-initiated Phase 2 clinical trial to study TNX-1900 in BED. The Phase 2 clinical trial is expected to start in the second quarter of 2023. We do not own an IND for BED. We also licensed technology to use TNX-1900 for the treatment of insulin resistance from the University of Geneva and also have rights to develop it as a treatment for craniofacial pain, but we are not imminently pursuing clinical trials in either of these indications at this time.
TNX-601 ER* (tianeptine hemioxalate extended-release tablets) is a CNS product candidate in development as a treatment for major depressive disorder, or depression, and with possible additional indications of PTSD, and neurocognitive dysfunction associated with corticosteroid use. TNX-601 ER represents a novel approach to treating depression in the U.S., since the active ingredient tianeptine induces a neuroprotective and resilient phenotype in both neurons and microglia under conditions of stress in animals. The dramatic and unique effects of tianeptine are illustrated in animal models by the restoration of dendritic arborization of pyramidal neurons of CA3 region of hippocampus and the dentate gyrus region new neuron formation and integration into hippocampal networks. In contrast, antidepressants that are marketed in the U.S. act by modulating the levels or receptor binding of neurotransmitters in the synapse. We have completed a Phase 1 trial for formulation development outside of the U.S. We expect to initiate a potentially pivotal Phase 2 study in the first quarter of 2023 for the treatment of major depressive disorder and we expect interim analysis results from the first 50 percent of patients enrolled in the fourth quarter of 2023.
Another CNS candidate in development is TNX-1300* (double-mutant cocaine esterase) which is in Phase 2 for the treatment of life-threatening cocaine intoxication. TNX-1300 has been granted Breakthrough Therapy designation, or BTD, by the U.S. Food and Drug Administration, or FDA. TNX-1300 was licensed from Columbia University in 2019 after a Phase 2 study showed that it rapidly and efficiently disintegrates cocaine in the blood of volunteers who received intravenous, or i.v., cocaine. In August of 2022, we received a Federal Grant from the National Institute on Drug Abuse (NIDA) to advance the development of TNX-1300 as a treatment for cocaine intoxication. We expect to initiate a potentially pivotal Phase 2 study of TNX-1300 in emergency rooms in the second quarter of 2023.
Finally, our CNS pipeline includes TNX-1600*, an inhibitor of the reuptake of neurotransmitters serotonin, norepinephrine and dopamine, or a triple reuptake inhibitor. TNX-1600 was licensed from Wayne State University in 2019 and is expected to be developed as a treatment for PTSD, depression and attention-deficit/hyperactivity disorder, or ADHD. TNX-1600 is in the preclinical stage of development.
Our rare disease portfolio consists of TNX-2900*, another magnesium-potentiated intranasal oxytocin-based therapeutic in development for the treatment of Prader-Willi syndrome, or PWS. The technology for TNX-2900 was licensed from Inserm, the French National Institute of Health and Medical Research. PWS, an orphan condition, is a rare genetic disorder of failure to thrive in infancy, associated with uncontrolled appetite beginning in childhood with complications of obesity and diabetes. We have sponsored a research program at Inserm to study oxytocin on suckling behavior in mice that have been engineered to express one of the Prader-Willi genes. TNX-2900 has been granted Orphan-Drug Designation for the treatment of PWS and is in the pre-IND stage of development.
Our lead candidate in the immunology pipeline is TNX-1500*, a humanized mAb, directed against CD40-ligand, or CD40L (also known as CD154), engineered to modulate binding to Fc receptors, that is being developed as a prophylaxis against organ transplant rejection as well as to treat autoimmune conditions. In experiments at the Massachusetts General Hospital or MGH, a teaching hospital of Harvard Medical School, TNX-1500 is being studied as monotherapy or in combination with other immunosuppressive agents in heart and kidney allogeneic organ transplants in non-human primates. Preliminary results from ongoing experiments in kidney and heart transplants indicate that TNX-1500 appears to have comparable efficacy to historical experiments using the chimeric mouse/human IgG1 version (5c8H1) of the anti-CD40L mAb 5c8. First generation anti-CD40L mAb therapies were associated with an increased risk of blood clots or thrombosis. In the non-human primate studies with TNX-1500 for the prevention of rejection in allogeneic organ transplants, no evidence of thrombosis has been observed so far. We expect to start a Phase 1 study of TNX-1500 in the second quarter of 2023. TNX-1500 also is being studied in combination with other immunosuppressive agents in xenogeneic organ transplants in non-human primates at MGH and at the University of Maryland at Baltimore or UMB. In experiments at UMB, TNX-1500 is being studied to prevent rejection of xenogeneic hearts from genetically engineered pigs developed by the Revivicor division of United Therapeutics Corporation.
Our immunology pipeline also includes TNX-1700*, a recombinant Trefoil Factor Family 2, or rTFF2, fusion protein that was licensed from Columbia University in 2019. TNX-1700 consists of TFF2 fused to human serum albumin or HSA and is a biologic being developed to treat gastric and colorectal cancers by an immune-oncology mechanism, in combination with PD1 blockers, and is in the preclinical stage of development. We recently presented data that show a murine version of TNX-1700 consisting of a fusion protein with murine serum albumin or MSA was able to evoke anti-tumor immunity in the MC38 mouse model of colorectal cancer as monotherapy and that TNX-1700 augmented the efficacy of anti-PD1 therapy in both the MC38 model and the CT26.wt mouse models of colorectal cancer.
Our infectious disease portfolio includes vaccines based on our live virus vaccine or recombinant pox vaccine, “RPV” platform. Live virus vaccines are believed to protect against poor clinical outcomes of infectious diseases by eliciting T cell responses in addition to antibody responses. TNX-801*, a live attenuated vaccine based on synthesized horsepox, is in the pre-IND stage of development to protect against smallpox and mpox. Non-human primates vaccinated with TNX-801 were protected from mpox in studies reported in the first quarter of 2020. A Phase 1 study of TNX-801 in humans is expected to start in the second half of 2023. TNX-801 also serves as the live virus vaccine platform for other infectious diseases for which subsequent products will be designed by expressing other viral antigens in the horsepox vector.
TNX-1850* is a live virus vaccine that expresses the SARS-CoV-2 spike protein from the BA.2 strain that has not yet been tested in animals. TNX-1800* is a live virus vaccine that expresses the SARS-CoV-2 spike protein from the ancestral Wuhan strain, which has shown encouraging results in non-human primates. Because the subsequent omicron variant out-competed the ancestral Wuhan strain, we began work on new vaccine versions, TNX-1840* and TNX-1850*, that are designed to express spike protein from the omicron variant and from the BA.2 variant, respectively. Of those, based on the trajectory of COVID-19, the focus is now on TNX-1850. The COVID-19 vaccines that are approved for use, or have emergency use authorization, or EUA, in the U.S. have provided significant health benefits to the vaccinated population; however, they have shown limitations in the durability of protection conferred and in their ability to block forward transmission. Live virus vaccines that protect against other viral diseases by eliciting T cell responses have shown durability of protection that lasts years to decades and some live virus vaccines have significantly inhibited forward transmission. With respect to TNX-1800 vaccination, we reported positive efficacy data from animal challenge studies using live SARS-CoV-2 in the first quarter of 2021. In this study, TNX-1800 vaccinated, SARS-CoV-2 challenged animals had undetectable SARS-CoV-2 in the upper airways, which we believe relates to potential inhibition of forward transmission of this respiratory pathogen.
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TNX-2300* is a live virus vaccine based on bovine parainfluenza virus in development to protect against COVID-19. In April 2022, Tonix extended a sponsored research agreement with Kansas State University to develop a vaccine candidate, TNX-2300, for the prevention of COVID-19 that utilizes a novel live virus vaccine vector platform based on bovine parainfluenza virus. The efficacy of co-expression of the CD40-ligand, also known as CD154, to stimulate T cell immunity will also be tested. Attenuated bovine parainfluenza virus has previously been shown to be an effective antigen delivery vector in humans. Previous work by others has shown that attenuated BPI3V is well tolerated and immunogenic in non-human primates and human infants and children. We believe the vector is well suited for mucosal immunization using a nasal atomizer, and can also be delivered parenterally. TNX-2300 is in the preclinical stage of development.
TNX-3600* and TNX-3800* are mAbs directed against SARS-CoV-2 which are in development as potential therapeutic or preventative agents for COVID-19. Given the unpredictable trajectory of the SARS-CoV-2 virus and new variants, we seek to contribute a broad set of anti-SARS-CoV-2 mAbs, that can be scaled up quickly and potentially combined with other mAbs. We envision the future of mAb therapy for COVID-19 to be cocktails of mAbs with specificity to variants of concern. TNX-3600 refers to a series of fully human mAbs generated by human-human hybridomas from COVID-19 convalescent volunteers. We are collaborating with Columbia University to produce these fully human mAbs to SARS-CoV-2 spike proteins from variants such as delta, omicron and XBB1.5 and to other viral targets. TNX-3800 refers to three humanized murine mAbs which we licensed exclusively in December 2022 from Curia Global, Inc. for the treatment or prophylaxis of SARS-CoV-2 infection. The initial focus is to develop COVID-19 therapeutic mAbs. We plan to seek indications similar to previously EUA-approved therapeutic mAbs for treating individuals with mild-to-moderate COVID-19 who are at high risk for progression to severe disease or for prophylaxis in individuals with compromised immune systems who are at high risk for severe COVID-19 disease. None of the previously EUA-approved therapeutic or preventative mAbs are still available, because each has become obsolete since the SARS-CoV-2 virus has mutated to evade their binding. TNX-3600 and TNX-3800 mAbs may also be used in combination therapy with other COVID-19 therapeutic mAbs. Combination therapies with other anti-SARS-CoV-2 mAbs may reduce the emergence of resistant viral strains. TNX-3600 and TNX-3800 are in the preclinical stage of development.
TNX-3700* is a COVID-19 mRNA vaccine candidate employing a zinc nanoparticle (ZNP) formulation. In collaboration with Kansas State University, we are developing this ZNP technology as a potential replacement for the lipid nanoparticle (LNP) technology used in current mRNA vaccines. ZNP technology potentially allows for improved stability which facilitates shipping and storage and addresses the limitations in current mRNA vaccines which require ultra-cold storage and shipping. This current requirement limits the use of mRNA vaccines in less developed countries. We plan to seek initial indications as a booster, similar to the current FDA approved mRNA vaccines for COVID-19. We intend to conduct research with Kansas State University on ZNP SARS-CoV-2 spike based vaccines in tissue culture and animals in the first half of 2023. TNX-3700 is in the preclinical stage of development.
Relating to our COVID-19 and other infectious disease development programs, we are developing the resources necessary to enable internal research, development and manufacturing capabilities necessary to meet the goal of producing new vaccine candidates within 100 days of recognition within weeks of obtaining sequence information from a novel pathogen. We seek to be a leader in the movement to re-build domestic U.S. research, development and manufacturing capabilities. Because this movement follows a protracted period when domestic research, development and manufacturing were moved out of the U.S., or “off-shore” by other companies to save on labor and other costs, the movement to reverse that trend has been described as “on-shoring” or “re-domestication”. The COVID-19 pandemic taught that national borders may close during a health emergency. Therefore, domestic capabilities are essential for the health security of the U.S., which has also been described as pandemic preparedness and biodefense. As articulated in the American Pandemic Preparedness Plan, or AP3, released by the U.S. Office of Science and Technology Policy, this 100-day goal for vaccines is a key component of preparedness for future pandemics. We believe we have established the infrastructure necessary to support the pandemic preparedness goals established in the AP3, specifically with respect to our RPV vaccine and potentially to other vaccine and therapeutic platforms. This infrastructure consists of (i) our R&D Center, or “RDC”, (ii) our Advanced Development Center, or “ADC”, and (iii) our Commercial Manufacturing Center, or “CMC”. We acquired the RDC in Frederick, Maryland consisting of one building totaling approximately 48,000 square feet. The acquisition closed in October 2021 and the facility is operational. The RDC facility focuses on our development of vaccines and antiviral drugs against SARS-CoV-2, its variants, and other infectious diseases. The RDC also conducts research on central nervous systema and immunology drugs. The RDC facility is mostly biosafety level 2 (BSL-2), with some components designated BSL-3. We completed the substantial renovation of the ADC located in the New Bedford business park in Dartmouth, Massachusetts, which became operational as of the fourth quarter 2022. This approximately 45,000 square foot BSL-2 facility is intended to accelerate development and clinical scale manufacturing of live-virus vaccines and biologics to support clinical trials. We also plan to build the CMC in Hamilton, Montana, where we purchased approximately 44 acres of land and have built a field office to manage construction of the facility. The CMC will focus on developing and manufacturing commercial scale live-virus vaccines and biologics and is also intended to be BSL-2. Site enabling work is expected to be initiated for the CMC in 2023. Together, we expect these facilities may qualify the RPV vaccine platform for programs that are designed to carry out the goals of AP3.
*All of our product candidates are investigational new drugs or biologics and have not been approved for any indication.
We are led by a management team with significant industry experience in drug development. We complement our management team with a network of scientific, clinical, and regulatory advisors that includes recognized experts in their respective fields.
Corporate Information
We were incorporated on November 16, 2007 under the laws of the State of Nevada as Tamandare Explorations Inc. On October 11, 2011, we changed our name to Tonix Pharmaceuticals Holding Corp. Our common stock is listed on The NASDAQ Capital Market under the symbol “TNXP”. Our principal executive offices are located at 26 Main Street, Suite 101, Chatham, New Jersey 07928, and our telephone number is (862) 799-8599. Our website address is www.tonixpharma.com.
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Our Strategy
Our strategy is to use our integrated development engine to advance innovative programs across multiple therapeutic areas into the clinic while maximizing asset potential, with the objective of developing and commercializing our product candidates. The principal components of our strategy are to:
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Pursue CNS, rare disease, immunology, and infectious disease indications with high unmet medical need and significant commercial potential. Within the therapeutic areas that Tonix is focusing on, we are pursuing multiple indications that are underserved with limited, effective treatment options. One of our latest stage product candidates, TNX-102 SL for the management of FM, a condition which affects between 6-12 million adults in the U.S. and fewer than half of those treated for FM receive relief from the three FDA-approved drugs.
We are also pursuing a treatment using TNX-102 SL for FM-type Long COVID, a condition for which there is no currently approved therapy. Our broader development strategy is to leverage the patented formulation and proven mechanism of action to explore the clinical potential of TNX-102 SL in multiple other, psychiatric, and addiction conditions, including PTSD, Agitation in Alzheimer’s disease and Alcohol Use Disorder (AUD), all of which are underserved by currently approved medications or have no approved treatment thus representing large unmet medical needs. Within CNS, Tonix is also developing TNX-1900 to treat chronic migraine, TNX-601 ER to treat major depressive disorder and TNX-1300 to treat cocaine intoxication. Although a number of drugs are approved for chronic migraine and major depressive disorder, there remains dissatisfaction with available options. Cocaine intoxication is one of the leading causes of overdose deaths and for which there is no currently approved drug. With TNX-1500, we are pursuing a treatment to prevent organ transplant rejection as well as autoimmune conditions. TNX-1500 is a third generation humanized mAb targeting the CD40L that has the potential to deliver efficacy without compromising safety, based on modulated binding to Fc receptors. At this time, no mAb against CD40L has been licensed anywhere in the world. Within infectious diseases, we are currently focusing on the development of TNX-801 to prevent smallpox and mpox, and TNX-1850 to protect against COVID-19. While there are FDA-approved vaccines to prevent smallpox and mpox, we believe TNX-801 has potential to provide durable protection. While there are FDA-approved COVID-19 vaccines which use mRNA technology, or other technologies, we believe that there are limitations to these vaccines relating to durability of protection and their relative inability to block forward transmission.
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| ● | Maximize the commercial potential of our lead product candidates. We plan to commercialize each of our lead product candidates, including our latest stage candidate, TNX-102 SL, either on our own or through collaboration with partners. We believe our lead candidates can be marketed to U.S. physicians either by an internal sales force that we would build or by a contract sales organization, which we would engage. An alternative strategy would be to enter into partnership agreements with drug companies that already have significant marketing capabilities in the same, or similar, therapeutic areas. If we determine that such a strategy would be more favorable than developing our own sales capabilities, we would seek to enter into collaborations with pharmaceutical or biotechnology companies for commercialization. |
| ● | Pursue a broad intellectual property strategy to protect our product candidates. We are pursuing a broad patent strategy for our product candidates, and we endeavor to generate new patent applications as supported by our innovations and conceptions as well as to advance their prosecution. In the case of TNX-102 SL, we own patents and patent applications protecting its composition-of-matter, certain methods of its use, its formulation, and its pharmacokinetic properties. In the case of TNX-801 and TNX-1850, we own patent applications protecting their composition-of-matter and certain methods of use. We also own patents through in-licensing transactions for TNX-1300, TNX-1900, TNX-2900, and TNX-1700. We own patents outright for TNX-601 ER and have filed patent applications for TNX-1500 and TNX-3700. We plan to opportunistically apply for new patents to protect our product candidates. |
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Pursue additional indications and commercial opportunities for our product candidates. We will seek to maximize the value of our other product candidates by pursuing other indications and commercial opportunities for such candidates. For example, we own rights related to the development and commercialization of TNX-102 SL for generalized anxiety disorder, depression, and fatigue related to disordered sleep. For TNX-1900, we own the rights to develop this for craniofacial pain, episodic migraine, acute migraine and insulin resistance, in addition to chronic migraine. For TNX-601 ER, we own the rights to develop this for PTSD and neurocognitive disorder from corticosteroid use, in addition to major depressive disorder. Finally, our live virus platform using our RPV technology may be developed as vaccines for future pandemics, infectious diseases generally and oncology, in addition to smallpox and mpox.
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Disease and Market Overview
Our product candidates address disorders that are not well served by currently available therapies or have no approved treatment which represent large potential commercial market opportunities. Background information on the disorders and related commercial markets that may be addressed by our product candidates in or nearing the clinical-stage is set forth below.
Central Nervous System
Fibromyalgia (FM)
FM is a chronic syndrome characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. The peak incidence of FM occurs between 20-50 years of age, and 80-90% of diagnosed patients are female. FM may have a substantial negative impact on social and occupational function, including disrupted relationships with family and friends, social isolation, reduced activities of daily living and leisure activities, avoidance of physical activity, and loss of career or inability to advance in career or education. According to the American Chronic Pain Association, an estimated six to twelve million adults in the U.S. have FM.
According to a report by Frost and Sullivan that we commissioned, despite the availability of approved medications, the majority of patients fail therapy due to either insufficient efficacy, poor tolerability, or both. Prescription pain and sleep medications are frequently prescribed off-label for symptomatic relief, despite the lack of evidence that such medications provide a meaningful or durable therapeutic benefit, and many of these medications carry significant safety risks and risk of dependence. For example, approximately 30% of patients diagnosed with FM take chronic opioids, despite the lack of evidence for their effectiveness and the risk of addiction and toxicity, including overdose.
Long COVID
Long COVID, or PASC, is a condition that some survivors of COVID-19 infection experience in varying degrees of severity. It is a chronic disabling condition that is expected to result in a significant global health and economic burden. We are focusing development of TNX-102 SL on FM-type Long COVID. The symptoms include intense fatigue, sleep problems, multi-site pain, and cognitive issues (“brain fog”). The proposed indication is for the management of multi-site pain associated with PASC.
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Post infection, many patients experience one or many of the symptoms of Long COVID: some patients have initial symptoms that become prolonged; others manifest entirely new syndromes that impact more than one system or organ. According to a 2021 publication in the Journal of American Medical Association (JAMA), over 1 in 10 healthcare workers who had recovered from COVID-19 were still coping with at least one moderate to severe symptom eight months later. Research shows that Long COVID occurs in approximately 13% of recovered COVID-19 patients. There is currently no approved drug for the treatment of Long COVID.
Migraine Headaches
Migraine is a primary headache disorder characterized by recurrent headaches that are moderate to severe. Typically, episodes affect one side of the head, are pulsating in nature, and last from a few hours to three days. Associated symptoms may include nausea, vomiting, and sensitivity to light, sound, or smell. The pain is generally made worse by physical activity, although regular exercise may have prophylactic effects. Up to one-third of people affected have aura, typically a short period of visual disturbance that signals that the headache will soon occur. Occasionally, aura can occur with little or no headache following it. Approximately one billion individuals worldwide suffer from migraine (~14% of the population). Migraine is the second leading cause of years lived with disability. Chronic migraine (≥ 15 headache/migraine days per month) affects about 1-2% of individuals (~75-150 million individuals worldwide; 3-7 million in the U.S.). CGRP antibodies are the only migraine specific prophylaxis drugs approved in decades, but they require parenteral administration and there are long term safety concerns with prolonged systemic blockade of CGRP or its receptor.
Major Depressive Disorder
According to the Substance Abuse and Mental Health Services Administration, an estimated 21.0 million adults in the U.S. in 2020 experienced at least one major depressive episode, representing 8.4% of all U.S. adults. According to the National Institute of Mental Health, depression affects approximately 17 million adults in the U.S., with approximately 2.5 million adults treated with adjunctive therapy. Depression is a condition characterized by symptoms such as a depressed mood or loss of interest or pleasure in daily activities most of the time for two weeks or more, accompanied by appetite changes, sleep disturbances, motor restlessness or retardation, loss of energy, feelings of worthlessness or excessive guilt, poor concentration, and suicidal thoughts and behaviors. These symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The majority of people who suffer from depression do not respond adequately to initial antidepressant therapy.
Cocaine Intoxication
Cocaine is an illegal recreational drug taken for its pleasurable effects and associated euphoria. Pharmacologically, cocaine blocks the reuptake of the neurotransmitter dopamine from central nervous system synapses, resulting in the accumulation of dopamine within the synapse and an amplification of dopamine signaling that is related to its role in creating positive feeling. With the continued use of cocaine, however, intense cocaine cravings occur resulting in a high potential for abuse and addiction, or dependence, as well as the risk of cocaine intoxication. Cocaine intoxication refers to the deleterious effects on other parts of the body, especially those involving the cardiovascular system. Common symptoms of cocaine intoxication include tachyarrhythmias and elevated blood pressure, either of which can be life-threatening. As a result, individuals with known or suspected cocaine intoxication are sent immediately to the emergency department, preferably by ambulance in case cardiac arrest occurs during transit. There are approximately 505,000 emergency room visits for cocaine abuse each year in the U.S., of which 61,000 require detoxification services. According to the National Institute on Drug Abuse, cocaine-involved deaths rose nearly 54% from 2019 to 2021, resulting in over 24,486 deaths total.
Posttraumatic Stress Disorder, or PTSD
PTSD is a chronic condition that may develop after a person is exposed to one or more traumatic events, such as warfare, sexual assault, serious injury, or threat of imminent death. The core symptom clusters of PTSD are avoidance, emotional numbing, hyperarousal, and intrusion, where the triggering traumatic event is commonly re-experienced by the individual through intrusive, recurrent recollections, flashbacks, and nightmares. People with PTSD suffer significant impairment in their daily functioning, including occupational activities and social relations, and are at elevated risk for impulsive violent behaviors toward others and themselves, including suicide. Of those who experience a significant trauma, approximately 20% of women and 8% of men develop PTSD. An estimated 12 million adults annually in the U.S. suffer from PTSD. According to the U.S. Department of Veterans Affairs, the prevalence rate of PTSD in the military population is higher than that among civilians.
Many patients fail to adequately respond to the medications approved for PTSD and approved medications show little evidence of a treatment effect in men, lack evidence of efficacy in those for whom the traumatic event was combat-related, and carry suicidality warnings. Sleep disturbances are central features of PTSD and are predictive of disease severity, depression, substance abuse, and suicidal ideation, yet are resistant to the approved medications and present a difficult therapeutic challenge. Current PTSD treatments include off-label use of anxiolytics, sedative-hypnotics, and antipsychotics, many of which lack reliable evidence of efficacy, and several have significant safety liabilities and dependence risk.
Rare Disease
Prader-Willi Syndrome
Prader-Willi syndrome (PWS) is recognized as the most common genetic cause of life-threatening childhood obesity and affects males and females with equal frequency and all races and ethnicities. The hallmarks of PWS are lack of suckling in infants and, in children and adults, severe hyperphagia, an overriding physiological drive to eat, leading to severe obesity and other complications associated with significant morbidity and mortality. PWS is an orphan disease that occurs in approximately one in 15,000 births. There is currently no approved treatment for obesity and hyperphagia in adults and older children associated with PWS.
Immunology
Organ Transplant Rejection
Organ transplant rejection occurs when the immune system of the organ recipient attacks the new organ as if it was an infection or tumor. Often transplantation is the last resort for most end-stage organ failure patients, affecting either kidneys, liver, heart, lungs, and/or pancreas. Genetic disparity between organ donor and recipient is often at the root of the rejection. Mismatched or not closely matched organs triggers an immune reaction that leads to rejection. Overcoming this difficulty is paramount to a patient’s survival as organ donations are in limited supply.
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Gastric and Colorectal cancers
Gastric or stomach cancer is a disease in which malignant cancer cells line the inner lumen of the stomach. Development of this form of cancer is often influenced by age, diet and other stomach diseases. This type of cancer begins to form in the mucosa, the surface of the lumen that is in direct contact with the contents of the stomach, and spreads through the outer layers of the stomach as the tumor grows.
Currently, per the National Cancer Institute, the 5-year relative survival for stomach cancer is 33.3%. According to 2017-2019 data, approximately 0.8 percent of men and women will be diagnosed with stomach cancer during their lifetime. In 2019, there were an estimated 123,920 people living with stomach cancer in the U.S.
Colorectal cancer includes cancers in the colon and the rectum, organs that are crucial to absorption of water by the body and the elimination of food-waste. Most colorectal cancers start as a growth or polyp on the inner lining of the colon or rectum. Some types of polyps can change into cancer over time (usually many years), but not all polyps become cancer. Adenomatous polyps are the ones that turn malignant with time. Similar to gastric cancer, the malignancy begins in the mucosal layer and spreads outwards.
The 5-year relative survival rate is 65.1%, per the National Cancer Institute. According to 2017-2019 data, approximately 4.1 percent of men and women will be diagnosed with colorectal cancer during their lifetime. In 2019, there were an estimated 1,369,005 people living with colorectal cancer in the United States.
Infectious Diseases
Smallpox and Mpox
Smallpox is an acute contagious disease caused by the variola virus, or VARV, which is a member of the orthopoxvirus family. Smallpox was declared eradicated in 1980 following a global immunization campaign. Smallpox is transmitted from person to person by infective droplets during close contact with infected symptomatic people. Mpox is an acute contagious disease caused by the monkeypox virus or MPXV, which is also a member of the orthopoxvirus family. Mpox symptoms are similar to those of smallpox, although less severe. Mpox is emerging as an important zoonotic infection in humans in Central and West Africa. Until 2022, only a few cases of mpox had been reported outside of Africa in patients who had been infected while in Africa. Starting in May of 2022, mpox cases spread rapidly in the U.S. and other countries. More than 30,000 cases in the U.S. have been reported according to the U.S. Centers for Disease Control and Prevention.
Smallpox was eradicated by a World Health Organization program that vaccinated individuals with live replicating vaccinia vaccines wherever smallpox appeared. In the 1970s, vaccination of civilians to protect against smallpox was discontinued in the U.S.; however, smallpox remains a material threat to national security and a proportion of military personnel, including members of the Global Response Force continue to be vaccinated. Vaccines for smallpox and mpox are stockpiled by the U.S. government in the strategic national stockpile and for potential widespread immunization in the event of malicious reintroduction of VARV.
COVID-19
SARS-CoV-2 is a contagious virus causing the disease COVID-19 that became a global pandemic in 2019 and has resulted in more than three million deaths. While the infection and mortality rates have slowed in regions of the world with high vaccination rates, the struggle with the pathogen is ongoing and evolving since SARS-CoV-2 is mutating into new variants. COVID-19 is characterized by fever, sore throat, acute shortness of breath, cough, and oxygen desaturation in the blood. At least three major variants have swept across the world in successive waves and overwhelmed healthcare systems during these waves. With new variants of the virus emerging, therapeutic research is addressing the challenge of keeping up with this rapidly mutating virus. The early vaccines have been effective in limiting the severity of disease in vaccinated individuals. Vaccines that elicit strong T cell responses are believed to have the potential to provide long-term or durable protection.
Lead Product Candidates
We believe that our product candidates offer innovative therapeutic approaches and may provide significant advantages relative to available therapies. We have worldwide commercialization rights to all of our product candidates listed below. The following table summarizes our later stage product candidates that are in or nearing the clinic:
| Product Candidate | Indication | Stage of Development | |||
| TNX-102 SL | Fibromyalgia | Mid-Phase 3, >50% enrolled | |||
| TNX-102 SL | FM-type Long COVID | Phase 2 enrolling | |||
| TNX-1900 | Chronic migraine | Phase 2, enrolling | |||
| TNX-601 ER | Depression | Phase 2, targeted 1Q 2023 start | |||
| TNX-1300 | Cocaine Intoxication | Mid-Phase 2, targeted 2Q 2023 start | |||
| TNX-1500 | Kidney Transplant Rejection | Phase 1, targeted 2Q 2023 start | |||
| TNX-801 | Smallpox and Mpox vaccine | Phase 1, targeted 2H 2023 start | |||
| TNX-2900 | Prader-Willi Syndrome | Phase 1 |
TNX-102 SL
Overview
TNX-102 SL, in clinical development for registration in five indications. TNX-102 SL is a proprietary sublingual tablet formulation of CBP that efficiently delivers CBP across the oral mucosal membrane into the systemic circulation. We are developing TNX-102 SL as a bedtime treatment for FM, PTSD, PASC or Long Covid, AAD and AUD. We own all rights to TNX-102 SL in all geographies, and we bear no obligations to third-parties for any future development or commercialization. Excipients used in TNX-102 SL are approved for pharmaceutical use. Some of the excipients were specially selected to promote a local oral environment that facilitates mucosal absorption of cyclobenzaprine or CBP.
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The current TNX-102 SL sublingual tablets contain 2.8 mg of CBP. For the treatment of FM, TNX-102 SL 5.6 mg (two 2.8 mg tablets) at bedtime is in Phase 3 development. We selected this dose with the goal of providing a balance of efficacy, safety, and tolerability that would be acceptable as a first-line therapy and for long-term use, and in-patient populations characterized by burdensome symptoms and sensitivity to medications.
The active ingredient in TNX-102 SL, is CBP, a serotonin-2A and alpha-1 adrenergic receptor antagonist as well as an inhibitor of serotonin and norepinephrine reuptake. In addition, TNX-102 SL acts upon other receptors in the central nervous system including muscarinic M1 and histaminergic H1 receptors.
CBP is the active ingredient of two products that are approved in the U.S. for the treatment of muscle spasm: Flexeril® (5 mg and 10 mg oral immediate-release, or IR, tablet) and Amrix® (15 mg and 30 mg oral extended-release capsule). The Flexeril brand of CBP IR tablet has been discontinued since May 2013. There are numerous generic versions of CBP IR tablets on the market. CBP-containing products are approved for short term use (two to three weeks) only as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. CBP IR tablets are recommended for three times per day dosing, which results in relatively stable blood levels of CBP after several days of treatment. Extended-release CBP capsules taken once a day mimic, and flatten, the pharmacokinetic profile of three times per day CBP IR tablets.
We designed TNX-102 SL to be administered once-daily at bedtime and with the intention for long-term use. We believe the selected dose of TNX-102 SL and its unique pharmacokinetic profile will enable it to achieve a desirable balance of efficacy, safety, and tolerability. Our Phase 1 comparative trials showed that, on a dose-adjusted basis, TNX-102 SL results in faster systemic absorption and significantly higher plasma levels of CBP in the first hour following sublingual administration relative to oral IR CBP tablets. It also showed that the sublingual route of administration, which largely bypasses the “first pass” hepatic metabolism that swallowed medications undergo, results in a higher plasma ratio of CBP to its main active metabolite, norcyclobenzaprine. In clinical studies, TNX-102 SL 2.8 mg and TNX-102 SL 5.6 mg were generally well-tolerated, with no drug-related serious and unexpected adverse reactions reported in these studies. Some subjects experienced transient numbness of the tongue after TNX-102 SL administration.
We have successfully completed the pivotal exposure bridging study with TNX-102 SL compared to Amrix. Results from this study support the approval of TNX-102 SL under Section 505(b)(2) of the Federal Food, Drug and Cosmetic Act, or FDCA, with Amrix as the reference listed drug, or RLD. In general, the development timeline for a 505(b)(2) NDA is shorter and less expensive than an NDA developed under Section 505(b)(1), which is for new chemical entities, or NCEs, that have never been approved in the U.S. We believe that TNX-102 SL has the potential to provide clinical benefit to FM, Long COVID, and PTSD patients and possibly other CNS (central nervous system) indications that are underserved by currently marketed products or have no approved treatment.
TNX-102 SL – FM program
We are developing TNX-102 SL as a bedtime treatment for FM under an active IND application. The potential approval of TNX-102 SL for FM is expected to be under Section 505(b)(2) of the FDCA.
Clinical Development Plan
Phase 3 RESILIENT (F307)
The first patient was enrolled in the potentially pivotal Phase 3 RESILIENT study in April 2022. The RESILIENT study is a double-blind, randomized, placebo-controlled adaptive design trial designed to evaluate the efficacy and safety of TNX-102 SL in FM. The two-arm trial is expected to enroll approximately 470 participants in the U.S. and was 50% enrolled as of December 2022. The first two weeks of treatment consist of a run-in period in which participants start on TNX-102 SL 2.8 mg (1 tablet) or placebo. Thereafter, all participants increase their dose to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets for the remaining 12 weeks. The primary endpoint is the daily diary pain severity score change (TNX-102 SL 5.6 mg vs. placebo) from baseline to Week 14 (using the weekly averages of the daily numerical rating scale scores), analyzed by mixed model repeated measures with multiple imputation. An interim analysis by an IDMC will be conducted on the primary endpoint based on the first 50% of enrolled participants for a potential sample size adjustment or early stop for futility. Interim data is expected in the second quarter of 2023. Topline data is expected in the fourth quarter of 2023.
Completed Phase 3 RALLY Study (F306)
We reported pre-planned interim analysis results from a Phase 3 study, RALLY (F306), in July 2021. Based on the recommendation from the independent data monitoring committee that the RALLY trial was unlikely to demonstrate a statistically significant improvement in the primary endpoint, we stopped enrollment of new participants but allowed those participants who were already enrolled to complete the study. We reported topline data from the completed study in March of 2022. As expected based on interim analysis results, TNX-102 SL did not achieve statistical significance over placebo on the primary endpoint of reduction in daily pain, and relative to the previous positive Phase 3 Study (RELIEF), RALLY had an unexpected increase in study participant adverse event-related discontinuations in both drug and placebo groups. The RALLY study was a double-blind, randomized, placebo-controlled adaptive design trial intended to evaluate the efficacy and safety of TNX-102 SL in FM. The trial was expected to enroll approximately 670 patients across approximately 40 U.S. sites. For the first two weeks of treatment, there was a run-in period in which patients started on TNX-102 SL 2.8 mg (1 tablet) or placebo. After the first two weeks, all patients had the dose increased to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets for 12 weeks. The primary endpoint was daily diary pain severity score change from baseline to Week 14 (using the weekly averages of the daily numerical rating scale scores), analyzed by mixed model repeated measures with multiple imputation.
Completed Phase 3 RELIEF Study (F304)
In the fourth quarter of 2020, we announced the results of a randomized, double-blind, placebo-controlled, 12-week Phase 3 study of TNX-102 SL in 503 participants with FM, which we refer to as the RELIEF study. The primary objective of this study was to evaluate the potential clinical benefit of using TNX-102 SL to treat FM at a dose of 5.6 mg, administered sublingually once daily at bedtime for 12 weeks. The primary endpoint of the RELIEF trial was the daily diary pain severity score change from baseline to Week 14 (using the weekly averages of the daily numerical rating scale scores), analyzed by mixed model repeated measures with multiple imputation. The RELIEF study achieved statistical significance on the primary efficacy endpoint: change from baseline in the weekly average of daily diary pain severity numerical rating scale (NRS) scores for TNX-102 SL 5.6 mg (LS mean [SE]: -1.9 [0.12] units) versus placebo (-1.5 [0.12] units), analyzed by mixed model repeated measures with multiple imputation (LS mean [SE] difference: -0.4 [0.16] units, p=0.010).
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The statistically significant improvement in pain is further substantiated when diary pain was analyzed by another standard statistical approach, a 30 percent responder analysis, with 46.8% on active and 34.9% on placebo having a 30 percent or greater reduction in pain (logistic regression; odds ratio [95% CI]: 1.67 [1.16, 2.40]; p=0.006). Consistent with the proposed mechanism that TNX-102 SL acts in fibromyalgia through improving sleep quality, TNX-102 SL showed nominal improvement of sleep by several measures. For daily diary sleep quality ratings, TNX-102 SL (-2.0 [0.12] units) compared to placebo (-1.5 [0.12] units) was nominally significant (LS mean difference: -0.6 [0.17] units; p<0.001). For the PROMIS Sleep Disturbance instrument, TNX-102 SL was also nominally significant over placebo on T-scores (LS mean difference: -2.9 [0.82] units; p<0.001). The effect sizes on the diary sleep ratings and PROMIS Sleep Disturbance instrument were 0.31 and 0.32, respectively.
In the RELIEF study, TNX-102 SL was similarly well tolerated as in the Phase 2 BESTFIT and Phase 3 AFFIRM studies, which both studied TNX-102 SL at a lower dose of 2.8 mg daily. There were no new safety signals observed in the RELIEF study at the 5.6 mg daily dose. Among participants randomized to the TNX-102 SL and placebo arms, 82.3% and 83.5%, respectively, completed the 14-week dosing period. As expected, based on prior TNX-102 SL studies, administration site reactions are the most commonly reported adverse events and were higher in the TNX-102 SL treatment group, including rates of oral numbness (17.3% vs. 0.8%), oral pain/discomfort (11.7% v. 2.0%), taste impairment (6.5% vs. 0.4%), and oral tingling (5.6% v. 0.4%). Oral numbness or tingling and taste impairment were local administration site effects nearly always temporally related to dose administration and transiently expressed (<60 minutes) in almost all occurrences. The only systemic treatment-emergent adverse events that occurred at a rate of 5.0% or greater in either arm was somnolence/sedation at 5.6% in the TNX-102 SL arm vs. 1.2% in placebo, which was consistent with known side effects of marketed oral cyclobenzaprine. Adverse events resulted in premature study discontinuation in 8.9% of those who received TNX-102 SL compared with 3.9% of placebo recipients. There was a total of seven serious adverse events reported during the study, none of which were deemed related to investigational product; five in placebo arm, and two in TNX-102 SL arm. Of the two in the TNX-102 SL arm, one was a motor vehicle accident with multiple bone fractures, and the other was a pneumonia secondary to an infection.
Completed Phase 3 AFFIRM Study (F301)
In the third quarter of 2016, we announced the results of a randomized, double-blind, placebo-controlled, 12-week Phase 3 study of TNX-102 SL in 519 participants with FM, which we refer to as the AFFIRM study. The primary objective of this study was to evaluate the potential clinical benefit of using TNX-102 SL to treat FM at a dose of 2.8 mg, administered sublingually once daily at bedtime for 12 weeks. The primary endpoint of the AFFIRM trial was the 30% pain responder analysis in which a responder is defined as a subject for whom pain intensity was reduced by at least 30% at Week 12 as compared to baseline. AFFIRM did not achieve statistical significance at the primary endpoint (p=0.095). Yet, statistical significance was achieved when pain was analyzed instead as a continuous variable, either by MMRM (p<0.001) or by MMRM with multiple imputation for missing data (p=0.005), a generally accepted approach to pain data. TNX-102 SL also showed statistically significant improvements in the declared secondary analyses of the Patient Global Impression of Change, or PGIC (p=0.038) and the Fibromyalgia Impact Questionnaire-Revised, or FIQ-R (p<0.001). The study also showed statistically significant improvement with TNX-102 SL on measures of sleep quality, including the Patient-Reported Outcomes Measurement Information System, or PROMIS, Sleep Disturbance instrument (p<0.001).
TNX-102 SL was well tolerated in the AFFIRM trial. Among patients randomized to the active and control arms, 78% and 86%, respectively, completed the 12-week dosing period. The most common adverse events were local in nature, with transient tongue or mouth numbness occurring in 40% of participants on TNX-102 SL vs. 1% on placebo. These local adverse events did not appear to affect either rates of retention of study participants or their compliance with taking TNX-102 SL. Systemic adverse events were similar between TNX-102 SL and placebo. No serious adverse events were reported.
Other NDA Requirements
The Agreed Initial Pediatric Study Plan, or Agreed iPSP, was accepted by the FDA in September 2015. An amendment to the Agreed iPSP will be submitted for FDA agreement prior to marketing application.
Based on our discussions with the FDA and the FDA official meeting minutes, we will not have to conduct special populations, such as geriatric and renal/hepatic impaired patients, drug-drug interaction or cardiovascular safety studies to support the TNX-102 SL NDA filing since the pivotal systemic exposure bridging study using Amrix as the reference listed drug, or RLD, has been successfully completed. Due to the well-established safety profile of CBP at much higher doses than we proposed for FM and the long-term safety data in PTSD, up to 15 months, on TNX-102 SL 5.6 mg, the FDA has not requested a risk management plan or medication guide for this product.
Phase 1 Bioequivalence, Bridging PK, Food-Effect and Dose-Proportionality Studies
We have completed the required Phase 1 bioequivalence, multi-dose bridging pharmacokinetic, and food effect and dose-proportionality studies.
Cyclobenzaprine Hydrochloride Nonclinical Development
In October 2016, we completed the six-month repeated-dose toxicology study of the active ingredient, CBP, in rats and a nine-month repeated-dose toxicology study in dogs required for the NDA filing. These chronic toxicity studies were requested by the FDA to augment the nonclinical information in the AMRIX prescribing information, or labeling, which is necessary to support the TNX-102 SL labeling for long-term use. Due to the lack of evidence of potential abuse in clinical studies of TNX-102 SL, the FDA agreed that nonclinical study to assess CBP abuse potential is not required to support the TNX-102 SL NDA filing.
We are planning to develop TNX-102 SL for the treatment of FM in Japan. Cyclobenzaprine, the active ingredient of TNX-102 SL, has not been approved in Japan, and is considered a NCE (new chemical entity). In February 2022, we held an End of Phase 2 Consultation with the Pharmaceuticals and Medical Devices Agency, or PMDA, an independent administrative institution responsible for ensuring the safety, efficacy and quality of pharmaceuticals and medical devices in Japan, to discuss the Japan development plan. Agreement was reached on the design of a Phase 1 bridging study (TNX-CY-F108/F108) in ethnic Japanese healthy volunteers to enable clinical studies of TNX-102 SL in Japan. PMDA also provided guidance on the overall nonclinical package to support a Japan NDA filing for TNX-102 SL for the treatment of FM.
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The F108 Phase 1 study was initiated in March 2022 and the clinical phase was completed in May 2022 and we are awaiting the final study report at the time of this filing.
We are completing nonclinical safety, pharmacology and embryo-fetal development toxicology studies as part of the agreed IND-enabling nonclinical data package to support clinical studies of TNX-102 SL in Japan.
TNX 102 SL – FM-type Long COVID Program
We are developing TNX-102 SL as a bedtime treatment for FM-type Long COVID. The potential approval of TNX-102 SL for Long COVID is expected to be under Section 505(b)(2) of the FDCA.
Phase 2 PREVAIL Study (PA201)
We initiated a Phase 2 study of TNX-102 SL as a treatment for FM-type Long COVID, which is a subset of patients affected by Long COVID whose symptoms overlap with fibromyalgia. The trial initiated in August 2022. The study is a randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of TNX-102 SL for FM-type Long COVID.
We completed a pre-IND meeting with the FDA in August 2021 to develop TNX-102 SL as a potential treatment for Long COVID. Long COVID is a protracted syndrome experienced by many people following SARS-CoV-2 infection that can include a number of persistent disabling symptoms, including fatigue, widespread pain, sleep disturbance, brain fog or difficulty concentrating, arthralgias, diffuse myalgia, olfactory dysfunction, and headache. The currently enrolling Phase 2 study focuses on Long COVID patients whose primary symptoms overlap with fibromyalgia, and, therefore, the Long COVID program leverages learnings about the pharmacodynamic activity of TNX-102 SL from more than 1,000 participants who have been or are enrolled in our fibromyalgia trials to date. Long COVID has been compared to fibromyalgia because of the common symptoms of sleep disturbance, persistent widespread pain, fatigue, and brain fog. Additionally, Long COVID, like fibromyalgia, is experienced by women at a rate approximately four times that of men.
TNX-102 SL – Posttraumatic Stress Disorder Program
We are developing TNX-102 SL as a bedtime treatment of PTSD under an active IND application. The potential approval of TNX-102 SL for PTSD is expected to be under Section 505(b)(2) of the FDCA.
Phase 3 RECOVERY Study (P302)
We initiated the RECOVERY study (P302) in March 2019. The RECOVERY Phase 3 study was a double-blind, randomized, placebo-controlled study of TNX-102 SL 5.6 mg (2 x 2.8 mg sublingual tablets) over 12 weeks of treatment. The RECOVERY study was conducted at approximately 30 U.S. sites. The study planned to enroll 250 participants with civilian and military-related PTSD. RECOVERY restricts enrollment of study participants to individuals with PTSD who experienced an index trauma within nine years of screening. The two previous PTSD studies of TNX-102 SL (P201 and P301) restricted enrollment to participants who experienced traumas during military service since 2001. The primary efficacy endpoint in P302 was the Week 12 mean change from baseline in the severity of PTSD symptoms as measured by CAPS-5 between those treated with TNX-102 SL and those receiving placebo. Based on interim analysis (IA) results of the first 50% of enrolled participants, an IDMC recommended stopping the Phase 3 RECOVERY trial (P302) in PTSD for futility as TNX-102 SL was unlikely to demonstrate a statistically significant improvement in the primary endpoint of overall change from baseline in the severity of PTSD symptoms between those treated with TNX-102 SL and those receiving placebo. New enrollment for the RECOVERY study was stopped in February 2020, but we continued studying those participants currently enrolled until completion and proceeded with a full analysis of the unblinded data to determine the next steps in this program. Topline data was reported during the fourth quarter of 2020, which revealed that the RECOVERY study did not achieve statistical significance in the prespecified primary efficacy endpoint of change from baseline to Week 12 in the CAPS-5 between TNX-102 SL and placebo (p=0.343; effect size (ES)=0.15). TNX-102 SL separated from placebo in the first key secondary endpoint, CGI-S scale (p=0.024; ES=0.36) and in the PGIC, (p=0.007; ES=0.43). TNX-102 SL also trended for improvement on the PROMIS Sleep Disturbance scale (p=0.055; ES=0.30), consistent with the proposed mechanism of targeting the PTSD sleep disturbance. TNX-102 SL is generally well tolerated and no new safety signals were observed. Tonix met with the FDA to discuss potential new endpoints for the indication of treatment of PTSD. The next PTSD study can use 1 month look-back CAPS-5 as endpoint v. 1 week look-back.
Discontinued Phase 3 HONOR Study (P301)
In the third quarter of 2018, we announced the results of a randomized, double-blind, placebo-controlled Phase 3 study of TNX-102 SL, planned for enrollment of approximately 550 participants with military-related PTSD conducted at approximately 40 U.S. sites, which we refer to as the HONOR study. This study was an adaptive design study based on the results of the Phase 2 AtEase study. The study design was very similar to the Phase 2 AtEase study, except there was one planned IA and the involvement of an IDMC, which reviewed the unblinded IA results. In addition, only one active dose (5.6 mg administered as 2 x 2.8 mg tablets) was investigated, and the baseline severity entrance criterion was a CAPS-5 total score ≥ 33 in this Phase 3 study. The primary efficacy endpoint of the HONOR study was the 12-week mean change from baseline in the severity of PTSD symptoms as measured by the Clinician-Administered PTSD Scale for DSM-5, or CAPS-5, between those treated with TNX-102 SL and those receiving placebo. The CAPS-5 is a standardized structured clinical interview and serves as the standard in research for measuring the symptom severity of PTSD. The IA was conducted when approximately 50% of the initially planned participant enrollment was evaluable for efficacy. HONOR was discontinued after the results of the IA indicated a pre-defined threshold p-value for continuing enrollment was not achieved, i.e. IDMC recommended stopping for futility. The modified Intent-to-Treat (mITT) population analyzed at the time of the IA included 252 participants.
The most common adverse events were mostly related to local administration site reactions, such as oral hypoaesthesia (37.3%), abnormal product taste (11.9%), and oral paraesthesia (9.7%). The most common systemic adverse event was somnolence (15.7%). Retrospective analysis of the HONOR study revealed a treatment effect in participants who experienced trauma less than or equal to nine years prior to screening.
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In the participants who experienced trauma within nine years, the p-value of the CAPS-5 primary endpoint at Week 12, using mixed model repeated measures with multiple imputation (MMRM with MI), was 0.039, with a least-squares mean difference from placebo of -5.9 units. In contrast, there was no difference in CAPS-5 in the participants who experienced trauma more than nine years prior to screening compared to placebo. This analysis defined an optimal treatment window for treatment with TNX-102 SL for PTSD of the first nine years after the index trauma that resulted in PTSD and guided the design of the next Phase 3 study in PTSD, RECOVERY.
Long-Term Safety Exposure Study for TNX-102 SL
In October 2019, we completed long-term safety exposure studies in participants with PTSD to evaluate the tolerability of TNX-102 SL 5.6 mg to support an NDA for the treatment of PTSD. The data provide us with exposure data of daily dosing of TNX-102 SL 5.6 mg for at least 12 months in more than 50 individuals, and daily dosing of TNX-102 SL 5.6 mg for at least 6 months in more than 100 individuals. The data was collected in OLE studies of the PTSD program. Based on the FDA’s guidance, the long-term safety exposure studies in PTSD are also expected to support an NDA for the management of FM.
Other NDA Requirements
An Agreed Initial Pediatric Study Plan, or Agreed iPSP, is required for the initial NDA submission. We submitted a revised iPSP in the first quarter of 2017, which incorporated the FDA comments received on our iPSP submitted in the third quarter of 2016. Additional comments from the FDA were received in second quarter of 2017 on our revised iPSP. We plan to submit an Agreed PSP once a therapeutic dose in adults is established. An acceptable Pediatric Study Plan will be determined at the time of the NDA approval.
Based on our discussions with the FDA and the FDA official meeting minutes, we will not have to conduct special populations (geriatric and renal/hepatic impaired), drug-drug interaction or cardiovascular safety studies to support the TNX-102 SL NDA filing since the pivotal systemic exposure bridging study using AMRIX as the reference listed drug, or RLD, has been successfully completed. Due to the well-established safety profile of CBP at much higher doses than we proposed for PTSD and the long-term safety data (up to 15 months) on TNX-102 SL 2.8 mg in a prior FM program, the FDA has not requested a risk management plan or medication guide for this product.
Manufacturing
TNX-102 SL drug product for Phase 3 and the associated registration batches for the NDA were manufactured at commercial cGMP facilities. We currently have 36-month stability data in the proposed packaging configurations ready for commercialization. The FDA has reviewed the proposed CMC data package to support TNX-102 SL’s NDA approval and commercial manufacturing plans as part of the IND process. Tonix is ready to manufacture TNX-102 SL commercial product for the forecasted FM market.
TNX-1900 – Migraine, Craniofacial Pain and Obesity-Associated Binge Eating Disorder
TNX-1900 (intranasal potentiated oxytocin) is a proprietary formulation of oxytocin in development for BED, prophylaxis of chronic migraine and for the treatment of craniofacial pain, insulin resistance and related conditions. In 2020, TNX-1900 was acquired from Trigemina, Inc. and licensed from Stanford University. TNX-1900 is a drug-device combination product, based on an intranasal actuator device that delivers oxytocin into the nose.
Oxytocin is a naturally occurring human hormone that acts as a neurotransmitter in the brain. Oxytocin has no recognized addiction potential. It has been observed that low oxytocin levels in the body can lead to an increase in migraine headache frequency, and that increased oxytocin levels can relieve migraine headaches. Certain other chronic pain conditions are also associated with decreased oxytocin levels. Migraine attacks are caused, in part, by the activity of pain-sensing trigeminal nerve cells which, when activated, release CGRP which binds to receptors on other nerve cells and starts a cascade of events that is believed to result in headache. Oxytocin when delivered via the nasal route, concentrates in the trigeminal system resulting in binding of oxytocin to receptors on neurons in the trigeminal system, inhibiting the release of CGRP and transmission of pain signals. Blocking CGRP release is a distinct mechanism compared with CGRP antagonist and anti-CGRP antibody drugs, which block the binding of CGRP to its receptor.
With TNX-1900, the addition of magnesium to the oxytocin formula enhances oxytocin receptor binding as well as its effects on trigeminal neurons and craniofacial analgesic effects in animal models. Intranasal oxytocin has been well tolerated in several clinical trials in both adults and children. Targeted nasal delivery results in low systemic exposure and lower risk of non-nervous system, off-target effects which could potentially occur with systemic CGRP antagonists such as anti-CGRP antibodies. For example, CGRP has roles in dilating blood vessels in response to ischemia, including in the heart. We believe nasally targeted delivery of oxytocin could translate into selective blockade of CGRP release in the trigeminal ganglion and not throughout the body, which could be a potential safety advantage over systemic CGRP inhibition. In addition, daily dosing is more quickly reversible, in contrast to monthly or quarterly dosing, as is the case with anti-CGRP antibodies, giving physicians and their patients greater control.
We initiated a Phase 2 study in chronic migraine in the first quarter of 2023. We also plan to develop TNX-1900 for treatment of episodic migraine, craniofacial pain and insulin resistance. Tonix has a license with the University of Geneva to use TNX-1900 for the treatment of insulin resistance and related conditions. TNX-1900 is also being studied as a potential treatment for BED in an investigator-initiated Phase 2 clinical trial. The Phase 2 clinical trial is expected to start in the second quarter of 2023. In March 2022, we announced an agreement with Massachusetts General Hospital, a teaching hospital of Harvard Medical School, to conduct this study. Tonix does not own this IND.
TNX-601 ER – Depression, PTSD, Neurocognitive Dysfunction from Corticosteroids
We announced the development of TNX-601 ER in July 2022, a potential abuse deterrent, extended-release formulation of tianeptine hemioxalate. TNX-601 ER is designed for once-daily daytime dosing and is being developed as a treatment for major depressive disorder (MDD), posttraumatic stress disorder, and neurocognitive dysfunction associated with corticosteroid use. TNX-601 ER represents a novel approach to treating depression in the U.S., since the active ingredient tianeptine induces a neuroprotective and resilient phenotype in both neurons and microglia under conditions of stress in animals. The dramatic and unique effects of tianeptine are illustrated in animal models by the restoration of dendritic arborization of pyramidal neurons of CA3 region of hippocampus and the dentate gyrus region new neuron formation and integration into hippocampal networks. In contrast, antidepressants that are marketed in the U.S. act by modulating the levels or receptor binding of neurotransmitters in the synapse. Tianeptine sodium (amorphous) immediate release (IR) tablets have been available in Europe and many countries in Asia and Latin America for the treatment of MDD over the more than three decades since it was first marketed in France in 1989. No tianeptine-containing product has been approved by the FDA. The proposed mechanism of action of TNX-601 ER is distinct from traditional monoaminergic antidepressants in the U.S. In addition to its glutamatergic properties central to its antidepressant effect, tianeptine has weak µ-opioid receptor agonist properties and has been linked to illicit misuse at much higher doses than those reported to be effective in the treatment of MDD (reported to be used daily at 8-80 times the antidepressant daily dose). Previously, we were developing a naloxone-containing tablet, TNX-601 CR (tianeptine oxalate and naloxone controlled-release) for MDD, that was designed to mitigate the risk of parenteral abuse.
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We intend to develop TNX-601 ER under Section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (FDCA). Tonix completed a Phase 1 clinical trial for formulation development outside of the U.S in 2019. Based on this study, the final formulation of TNX-601 ER to be used in Phase 2 testing will be 39.4 mg tianeptine hemioxalate for once daily treatment of MDD (which is equivalent in tianeptine content to three 12.5 mg doses of tianeptine sodium). Based on the clearance of IND 152371 by the FDA, we expect to initiate a Phase 2 study in the first quarter of 2023.
The Phase 2 study is planned to be a randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of TNX-601 ER monotherapy compared to placebo in MDD. Treatment duration will be six weeks, preceded by up to five weeks in screening and followed by a two-week safety follow-up period (total up to 13 weeks of participation). We plan to randomize approximately 300 individuals with MDD at a 1:1 ratio to two arms of 150 each for drug and placebo at approximately 30 U.S. sites. The primary efficacy endpoint will be the change from baseline to Week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. An IA will be conducted once the first 50 percent of the sample has completed the study, estimated to occur in the fourth quarter of 2023.
TNX-1300 – Cocaine Intoxication
TNX-1300 (T172R/G173Q double-mutant cocaine esterase 200 mg, i.v. solution) is being developed for the treatment of cocaine intoxication. TNX-1300 is a recombinant protein enzyme produced through rDNA technology in a non-disease-producing strain of E. coli bacteria. Cocaine Esterase (CocE) was identified in bacteria (Rhodococcus) that use cocaine as the sole source of carbon and nitrogen and that grow in soil surrounding coca plants. The gene encoding CocE was identified and the protein was extensively characterized. CocE catalyzes the breakdown of cocaine into metabolite ecgonine methyl ester and benzoic acid. Wild-type CocE is unstable at body temperature, so targeted mutations were introduced in the CocE gene and resulted in the T172R/G173Q double-mutant CocE, which is active for approximately 6 hours at body temperature.
Currently there is no specific pharmacotherapy indicated for cocaine intoxication, a state characterized by acute agitation, hyperthermia, tachycardia, arrhythmias, and hypertension, with the potential life-threatening sequalae of myocardial infarction, cerebrovascular accident, rhabdomyolysis, respiratory failure, and seizures. Patients are currently managed only by supportive care for the adverse effects of cocaine overdose on the cardiovascular and central nervous systems. By targeting the cause of cocaine intoxication, rather than the symptoms like other medicines in emergency usage, we believe TNX-1300 may offer significant advantages to the current standard of care for cocaine overdose. TNX-1300 was developed by Columbia University, University of Kentucky and University of Michigan, and in-licensed by Tonix from Columbia University in 2019.
In a Phase 2 randomized, double-blind, placebo-controlled clinical study, TNX-1300 at 100 mg or 200 mg i.v. doses was well tolerated and interrupted cocaine effects after cocaine 50 mg i.v. challenge.
In August 2022, we announced that we received a Cooperative Agreement grant from the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH), to support development of TNX-1300. The Company expects to initiate a new Phase 2 clinical study of TNX-1300 for the treatment of cocaine intoxication in the second quarter of 2023, pending agreement on protocol design with the U.S. Food and Drug Administration (FDA). The Phase 2 trial is a single-blind, open-label, placebo-controlled, randomized study comparing the safety of a single 200 mg dose of TNX-1300 to standard of care alone in approximately 60 emergency department patients presenting with cocaine intoxication. A positive Phase 2a study of volunteer cocaine users in a controlled laboratory setting has been previously completed. TNX-1300 has been granted Breakthrough Therapy designation by the FDA.
As a biologic and new molecular entity, TNX-1300 is eligible for 12 years of U.S. market exclusivity upon approval by the FDA, in addition to expected patent protection through 2029. Since in-licensing, Tonix has requalified existing inventory, developed a lyophilized drug product to facilitate enhanced stability and handling conditions applicable for an ER treatment, updated the process and analytical methods to current standards and is in the process of manufacturing Phase 2/3 drug product clinical supply.
TNX-2900 – Prader-Willi Syndrome
TNX-2900 is based on our patented intranasal potentiated oxytocin formulation, or TNX-1900, but being developed for Prader-Willi syndrome. Tonix licensed technology using oxytocin-based therapeutics for the treatment of Prader-Willi syndrome and non-organic failure to thrive disease from the French National Institute of Health and Medical Research (Inserm). The licensing agreement has been negotiated and signed by Inserm Transfert, the private subsidiary of Inserm, on behalf of Inserm (the French National Institute of Health and Medical Research), Aix-Marseille Université and Centre Hospitalier Universitaire of Toulouse. Prader-Willi syndrome is recognized as the most common genetic cause of life-threatening childhood obesity and affects males and females with equal frequency and all races and ethnicities. There is currently no approved treatment for either the suckling deficit in infants or the obesity and hyperphagia in older children associated with Prader-Willi syndrome. Since Prader-Willi syndrome is an orphan disease that occurs in approximately one in 15,000 births, Tonix has been granted Orphan Drug Designation for TNX-2900 by the FDA. Tonix completed a pre-IND meeting with the FDA in November 2022 to discuss the most efficient and appropriate investigational plan to establish the safety and effectiveness evidence to support the approval of TNX-2900.
In 2022, Tonix entered into a research collaboration with Inserm involving in vitro and in vivo animal studies designed to validate and characterize the role of oxytocin in suckling and in the maturation of feeding behavior during infancy in order to support an intranasal therapeutic approach to restore a normal nutritive suckling. The studies will include mice that have been engineered to precisely recapitulate the genetic issue underlying Prader-Willi in humans.
The mechanisms involved in suckling activity required for normal feeding and the role of oxytocin system in this process will be investigated. The results of this work are expected to be useful in the clinical care of infants requiring support to achieve efficient suckling behavior. Intranasal oxytocin has previously been shown to improve suckling in newborn animals and suppress feeding behaviors in adult animal models.
TNX-1500 – Organ Transplant Rejection/Autoimmune Conditions
TNX-1500 is a humanized mAb directed against CD40-ligand, or CD40L (also known as CD154), engineered to modulate binding to Fc receptors, that is being developed to prevent and treat organ transplant rejection as well as to treat autoimmune conditions. TNX-1500 incorporates the antigen binding fragment (Fab) region of hu5c8, which has been extensively characterized including at the atomic level in complex with CD40-ligand.
In experiments at the Massachusetts General Hospital, a teaching hospital of Harvard Medical School, TNX-1500 is being studied as monotherapy or in combination with immunosuppressive drugs in heart and kidney organ transplants in non-human primates. Preliminary results from ongoing animal experiments in kidney and heart allogeneic transplants indicate that TNX-1500 appears to have comparable efficacy to historical experiments using the chimeric mouse/primate version of the anti-CD40L mAb 5c8, but to date has not shown evidence of the thromboembolic adverse events associated with the first generation mAb directed against CD40L.
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CD40-ligand is a protein expressed on the surface of activated T lymphocytes that mediates T cell helper function. CD40-ligand is also known as CD154, the T cell-B cell activating molecule (T-BAM), TRAP and gp39. CD154 is a member of the Tumor Necrosis Factor (TNF) Super Family. No mAb against CD154 has been approved for commercial use anywhere in the world. Other TNF Super Family members have been successfully targeted by antagonist mAbs. Approved mAbs against TNFα include: infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), and golimumab (Simponi®) for the treatment of certain autoimmune conditions. Also, etanercept (Enbrel®) is a TNFα antagonist receptor fusion protein. An approved mAb against RANKL (CD254) is denosumab (Prolia® or Xgeva®) for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone.
In January 2021, the World Intellectual Property Organization published a patent application filed under the Patent Cooperation Treaty covering TNX-1500, a humanized mAb directed against CD40-ligand, which is also known as CD154. The patent application is titled “Anti-CD154 Antibodies and Uses Thereof” and published under International Publication No. WO 2021/001458 A1. The application entered national phase in December 2021. The patent applications include claims related to proprietary anti-human CD40-ligand mAbs that were engineered to have modified effector function, including TNX-1500, which have reduced potential for Fc binding to FcγRII. The patent applications also claim uses of TNX-1500 for preventing and treating conditions, such as organ transplant rejection and autoimmune disorders. If claims are granted, a patent issuing from a national stage of this application could potentially provide U.S. patent coverage for the TNX-1500 composition of matter through 2040 excluding possible patent term extensions or patent term adjustments. We also have filed a PCT patent application, PCT/US2022/011404, in January 2022, entitled “Methods of Inducing Immune Tolerance with Modified Anti-CD154 Antibodies.” It claims methods of inducing immune tolerance in transplant recipients using anti-CD154 antibodies having modified effector functions. Tonix completed a pre-IND meeting with the FDA in October 2022 to discuss the most efficient and appropriate investigational plan to establish the safety and effectiveness evidence to support the licensure of TNX-1500. We expect to start a Phase 1 study of TNX-1500 in the second quarter of 2023.
Remicade® and Simponi® are trademarks of Janssen; Humira® is a trademark of AbbVie Inc.; Cimzia® is a trademark of UCB S. A.; Enbrel®, Prolia® and Xgeva® are trademarks of Amgen Inc.
TNX-801 – Potential Smallpox and Mpox Vaccine
TNX-801 is a novel potential smallpox- and mpox-preventing vaccine based on a synthetic version of live horsepox virus, grown in cell culture. Though it shares structural characteristics with vaccinia-based vaccines, TNX-801 has unique properties that we believe indicate potential safety advantages over existing live replicating vaccinia virus vaccines, which have been associated with adverse side effects such as myopericarditis in some individuals. Emergent BioSolutions’ ACAM2000® is the only replicating vaccinia virus vaccine currently approved by the FDA to protect against smallpox. We believe replicating virus vaccines have potential efficacy advantages over non-replicating vaccines, relating to the stimulation of cell mediated immunity. Bavarian Nordic’s Jynneos® is the only non-replicating virus vaccine currently approved by the FDA to protect against smallpox and mpox. We believe TNX-801 has the potential to have improved tolerability relative to replicating vaccinia vaccines and the potential to have improved efficacy relative to non-replicating vaccinia vaccines.
Smallpox was eradicated by a World Health Organization program that vaccinated individuals with live replicating vaccinia vaccines wherever smallpox appeared. In the 1970s, vaccination of civilians to protect against smallpox was discontinued in the U.S.; however, smallpox remains a material threat to national security and a proportion of military personnel, including members of the Global Response Force, continue to be vaccinated. We are developing TNX-801 as a potential smallpox- and mpox-preventing vaccine for the U.S. strategic national stockpile and for potential widespread immunization in the event of malicious reintroduction of variola, the virus that causes smallpox.
Mpox is a growing problem in certain regions of Africa. Starting in May of 2022, cases of mpox have been reported outside of Africa in patients who had not been infected while in Africa. More than 30,000 cases in the U.S. have been reported according to the U.S. Centers for Disease Control and Prevention.
In January 2020 at the American Society of Microbiology Biothreats conference, we reported the results of experiments on TNX-801 that were performed in collaboration with Southern Research, that showed TNX-801 vaccinated macaques were protected against monkeypox challenge. The TNX-801 vaccinated macaques showed no overt clinical signs after monkeypox challenge. Furthermore, eight of eight animals vaccinated with two different doses of TNX-801 showed no lesions after monkeypox challenge. Those studies were published as an article in the peer reviewed journal, Viruses in 2023.
We hold a U.S. Patent for TNX-801 smallpox and mpox vaccine and Recombinant Pox Virus (RPV) platform technology. This patent is expected to provide Tonix with U.S. market exclusivity until 2037, excluding any possible patent term extensions or patent term adjustments. In addition, we expect that TNX-801 will be eligible for 12 years of non-patent-based exclusivity under the Patient Protection and Affordable Care Act, or PPACA.
We intend to meet with the FDA to discuss the most efficient and appropriate investigational plan for TNX-801, to establish the safety and effectiveness evidence to support the licensure TNX-801. We are currently working to develop a vaccine that meets cGMP quality to support a clinical study. A Phase 1 study of TNX-801 is expected to be initiated in the second half of 2023.
TNX-1850 – Potential COVID-19 Vaccine
Our infectious disease portfolio includes a platform for vaccines for COVID-19. TNX-1800 is live virus vaccine based on our RPV platform that expresses the SARS-CoV-2 spike protein from the ancestral Wuhan strain. Because the subsequent omicron variant has out-competed the ancestral Wuhan strain, we are now planning new versions of this vaccine, TNX-1840 and TNX-1850, that are designed to express spike protein from the omicron variant and from the BA.2 variant, respectively. Each of these RPV vaccines is being developed to protect against COVID-19 primarily by eliciting T cell responses.
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The COVID-19 vaccines that are approved for use, or have emergency use authorization, or EUA, in the U.S. have provided significant health benefits to the vaccinated population; however, they are showing limitations in the durability of protection conferred and in their ability to block forward transmission. Live virus vaccines that protect against other viral diseases by eliciting T cell responses have shown durability of protection that lasts years to decades and some live virus vaccines have significantly inhibited forward transmission.
We reported positive efficacy data for the TNX-1800 (spike from Wuhan strain) from animal challenge studies using live SARS-CoV-2 in the first quarter of 2021. In this study, TNX-1800 vaccinated, SARS-CoV-2 challenged animals had undetectable SARS-CoV-2 in the upper airways, which we believe relates to potential inhibition of forward transmission of this respiratory pathogen. This study of non-human primates compared TNX-1800 (modified horsepox virus encoding CoV-2 spike protein) to TNX-801 (horsepox virus, live vaccine) at two doses. A control group received a placebo. Each of these five groups (TNX-1800 high and low dose; TNX-801 high and low dose and placebo) included four animals. At day 41 after vaccination (or placebo), each animal was exposed to SARS-COV-2 by intra-tracheal (1 x 106 TCID50) and intra-nasal (1 x 106 TCID50) administration. Upper airway virus was studied by oropharyngeal swabs and lower airway virus by tracheal lavage using qRT-PCR to determine the number of genome copies of SARS-CoV-2 present in the samples. Six days after challenge, no (0/8) samples taken from animals vaccinated with TNX-1800 showed infection (more than 1,000 genome copies of SARS CoV-2) in either upper or lower airway samples. In contrast, all (8/8) animals vaccinated with the control vaccine TNX-801 showed infection in either the upper or lower airway samples as did all (4/4) monkeys vaccinated with vehicle control. At day 14 after a single vaccination, all eight of the TNX-1800 vaccinated animals made anti-CoV-2 neutralizing antibodies (≥1:40 titer) and, as expected, none of the eight TNX-801 vaccinated control animals, or any of the four animals in the placebo group made anti-CoV-2 neutralizing antibodies (≤1:10 titer). At 6 days after CoV-2 challenge, TNX-1800 vaccinated animals showed neutralizing antibody titers of (≥1:1280 titer). The level of neutralizing anti-CoV-2 antibody production was similar between the low and high dose TNX-1800 groups (1 x 106 Plaque Forming Units [PFU] and 3 x 106 PFU, (respectively). For unvaccinated animals challenged with SARS-CoV-2, neutralizing antibodies were measurable after vaccination (≥1:40 titer) that were lower and appeared later than neutralizing antibodies in TNX-1800 vaccinated animals. TNX-1800 and TNX-801 were well tolerated at both doses. Further, as an expected additional outcome, all 16 animals vaccinated with either dose of TNX-1800 or the control TNX-801 manifested a “take”, or cutaneous response, signaling that the horsepox vector elicits a strong T cell immune response. These results support the expectation that TNX-1800 at the low dose of 1 x 106 PFU is an appropriate dose for a one-shot vaccine in humans and indicate that 100 doses per vial is the target format for commercialization, which is well suited to manufacturing and distribution at large scale.
Together, these data show that TNX-1800 induces protection against SARS-COV-2 infection in non-human primates. These data confirm that “take” is a biomarker of protection of upper and lower airways from SARS-CoV-2 challenge, and a biomarker of immunological response to TNX-1800’s cargo COVID-19 antigen, which is the CoV-2 spike protein. Tonix completed a pre-IND meeting with the FDA to discuss the most efficient and appropriate investigational plan to establish the safety and effectiveness evidence to support the licensure of TNX-1800. We believe that the animal data and manufacturing process information that we have developed for TNX-1800 will facilitate expedited development of TNX-1840 and TNX-1850. In addition, we believe the RPV platform can be engineered to express relevant protein antigens from different infectious diseases to make a variety of vaccines.
In June 2020, we announced a partnership with FUJIFILM Diosynth Biotechnologies (FDBT) to provide contract manufacturing and development services to support the manufacturing of our COVID-19 vaccine candidate at the time, TNX-1800, for clinical trial supply. In February 2022, this contract ended. We continue to work with other third party CMOs for the manufacturing and development of TNX-1850, in addition to ultimately planning to utilize our in-house manufacturing capabilities which are currently in development.
Tonix announced the issuance of U.S. Patent for TNX-801 smallpox and mpox vaccine and Recombinant Pox Virus (RPV) platform technology. This patent is expected to provide Tonix with U.S. market exclusivity until 2037, excluding any possible patent term extensions or patent term adjustments, and also expect 12 years of non-patent-based exclusivity under PPACA.
Our preclinical pipeline of drugs and biologic candidates also includes TNX-1600, a preclinical candidate for PTSD, ADHD and depression; TNX-1700 a preclinical candidate for cancers of the gastrointestinal system; TNX-2300, a live-virus vaccine based on bovine parainfluenza virus for COVID-19; TNX-3600, a COVID-19 therapeutic platform; TNX-3700, a COVID-19 vaccine; TNX-3800, a COVID-19 Therapeutic/Preventative.
Tonix’s Facilities Overview
Relating to our COVID-19 and other infectious disease development programs, we are developing the resources necessary to enable internal research, development and manufacturing capabilities necessary to meet the goal of producing new vaccine candidates within 100 days and new diagnostics within weeks of obtaining sequence information of a novel pathogen. We seek to be a leader in the movement to re-build domestic U.S. research, development and manufacturing capabilities. Because this movement follows a protracted period when domestic research, development and manufacturing were moved out of the U.S., or “off-shore” by other companies to save on labor and other costs, the movement to reverse that trend has been described as “on-shoring” or “re-domestication”. The COVID-19 pandemic taught that national borders may close during a health emergency. Therefore, domestic capabilities are essential for the health security of the U.S., which has also been described as pandemic preparedness and biodefense. As articulated in the American Pandemic Preparedness Plan, or AP3 released by the U.S. Office of Science and Technology Policy, this 100-day goal for vaccines is a key component of preparedness for future pandemics. We are establishing the infrastructure necessary to support the pandemic preparedness goals established in the AP3, specifically with respect to our RPV vaccine platform and potentially to other vaccine and therapeutic platforms.
The Research & Development Center (RDC)
We own the approximately 48,000 square foot RDC facility in Frederick, Maryland. The RDC facility is operational and focuses on our development of vaccines and antiviral drugs against COVID-19, its variants, and other infectious diseases. The RDC also conducts research on CNS and immunology drugs. The RDC facility is biosafety level 2 (BSL-2) with BSL-3 components. The RDC currently employs 26 staff. At full capacity, the RDC can employ 80-100 scientists and technical support staff.
The Advanced Development Center (ADC)
The ADC located in the New Bedford business park in Dartmouth, Massachusetts is operational and intended to accelerate development and clinical scale manufacturing of live-virus vaccines and biologics to support Phase 1 and Phase 2 clinical trials. ADC includes single-use bioreactors and purification suites with equipment for Good Manufacturing Practice (GMP) production of vaccines for and biologics clinical trials, including the capability of producing sterile vaccines in glass bottles.
The ADC is an approximately 45,000 square foot BSL-2 facility that currently employs 35 staff. At full capacity, the facility can employ up to 70 researchers, scientists, manufacturing, and technical support staff.
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The Commercial Manufacturing Center (CMC)
We intend to build the CMC in Hamilton, Montana where we purchased approximately 44 acres of land. The site is on land designated by Ravalli County as a Target Economic Development District. The CMC will focus on developing and manufacturing Phase 3 and commercial scale live-virus vaccines and biologics and is also intended to be BSL-2. We have constructed a field office on the site to direct construction.
Competition
Our industry is highly competitive and subject to rapid and significant technological change. Our potential competitors include large pharmaceutical and biotechnology companies, specialty pharmaceutical and generic drug companies, academic institutions, government agencies and research institutions. We believe that key competitive factors that will affect the development and commercial success of our product candidates are efficacy, safety, tolerability, reliability, price and reimbursement level. Many of our potential competitors, including many of the organizations named below, have substantially greater financial, technical, and human resources than we do and significantly greater experience in the discovery and development of product candidates, obtaining the FDA’s and other regulatory approvals of products and the commercialization of those products. Accordingly, our competitors may be more successful than we may be in obtaining FDA approval for drugs and achieving widespread market acceptance. Our competitors’ drugs may be more effective, or more effectively marketed and sold, than any drug we may commercialize and may render our product candidates obsolete or non-competitive before we can recover the expenses of developing and commercializing any of our product candidates. We anticipate that we will face intense and increasing competition as new drugs enter the market and advanced technologies become available. Further, the development of new treatment methods for the conditions we are targeting could render our drugs non-competitive or obsolete. Summarized below is the competitive landscape for the indications in which Tonix has product candidates in or nearing the clinical stages of development.
Fibromyalgia
Products approved for the treatment of fibromyalgia include Lyrica® (pregabalin), marketed by Pfizer; Cymbalta® (duloxetine), marketed by Eli Lilly; and Savella® (milnacipran), marketed by Allergan (acquired by AbbVie). Tonix is aware of several other companies developing treatments for fibromyalgia including Virios Therapeutics, Axsome Therapeutics, Tryp Therapeutics, Biomind Labs, Cortene, and Sorrento Therapeutics.
Chronic or Episodic Migraine Prophylaxis
Currently there are several classes of drugs that are approved for the prophylactic treatment of chronic or episodic migraine, including generic beta blockers (propranolol, timolol), and anticonvulsants (divalproex, topiramate). Other drug classes that are used off-label to treat migraine prophylaxis, include tricyclic antidepressants (e.g., amitriptyline). Also, Allergan markets Botox® (onabotulinumtoxinA). More recently, several products have received FDA approval including Aimovig® (erenumab), which is marketed by Amgen/Novartis; Ajovy® (fremanezumab), which is marketed by Teva Pharmaceuticals; Emgality® (galcanezumab) which is marketed by Eli Lilly; and Yvepti® (eptinezumab), which is marketed by Lundbeck. Also, Nurtec ODT® (Rimegepant) was more recently approved as both a preventive and an acute treatment for episodic migraine, marketed by Pfizer; and Qulipta® (atogepant) was approved for prevention of episodic migraine, marketed by AbbVie. We are aware of other companies working to develop therapeutics for the treatment or prophylaxis of migraine including Astrocyte Pharmaceuticals, Protox, Kallyope, Crystec Pharma, Pulmatrix, and Epalex.
Major Depressive Disorder
Many antidepressant medications are beyond their patent life and are generally produced by generic drug companies, including several compounds in the tricyclic class (e.g., amitriptyline), the serotonin-selective reuptake inhibitor class (e.g, fluoxetine, paroxetine and sertraline), the serotonin-norepinephrine reuptake inhibitor class (e.g., venlafaxine), as well as the norepinephrine-dopamine reuptake inhibitor, bupropion. Recently, Auvelity, developed by Axsome Therapeutics, and Vraylar, developed by Allergan, received FDA approval. Tonix is aware of several companies developing novel prescription medicines for depression including Janssen, Neumora Therapeutics (formerly BlackThorn Therapeutics), Sage Therapeutics, Relmada Therapeutics, Clexio Biosciences Ltd., Otsuka, Seelos Therapeutics, Biomind Labs, FSD Pharma, Bright Minds Bioscienes, Vistagen, Alto Neuroscience, Addex Therapeutics, and BetterLife Pharma.
Long COVID (Post-Acute Sequelae of SARS-CoV-2 Infection or PASC)
There currently are no approved products for the treatment of long COVID/PASC. Tonix is aware of several other companies developing therapeutics for long COVID including Direct Biologics, American CryoStem, HopeBiosciences, Axcella Health Inc., Ampio Pharmaceuticals, Pieris Pharmaceuticals, Resolve Therapeutics, PaxMedia, GeNeuro, Organicell, Ampio Pharmaceuticals, Lyramid, Virios Therapeutics, Berlin Cures, and Statera Biopharma.
PTSD
Products approved for the treatment of PTSD include Paxil® (paroxetine), marketed by GlaxoSmithKline and Zoloft® (sertraline), marketed by Pfizer. Tonix is aware of other companies working to develop therapeutics for the treatment of PTSD including Bionomics, Otsuka/Lundbeck, Nobilis Therapeutics, Bright Minds Biosciences, Alto Neuroscience, Addex Therapeutics, Ophidion, Artelo Biosciences, Roche, Boehringer Ingelheim, NRx Pharmaceuticals, Nanomerics, Seelos Therapeutics, and the Multidisciplinary Association of Psychedelic Studies (MAPS). Acadia Pharmaceuticals is testing Nuplazid® (pimavanserin) for the treatment of insomnia in veterans with PTSD.
Cocaine Intoxication
There are no approved antidotes for the treatment of cocaine intoxication. Patients generally receive supportive care. Tonix is not aware of any drugs in development for the treatment of cocaine intoxication.
Anti-CD40-ligand Monoclonal Antibodies
Tonix is aware of several companies developing biologics that target the CD40L molecule and block its interaction with CD40 including UCB/Biogen, Eledon Pharmaceuticals, Horizon Therapeutics Plc. (which is being acquired by Amgen), Lundbeck (in partnership with Aprilbio), and Sanofi. Furthermore, Tonix is aware of several companies developing antagonistic anti-CD40 mAbs including Novartis, Boehringer Ingelheim, Kiniska Pharmaceuticals, Boston Immune Therapies, and NapaJen Pharma, Inc.
Prader-Willi Syndrome
There are no approved products for the treatment of Prader-Willi syndrome. Patients generally receive care to best manage individual symptom presentation. Tonix is aware of two companies developing a therapeutic for Prader Willi Syndrome including Acadia (which purchased Levo Therapeutics in 2022) and OT4B. Several other companies are developing treatments for Prader-Willi syndrome including Aadvark Therapeutics, ConSynance Therapeutics, Soleno Therapeutics, Lipidio Pharma, Helsinn, Inversago Pharma, Saniona, 9 Meters Biopharma, Neuren Pharmaceuticals, Neuracle Science, Harmony Biosciences, and Notitia Biotechnologies.
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Gastric and Colorectal Cancer
Tonix is developing a small peptide/biologic for the treatment of gastric and colorectal cancer. Tonix is aware of several other companies developing biologics for the treatment of gastric and colorectal cancer including Bexion Pharmaceuticals Inc., Faeth Therapeutics Inc., PDS Biotechnology Corp, and F-star Alpha Ltd.
COVID-19 Vaccine
Vaccines granted full FDA regulatory approval include Comirnaty® (BNT162b2), marketed by Pfizer-BioNTech and Spikevax® (mRNA-1273), marketed by Moderna. Ad.26.COV2S, developed by Janssen, has FDA approval for limited use. Covovax® (NVX-CoV2373), developed by Novavax, has received EUA from the FDA. Other vaccines have received EUA in international markets.
Smallpox and Mpox Vaccines and Antivirals
Vaccines approved for the prevention of smallpox include ACAM2000®, marketed by Emergent BioSolutions and JYNNEOS®, marketed by Bavarian Nordic. JYNNEOS® is also approved for the prevention of mpox. Approved antivirals for smallpox include TPOXX®, marketed by SIGA and TEMBEXA®, marketed by Chimerix. These antivirals are not FDA approved for the treatment of mpox. Tonix is aware of other companies developing treatments for smallpox and mpox including EpiVax, HK inno.N, BioFactura, Blue Water Vaccines, NightHawk Biosciences, Ascletis, and Hyundai Biosciences.
Intellectual Property
We believe that we have an extensive patent portfolio and substantial know-how relating to TNX-102 SL, TNX-1300, TNX-1500, TNX-601 ER, TNX-801 and our other product candidates. Our patent portfolio, described more fully below, includes claims directed to various compositions and methods of use related to our product candidates. As of March 8, 2023, the patents we are either the owner of record of or own the contractual right to include 34 issued U.S. patents and 271 issued non-U.S. patents. We are actively pursuing an additional 32 U.S. patent applications, of which 7 are provisional and 25 are non-provisional, 11 international patent applications, and 247 non-U.S./non-international patent applications.
We strive to protect the proprietary technology that we believe is important to our business, including our proprietary technology platform, our product candidates, and our processes. We seek patent protection in the U.S. and internationally for our products, their methods of use and processes of manufacture, and any other technology to which we have rights, where available and when appropriate. We also rely on trade secrets that may be important to the development of our business.
Our success will depend on 1) the ability to obtain and maintain patent and other proprietary rights in commercially important technology, inventions and know-how related to our business, 2) the validity and enforceability of our patents, 3) the continued confidentiality of our trade secrets, and 4) our ability to operate without infringing the valid and enforceable patents and proprietary rights of third parties. We also rely on continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary position.
We cannot be certain that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications we may own or license in the future, nor can we be certain that any of our existing patents or any patents we may own or license in the future will be useful in protecting our technology. For this and more comprehensive risks related to our intellectual property, please see “Risk Factors — Risks Relating to Our Intellectual Property.”
The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, the patent term is 20 years from the date of filing the first non-provisional priority application. In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the PTO in granting a patent or may be shortened if a patent is terminally disclaimed over another patent.
The term of a U.S. patent that covers a drug approved by the FDA or methods of making or using that drug may also be eligible for patent term extension, which permits patent term restoration as compensation for the patent term lost during the FDA regulatory review process. The Drug Price Competition and Patent Term Restoration Act, also known as the Hatch-Waxman Act, is a federal law that encourages new drug research by restoring patent term lost to regulatory delays by permitting a patent term extension of up to five years beyond the statutory 20-year term of the patent for the approved product or its methods of manufacture or use if the active ingredient has not been previously approved in the U.S. The length of the patent term extension is related to the length of time the drug is under regulatory review. A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug may be extended. Similar provisions are available in Europe and some other foreign jurisdictions to extend the term of a patent that covers an approved drug.
When possible, depending upon the length of clinical trials and other factors involved in the filing of an NDA, we expect to apply for patent term extensions for patents covering our product candidates and their methods of use.
The patent portfolios for our proprietary technology platform and our most advanced product candidates as of March 8, 2023 are summarized below.
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TNX-102 SL — Central Nervous System Conditions
Our patent portfolio for TNX-102 SL includes patent applications directed to compositions of matter of CBP, formulations containing CBP, and methods for treating CNS conditions, such as TNX-102 SL for PTSD, for acute stress disorder, for sleep disturbances in fibromyalgia, for alcohol abuse, for disordered sleep, for sexual dysfunction, for depression in fibromyalgia, fatigue, e.g., CAP rates, post-acute sequelae of SARS-CoV-2 infection, and for agitation in neurodegenerative conditions, e.g., AAD, utilizing these compositions and formulations.
Certain eutectic compositions were discovered by development partners and are termed the “Eutectic Technology.” The patent portfolio for TNX-102 SL relating to the Eutectic Technology includes patent applications directed to eutectic compositions containing CBP, eutectic CBP formulations, methods for treating PTSD and other CNS conditions utilizing eutectic CBP compositions and formulations, and methods of manufacturing eutectic CBP compositions. The Eutectic Technology patent portfolio includes U.S. patents, such as U.S. Patent No. 9,636,408, U.S. Patent No. 9,956,188, U.S. Patent No. 10,117,936, U.S. Patent No. 10,357,465, U.S. Patent No. 10,864,175, and U.S. Patent No. 11,026,898. If U.S. and non-U.S. patents claiming priority from those applications issue, those patents would expire in 2034 or 2035, excluding any patent term adjustments or extensions.
The unique pharmacokinetic profile of TNX-102 SL, or the PK Technology, was discovered by Tonix and its development partners. The patent portfolio for TNX-102 SL relating to the PK Technology includes patent applications directed to compositions of matter of CBP, formulations containing CBP, methods for treating PTSD, agitation in neurodegenerative conditions, and other CNS conditions utilizing these compositions and formulations. The PK Technology patent portfolio includes U.S. Patent Application No. 13/918,692. If U.S. and non-U.S. patents claiming priority from those applications issue, those patents would expire in 2033, excluding any patent term adjustments or extensions.
On May 2, 2017, U.S. Patent No. 9,636,408 entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The patent claims recite pharmaceutical compositions comprising the eutectic. The patent claims also recite methods of manufacturing the eutectic.
On September 13, 2017, European patent 2,501,234, entitled “Methods and Compositions for Treating Symptoms Associated with PTSD Using Cyclobenzaprine”, issued. This patent recites the use of CBP for the treatment of PTSD, which covers the use of TNX-102 SL for the treatment of PTSD, since the active ingredient in TNX-102 SL is CBP and provides TNX-102 SL with European market exclusivity until 2030 and may be extended based on the timing of the European marketing authorization of TNX-102 SL for PTSD. In response to an opposition filed in June 2018 by a German law firm, the European Patent Office’s Opposition Division in October 2019 upheld the patent in unamended form. Opponent has appealed. The Technical Board of the European Patent Office has canceled the April 27, 2023 Oral Proceedings pending the decision of the Enlarged Board of Appeal in G 2/21 (plausibility), which seeks to clarify whether a technical effect can be relied on when proof for the effect rests solely in post-published evidence and what role, if any, plausibility should play in this assessment.
On December 15, 2017, Japanese Patent No. 6259452, entitled “Compositions and Methods for Transmucosal Absorption,” issued. These claims relate to the pharmacokinetic profile of TNX-102 SL.
On August 3, 2022, European Patent No. 2861223, entitled “Compositions and Methods for Transmucosal Absorption,” issued. These claims relate to the pharmacokinetic profile of TNX-102 SL.
On March 20, 2018, U.S. Patent No. 9,918,948 entitled “Methods and Compositions for Treating Symptoms Associated with PTSD Using Cyclobenzaprine,” issued. The claims recite a method of using TNX-102 SL’s active ingredient cyclobenzaprine to treat PTSD and provides TNX-102 SL with US market exclusivity until 2030, excluding any patent term extensions.
On March 23, 2018, Japanese Patent No. 6310542 entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The claims recite pharmaceutical compositions comprising the eutectics and methods of manufacturing these eutectic formulations.
On May 1, 2018, U.S. Patent No. 9,956,188, entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The claims recite a eutectic of cyclobenzaprine hydrochloride and mannitol and methods of making those eutectics.
On November 6, 2018, U.S. Patent No. 10,117,936, entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The claims recite pharmaceutical compositions of eutectics of cyclobenzaprine hydrochloride and mannitol and methods of making those compositions.
On April 16, 2019, Chinese Patent No. ZL 201480024011.1 entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The claims recite pharmaceutical compositions comprising eutectics of cyclobenzaprine hydrochloride and mannitol and methods of making those compositions.
On July 23, 2019, U.S. Patent No. 10,357,465 entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride”, issued. The claims recite pharmaceutical compositions comprising eutectics of cyclobenzaprine hydrochloride and mannitol and methods of making those compositions.
On December 11, 2019, European patent 2968992, entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride”, issued. This patent recites pharmaceutical compositions comprising a eutectic of mannitol and Cyclobenzaprine HCl and methods of making the same. In response to an opposition filed in September 2020 by Hexal AG, the European Patent Office’s Opposition Division upheld the patent in unamended form in the January 2022 oral proceedings. The written decision is pending.
On December 25, 2019, European patent 2,683,245, entitled “Methods and Compositions for Treating Depression Using Cyclobenzaprine”, issued. The claims recite the use of CBP for the treatment of depression in a FM patient. This patent provides TNX-102 SL with European market exclusivity until March 2032 and may be extended based on the timing of the European marketing authorization of TNX-102 SL for depression in a FM patient. In September 2020, Hexal AG filed an opposition against this patent. The European Patent Office’s Opposition Division upheld the patent claims in unamended form at the February 2022 oral proceedings. The written decision is pending.
On December 15, 2020, U.S. Patent No. 10,864,175 entitled “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride”, issued. The claims recite a eutectic comprising cyclobenzaprine hydrochloride and beta-mannitol.
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On April 8, 2021, U.S. non-provisional Patent Application No. 17/226,058 and International Patent Application No. PCT/US2021/026492, entitled “Cyclobenzaprine Treatment for Sexual Dysfunction” were filed. The PCT application is now nationalized in Australia, Canada, China, European Patent Office and Japan. On October 5, 2022, International Patent Application No. PCT/US2022/045791, entitled “Cyclobenzaprine Treatment for Sexual Dysfunction” was filed. The claims of these applications are directed to methods using pharmaceutical compositions and combinations for treating sexual dysfunction with cyclobenzaprine or pharmaceutically acceptable salts of cyclobenzaprine.
On October 25, 2016 and July 28, 2020, U.S. Patent No. 9,474,728 and U.S. Patent No. 10,722,478, entitled “Methods and Compositions for Treating Fatigue Associated with Disordered Sleep Using Very Low Dose Cyclobenzaprine”, issued, respectively. The claims are directed to a method for monitoring the effectiveness of cyclobenzaprine treatment for disordered sleep and method for reducing CAP rates A2 or A3 by treating a subject with a pharmaceutical composition comprising cyclobenzaprine.
On December 11, 2018, U.S. non-provisional Patent Application No. 16/215,952 and International Patent Application No. PCT/IB2018/001509, entitled “Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions,” were filed. The PCT application is now nationalized in 16 countries. The claims are directed to methods for treating or preventing agitation, cognitive decline, psychosis, and associated symptoms thereof using pharmaceutical compositions and combinations with cyclobenzaprine or pharmaceutically acceptable salts of cyclobenzaprine.
On August 20, 2019, International Patent Application No. PCT/IB2019/000940, entitled “Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder,” was filed. The PCT application is now nationalized in 18 countries. The claims are directed to methods of treating acute stress disorder or post-traumatic stress disorder in a subject who has experienced a traumatic event using pharmaceutical compositions with cyclobenzaprine, amitriptyline or pharmaceutically acceptable salts of cyclobenzaprine or amitriptyline.
On November 19, 2021, International Patent Application No. PCT/US2021/060011, entitled “Cyclobenzaprine Treatment for Alcohol Use Disorder,” was filed. The claims are directed to methods for treating alcohol use disorder and associated symptoms using pharmaceutical compositions with cyclobenzaprine or pharmaceutically acceptable salts of cyclobenzaprine.
On December 7, 2021, International Patent Application No. PCT/US2021/062244, entitled, “Cyclobenzaprine Treatment for Fibromyalgia,” was filed. The claims are directed to methods for treating fibromyalgia and its associated symptoms of pain, sleep disturbance and/or fatigue by transmucosally administering a eutectic with cyclobenzaprine hydrochloride and mannitol in dosage units with a basifying agent.
TNX-1900 — Oxytocin-based treatments for Migraine, Pain, Insulin Resistance, Diabetes and Obesity
We have acquired the migraine and pain treatment technologies of Trigemina, Inc., and have assumed its license rights to related technologies from The Board of Trustees of the Leland Stanford Junior University. TNX-1900, an enhanced formulation of nasal oxytocin, has demonstrated activity in several non-clinical studies in pain, including migraine.
As part of our acquisition, we acquired International Patent Application No. PCT/US2016/012512, filed on January 7, 2016, entitled “Magnesium-Containing Oxytocin Formulations and Methods of Use” (nationalized in 13 countries). We also acquired U.S. Patent Nos. 9,629,894 and 11,389,473, entitled “Magnesium-Containing Oxytocin Formulations and Methods of Use”, which will expire in January 2036, excluding any patent term extensions. We also have rights to International Patent Application No. PCT/US2019/020419, filed on April 12, 2017, entitled “Labeled Oxytocin and Method of Manufacture and Use” (nationalized in the U.S., European Patent Office and Japan).
We have entered into an exclusive license to the University of Geneva’s technology for using oxytocin to treat insulin resistance and related syndromes, including obesity. This license expands our intranasal potentiated oxytocin development program, TNX-1900, into cardiometabolic syndromes. Under the license, we have rights to European Patent No. EP2571511B1, entitled “New Uses of Oxytocin-like Molecules and Related Methods.” We also have rights to U.S. Patent No. 9,101,569, entitled “Methods for the Treatment of Insulin Resistance.” The U.S. and non-U.S. patents expire in May 2031, excluding any patent term adjustments or extensions.
TNX-2900 — Oxytocin-based therapeutics treatments for Prader-Willi syndrome
We have licensed technology using oxytocin-based therapeutics for the treatment of Prader-Willi syndrome and non-organic failure to thrive disease from the French National Institute of Health and Medical Research (INSERM). The co-exclusive license relates to TNX-2900, an intranasal potentiated oxytocin, for the treatment of Prader-Willi syndrome and other feeding disorders. Under the license, we have rights to European Patent No. EP2575853B1, entitled “Methods and Pharmaceutical Composition for the Treatment of a Feeding Disorder with Early-Onset in a Patient”; U.S. Patent No. 8,853,158, entitled “Methods for the Treatment of a Feeding Disorder with Onset During Neonate Development Using an Agonist of the Oxytocin Receptor”; and U.S. Patent No. 9,125,862, entitled “Methods for the Treatment of Prader-Willi-like Syndrome or Non-Organic Failure to Thrive (NOFITT) Feeding Disorder Using an Agonist of the Oxytocin Receptor.” The U.S. and non-U.S. patents expire in May 2031, excluding any patent term extensions.
TNX-601 and TNX-601 ER— Depression, Posttraumatic Stress Disorder, Neurocognitive Dysfunction
Our patent portfolio for tianeptine oxalate includes U.S. Patent No. 9,314,469 and European Patent No. 2,299,822, both entitled “Method for Treating Neurocognitive Dysfunction”, which issued on April 29, 2016 and July 26, 2017, respectively. The ’822 patent recites pharmaceutical compositions comprising various compounds (which include tianeptine) and uses thereof. This patent provides TNX-601 with European market exclusivity until April 2029 and may be extended based on the timing of the European marketing authorization of TNX-601 for neurocognitive side effects associated with the use of corticosteroids. The ‘469 patent claims methods of treating cognitive impairment associated with corticosteroid treatment using compounds, including tianeptine, excluding patent term extensions, the patent provides TNX-601 with US marketing exclusivity until 2028.
On February 27, 2019, European Patent No. 3,246,031 entitled “Method for Treating Neurodegenerative Dysfunction,” issued. The claims recite the use of TNX-601, or tianeptine oxalate and other salts, for treating neurocognitive dysfunction associated with corticosteroid treatment. This patent provides TNX-601 with European market exclusivity until April 2029 and may be extended based on the timing of the European market authorization of TNX-601 for neurocognitive disfunction associated with corticosteroid treatment.
On October 22, 2019, U.S. Patent No. 10,449,203 issued. The claims recite anhydrous crystalline oxalate salts of tianeptine and provides TNX-601 with US market exclusivity until 2037, excluding any patent term extensions.
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On March 16, 2021, U.S. Patent No. 10,946,027 issued. The claims recite pharmaceutical compositions of anhydrous crystalline oxalate salts of tianeptine and provides TNX-601 with US market exclusivity until 2037, excluding any patent term extensions.
Our patent portfolio for TNX-601 also includes International Patent Application PCT/IB2017/001709 (now nationalized in 16 countries). It includes claims directed to crystalline tianeptine oxalate and compositions of those crystal forms, and disclosures directed to methods of using those crystalline forms and their compositions.
Our patent portfolio for TNX-601 CR includes International Patent Application No. PCT/US2022/020406, entitled “Tianeptine Oxalate and Naloxone Treatment for Major Depressive Disorder,” was filed March 15, 2022. It includes claims directed to compositions with tianeptine and naloxone or pharmaceutically acceptable salts of tianeptine and naloxone and methods of preventing or treating major depressive disorder using the compositions.
TNX-1300 — Cocaine Intoxication Treatment
We have licensed rights from The Trustees of Columbia University in the City of New York, The Regents of the University of Michigan, and University of Kentucky Research Foundation to develop a potential product, TNX-1300, for the treatment of cocaine intoxication. The licensed patents are directed to mutant cocaine esterase polypeptides and methods of using these polypeptides as anti-cocaine therapeutics. They include U.S. Patent Nos. 8,318,156 and 9,200,265, entitled “Anti-Cocaine Compositions and Treatment” and various counterpart patents outside of the U.S (e.g., European Patent 2046368). These patents provide TNX-1300 with US market exclusivity until February 2029, and market exclusivity outside of the U.S. until July 10, 2027, subject to any patent term extensions.
TNX-1500 — anti-CD40L Therapeutics
We are developing TNX-1500, a humanized mAb that targets CD40L for the prevention and treatment of organ transplant rejection. In this regard, we filed International Application No. PCT/EP2020/068589, entitled “Anti-CD154 antibodies and uses thereof” on July 1, 2020 (nationalized in 15 countries). We also filed International Patent Application No. PCT/US2020/028002 on April 13, 2020, entitled “Inhibitors of CD40-CD154 Binding” (nationalized in U.S., Canada, China, European Patent Office and Japan). We also filed International Patent Application No. PCT/US2022/011404, entitled “Methods of Inducing Immune Tolerance with Modified Anti-CD154 Antibodies” on January 6, 2022.
TNX-801 — Live Horsepox Vaccine for Prevention of Smallpox and Mpox
We own the rights to develop a potential biodefense technology, TNX-801, a live horsepox that is being developed as a new smallpox and mpox preventing vaccine, we have filed patent applications directed to synthetic chimeric poxviruses and methods of using these poxviruses to protect individuals against smallpox. These applications include U.S. non-provisional Patent Application No. 15/802,189 and International Patent Application No. PCT/US2017/059782 (nationalized in 15 countries and filed in 4 non-PCT countries). We also own the rights to develop other vaccine candidates against smallpox. With respect to these vaccine candidates, we own International Patent Application No. PCT/US2019/030486 and the non-convention and national phase applications related thereto (nationalized in 17 countries and filed in 2 non-PCT countries). The smallpox vaccine technologies relate to proprietary forms of live horsepox and vaccinia vaccines which may be safer than ACAM2000, the only currently available replication competent, live vaccinia vaccine to protect against smallpox disease. We believe that this technology, after further development, may be of interest to biodefense agencies in the U.S. and other countries.
On May 31, 2022, U.S. Patent No. 11,345,896 was issued. The claims recite a synthetic chimeric orthopoxvirus (scOPV), a synthetic chimeric horsepox virus (scHPXV), methods of generating the scOPV and scHPXV, and compositions comprising the scOPV or scHPXV.
TNX-1850 — Live Modified Horsepox Vaccine for Prevention of COVID-19
We are developing TNX-1850, a live HPXV that is being developed as a new COVID-19 preventing vaccine. On February 26, 2021, we filed International Patent Application No. PCT/US2021/020119, entitled “Recombinant Poxvirus Based Vaccine Against SARS-CoV-2.” On the same date, we also filed applications in Argentina and Taiwan and we filed U.S. Application No. 17/187,678. The PCT application is not nationalized in 18 countries. These applications are directed to synthetic poxviruses comprising a SARS-CoV-2 protein, poxvirus delivery vectors for SARS-CoV-2 proteins and methods of using these modified poxviruses to protect individuals against COVID-19.
TNX-1700 — Recombinant Trefoil Family Factor 2 (rTFF2) to Treat Gastric and Pancreatic Cancers
We have licensed rights from The Trustees of Columbia University in the City of New York to develop a potential product, TNX-1700, for the treatment of gastric and pancreatic cancers. The licensed patents are directed to TFF2 compositions and methods of treatment. The licensed patents U.S. Patent No. 10,124,037 and U.S. Patent No. 11,167,010. The licensed patents provide TNX-1700 with US market exclusivity until April 2033, subject to any patent term extensions. On August 27, 2020, we filed International Patent Application No. PCT/IB2020/000699 entitled “Modified TFF2 Polypeptides.” The PCT application is now nationalized in 12 countries.
TNX-1600 — Triple Reuptake Inhibitor to Treat PTSD
We have licensed rights from Wayne State University to develop a potential product, TNX-1600, for PTSD treatment. The licensed patents directed to pyran-based derivatives and analogues.
They include U.S. Patent Nos. 7,915,433, 8,017,791, 8,519,159, 8,841,464, and 8,937,189, entitled “Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives” and U.S. Patent No. 9,458,124, entitled “Substituted Pyran Derivatives”. These patents provide TNX-1600 with US market exclusivity between April 2024 and February 2034, respectively, subject to any patent term extensions.
TNX-701 — Radioprotection Biodefense Technology
We own the rights to develop a potential biodefense technology, which is a potential radioprotective therapy. For protection of our intellectual property, we have not disclosed the identity of the new development candidate.
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On May 7, 2021, we filed International Patent Application No. PCT/US2021/031441, entitled “Radio-and Chemo-Protective Compounds,” and U.S. non-provisional Patent Application No. 17/315,258, entitled “Radio-Protective and Chemo-Protective Substituted Thiols.” The PCT application is now nationalized in 10 countries. The applications claim compounds, compositions and methods of use in radioprotection.
On January 31, 2023, U.S. Patent No. 11,566,032 issued. The claims recite compounds of a formula I or a pharmaceutically acceptable salt thereof or stereoisomer thereof and a pharmaceutical composition comprising a compound of formula I.
TNX-1200 — Smallpox Vaccine Technology
We own the rights to develop a potential biodefense technology, TNX-1200, a live vaccinia virus that is being developed as a new smallpox preventing vaccine, we have patent applications directed to synthetic chimeric poxviruses and methods of using these poxviruses to protect individuals against smallpox. These applications, entitled “Synthetic Chimeric Vaccinia Virus,” include U.S. non-provisional Patent Application No. 17/050,946 and International Patent Application No. PCT/US2019/030486 (now nationalized in 16 countries) and applications filed in Argentina, Taiwan and Venezuela. We believe that this technology, after further development, may be of interest to biodefense agencies in the U.S. and other countries.
TNX-2300 — Bovine Parainfluenza 3 Virus vaccine
We have an exclusive field-of-use option agreement with Kansas State University Research Foundation to develop TNX-2300, a bovine parainfluenza virus vaccine, as a new COVID-19 preventing vaccine or treatment. The patent applications in this agreement include International Patent Application No. PCT/US2020/070725, entitled “Broadly Protective Bovine Parainfluenza 3 Virus and Bovine Viral Diarrhea Virus Vaccine” (nationalized in U.S. as Patent Application No. 17/755,359), and International Patent Application No. PCT/US2022/072433, entitled “SARS-Coronavirus 2 (SARS-CoV-2) Spike Protein Subunit Vaccines.”
TNX-3700 — Zinc Nanoparticle mRNA vaccine
We have an exclusive field-of-use option agreement with Kansas State University Research Foundation to develop TNX-3700, a zinc nanoparticle mRNA vaccine, as a new COVID-19 preventing vaccine or treatment. The patent applications in this agreement include International Patent Application No. PCT/US2022/070739, entitled “RNA Stabilizing Nanoparticles,” and International Patent Application No. PCT/US2022/075944, entitled “mRNA Vaccine Formulations and Methods of Using the Same.”
TNX-3900 — antiviral drugs
We have acquired the intellectual property rights of Healion Bio, Inc. to develop antiviral drugs. These rights include International Patent Application No. PCT/US2021/032461 (nationalized in 4 countries) and U.S. Patent Application No. 18/055,596, both entitled “Compositions and Methods for Increasing Efficacy of a Drug,” as well as International Patent Application No. PCT/US2021/052664, entitled “Methods and Compositions for the Treatment of Viral Diseases.”
TNX-4100 — murine anti-SARS-CoV-2 antibodies
We have exercised the option to obtain an exclusive license from Columbia University to develop, TNX-4100, a series of murine and humanized anti-SARS-CoV-2 mAbs as new COVID-19 preventatives or treatments.
Trade Secrets
In addition to patents, we rely on trade secrets and know-how to develop and maintain our competitive position. For example, significant aspects of our proprietary technology platform are based on unpatented trade secrets and know-how. Trade secrets and know-how can be difficult to protect. We seek to protect our proprietary technology and processes, in part, by confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors, and commercial partners. These agreements are designed to protect our proprietary information and, in the case of the invention assignment agreements, to grant us ownership of technologies that are developed through a relationship with a third party. We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems. While we have confidence in these individuals, organizations and systems, agreements or security measures may be breached, and we may not have adequate remedies for any breach. In addition, our trade secrets may otherwise become known or be independently discovered by competitors. To the extent that our contractors use intellectual property owned by others in their work for us, disputes may arise as to rights in related or resulting inventions and know-how.
Issued Patents
Our current patents owned or licensed include:
Anti-Cocaine Therapeutics
| Patent No. | Title | Country / Region | Expiration Date | |||
| 8,318,156 | Anti-Cocaine Compositions and Treatment | U.S.A. | February 14, 2029 | |||
| 9,200,265 | Anti-Cocaine Compositions and Treatment | U.S.A. | December 30, 2027 | |||
| 2007272955 | Anti-Cocaine Compositions and Treatment | Australia | July 10, 2027 | |||
| 2014201653 | Anti-Cocaine Compositions and Treatment | Australia | July 10, 2027 | |||
| 2657246 | Anti-Cocaine Compositions and Treatment | Canada | July 10, 2027 | |||
| 612929 | Anti-Cocaine Compositions and Treatment | New Zealand | July 10, 2027 | |||
| 2046368 (602007045044.6 in Germany; 502016000056543 in Italy) | Anti-Cocaine Compositions and Treatment | Europe – (Germany, Spain, France, United Kingdom, and Italy) | July 10, 2027 | |||
| 2009/00197 | Anti-Cocaine Compositions and Treatment | South Africa | July 10, 2027 | |||
| 305483 | Anti-Cocaine Compositions and Treatment | Mexico | July 10, 2027 | |||
| 196411 | Anti-Cocaine Compositions and Treatment | Israel | July 10, 2027 |
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Sublingual CBP/Amitriptyline
| Patent No. | Title | Country / Region | Expiration Date | |||
| 6259452 | Compositions and Methods for Transmucosal Absorption | Japan | June 14, 2033 | |||
| 631144 | Compositions and Methods for Transmucosal Absorption | New Zealand | June 14, 2033 | |||
| I590820 | Compositions and Methods for Transmucosal Absorption | Taiwan R.O.C. | June 14, 2033 | |||
| 2013274003 | Compositions and Methods for Transmucosal Absorption | Australia | June 14, 2033 | |||
| I642429 | Compositions and Methods for Transmucosal Absorption | Taiwan R.O.C. | June 14, 2033 | |||
| 726488 | Compositions and Methods for Transmucosal Absorption | New Zealand | June 14, 2033 | |||
| I683660 | Compositions and Methods for Transmucosal Absorption | Taiwan R.O.C. | June 14, 2033 | |||
| 2018241128 | Compositions and Methods for Transmucosal Absorption | Australia | June 14, 2033 | |||
| 2876902 | Compositions and Methods for Transmucosal Absorption | Canada | June 14, 2033 | |||
| IDP000076019 | Compositions and Methods for Transmucosal Absorption | Indonesia | June 14, 2033 | |||
| 382516 | Compositions and Methods for Transmucosal Absorption | Mexico | June 14, 2033 | |||
| 2861223 | Compositions and Methods for Transmucosal Absorption | European Patent Office – Italy, Albania, Austria, Belgium, Bulgaria, Cyprus, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Latvia, Lithuania, Luxembourg, Malta, Monaco, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom, San Marino, Serbia, Croatia, North Macedonia and Turkey | June 14, 2033 | |||
| 236268 | Compositions for Transmucosal Delivery and Uses Thereof | Israel | June 14, 2033 | |||
| 2015/00288 | Compositions and Methods for Transmucosal Absorption | South Africa | June 14, 2033 | |||
| BR112014031394-6 | Compositions and Methods for Transmucosal Absorption | Brazil | June 14, 2033 | |||
| 1209361 | Compositions and Methods for Transmucosal Absorption | Hong Kong | June 14, 2033 | |||
| 398632 | Compositions and Methods for Transmucosal Absorption | Mexico | June 14, 2033 | |||
| A059897 | Compositions and Methods for Transmucosal Absorption | Venezuela | June 14, 2033 | |||
| MY-194495-A | Compositions and Methods for Transmucosal Absorption | Malaysia | June 14, 2033 |
CBP – Depression
| Patent No. | Title | Country / Region | Expiration Date | |||
| 2012225548 | Methods and Compositions for Treating Depression Using Cyclobenzaprine | Australia | March 6, 2032 | |||
| 2016222412 | Methods and Compositions for Treating Depression Using Cyclobenzaprine | Australia | March 6, 2032 | |||
| 2018204633 | Methods and Compositions for Treating Depression Using Cyclobenzaprine | Australia | March 6, 2032 | |||
| 2020203874 | Methods and Compositions for Treating Depression Using Cyclobenzaprine | Australia |
March 6, 2032 | |||
| 614725 | Methods and Compositions for Treating Depression Using Cyclobenzaprine | New Zealand | March 6, 2032 | |||
| 714294 |
Methods and Compositions for Treating Depression Using Cyclobenzaprine |
New Zealand |
March 6, 2032 | |||
| 2,829,200 | Methods and Compositions for Treating Depression Using Cyclobenzaprine | Canada | March 6, 2032 | |||
| 2683245 |
Methods and Compositions for Treating Depression Using Cyclobenzaprine
|
European Patent Office – Albania, Austria, Belgium, Bulgaria, Switzerland, Cyprus, Czechia, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Monaco, Republic of North Macedonia, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Sweden, Slovenia, Slovakia, San Marino, and Turkey | March 6, 2032 |
22
CBP – PTSD
| Patent No. | Title | Country / Region | Expiration Date | |||
| 9,918,948 | Methods and Compositions for Treating Symptoms Associated with Post-Traumatic Stress Disorder Using Cyclobenzaprine | U.S.A. | November 18, 2030 | |||
|
2501234
(AL/P/17/691 in Albania; 602010045270.0 in Germany; 3094254 in Greece; 502017000142469 in Italy; MK/P/17/000807 in Republic of North Macedonia; 56634 in Serbia; SM-T-201700578 in San Marino; 201717905 in Turkey)
|
Methods and Compositions for Treating Symptoms Associated with Post-Traumatic Stress Disorder Using Cyclobenzaprine | European Patent Office – Albania, Austria, Belgium, Bulgaria, Switzerland, Cyprus, Czechia, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Croatia, Hungary, Ireland, Iceland, Italy, Lithuania, Luxembourg, Latvia, Monaco, Republic of North Macedonia, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Sweden, Slovenia, Slovakia, San Marino, Turkey | November 16, 2030 | |||
| HK1176235 | Methods and Compositions for Treating Symptoms Associated with Post-Traumatic Stress Disorder Using Cyclobenzaprine | Hong Kong | November 16, 2030 |
CBP Fatigue
| Patent No. | Title | Country / Region | Expiration Date | |||
| 9,474,728 | Methods and Compositions for Treating Fatigue Associated with Disordered Sleep Using Very Low Dose Cyclobenzaprine | U.S.A. | June 9, 2031 | |||
| 10,722,478 | Methods and Compositions for Treating Fatigue Associated with Disordered Sleep Using Very Low Dose Cyclobenzaprine | U.S.A. | June 9, 2031 |
CBP/Amitriptyline Eutectic Formulations
| Patent No. | Title | Country / Region | Expiration Date | |||
| 631152 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | New Zealand | March 14, 2034 | |||
| 747040 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | New Zealand | March 14, 2034 | |||
| 9,636,408 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | U.S.A. | March 14, 2034 | |||
| 9,956,188 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | U.S.A. | March 14, 2034 | |||
| 10,117,936 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | U.S.A. | March 14, 2034 | |||
| 10,322,094 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | U.S.A. | March 14, 2034 | |||
| 10,357,465 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | U.S.A. | September 18, 2035 | |||
| 10,736,859 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | U.S.A. | March 14, 2034 | |||
| 10,864,175 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | U.S.A. | March 14, 2034 | |||
| 10,864,176 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | U.S.A. | March 14, 2034 | |||
| 11,026,898 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | U.S.A. | September 18, 2035 | |||
| 6310542 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Japan | March 14, 2034 | |||
| 6614724 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Japan | September 18, 2035 | |||
| 6717902 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Japan | September 18, 2035 | |||
| 6088 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Saudi Arabia | March 14, 2034 | |||
| ZL201480024011.1 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | China | March 14, 2034 | |||
| ZL.201580050140.2 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | China | September 18, 2035 | |||
| 2014233277 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Australia | March 14, 2034 | |||
| 2015317336 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Australia | September 18, 2035 | |||
| I661825 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Taiwan R.O.C. | March 14, 2034 |
23
| I740136 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Taiwan R.O.C. | March 14, 2034 | |||
| IDP000055516 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Indonesia | March 14, 2034 | |||
| IDP000063221 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Indonesia | September 18, 2035 | |||
| IDP000076872 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Indonesia | March 14, 2034 | |||
|
2968992
(1211591 in Austria, CZ2014-762323 in Czechia, 602014058260.5 in Germany, E018723 in Estonia, P20200055 in Croatia, 201361792757 P in Ireland, 2020.67 in Monaco, P-2020/0094 in Serbia, 201431487 in Slovenia, 33269 in Slovakia, 2020000045 in San Marino, AL/P/2019/906 in Albania, MK/P/2020/67 in Republic of North Macedonia, 3102655 in Greece, 502020000007756 in Italy) |
Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | European Patent Office -Albania, Austria, Belgium, Bulgaria, Croatia, Cyprus, Czechia, Denmark, Estonia, Finland, France, Republic of North Macedonia, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Monaco, Netherlands, Norway, Poland, Portugal, Romania, San Marino, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, United Kingdom |
March 14, 2034
| |||
| 241353 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Israel | March 14, 2034 | |||
| 251218 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Methods of Producing Same | Israel | September 18, 2035 | |||
| 277814 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Methods of Producing Same | Israel | September 18, 2034 | |||
| 370021 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Mexico | March 14, 2034 | |||
| 387402 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Mexico | September 18, 2035 | |||
| 388137 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Mexico | March 14, 2034 | |||
| 2015/07443 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride |
South Africa |
March 14, 2034 | |||
| 2017/01637 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | South Africa | September 18, 2035 | |||
| BR112015022095-9 | Pharmaceutical Composition, Method of Fabrication, Eutectic Composition and Use of Compositions Containing Cyclobenzaprine HCl and Mannitol | Brazil | March 14, 2034 | |||
| 2904812 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Canada | March 14, 2034 | |||
| HK1218727 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Hong Kong | March 14, 2034 | |||
| MY-186047-A | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Malaysia | September 18, 2035 | |||
| 398845 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | India | September 18, 2035 |
Oxytocin therapeutics
| Patent No. | Title | Country / Region | Expiration Date | |||
| 9,629,894 | Magnesium-Containing Oxytocin Formulations and Methods of Use | U.S.A. | January 7, 2036 | |||
| 11,389,473 | Magnesium-Containing Oxytocin Formulations and Methods of Use | U.S.A. | January 7, 2036 | |||
| 11201705591P | Magnesium-Containing Oxytocin Formulations and Methods of Use | Singapore | January 7, 2036 | |||
| 388286 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Mexico | January 7, 2036 | |||
| 253347 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Israel | January 7, 2036 | |||
| 7030517 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Japan | January 7, 2036 | |||
| ZL201680013809.5 | Magnesium-Containing Oxytocin Formulations and Methods of Use | China | January 7, 2036 | |||
| 7093559 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Japan | April 12, 2037 | |||
| 2575853 | Methods and Pharmaceutical Composition for the Treatment of a Feeding Disorder with Early-Onset in a Patient | Europe – (Spain, France, and United Kingdom) | May 25, 2031 | |||
| 8,853,158 | Methods for the Treatment of a Feeding Disorder with Onset During Neonate Development Using an Agonist of the Oxytocin Receptor | U.S.A. | May 25, 2031 | |||
| 9,125,862 | Methods for the Treatment of Prader-Willi-like Syndrome or Non-Organic Failure to Thrive (NOFITT) Feeding Disorder Using an Agonist of the Oxytocin Receptor | U.S.A. | May 25, 2031 | |||
| 2571511 | New Uses of Oxytocin-like Molecules and Related Methods | Europe – (Switzerland, Spain, France, United Kingdom, and Ireland) | May 17, 2031 | |||
| 9,101,569 | Methods for the Treatment of Insulin Resistance | U.S.A. | June 22, 2031 |
24
Nociceptin/Orphanin FQ therapeutics
| Patent No. | Title | Country / Region | Expiration Date | |||
| 8,551,949 | Methods for treatment of pain | U.S.A. | August 11, 2031 | |||
| 9,238,053 | Methods for treatment of pain | U.S.A. | October 12, 2030 | |||
| 2010281436 | Methods for treatment of pain | Australia | July 27, 2030 | |||
| ZL 201080042858.4 | Methods for treatment of pain | China | July 27, 2030 | |||
| 2459183 (602010028120.5 in Germany) | Methods for treatment of pain | Europe – (Switzerland, Germany, Denmark, France, and United Kingdom) | July 27, 2030 | |||
| 1169804 | Methods for treatment of pain | Hong Kong | July 27, 2030 | |||
| 329837 | Methods for treatment of pain | Mexico | July 27, 2030 | |||
| 597763 | Methods for treatment of pain | New Zealand | July 27, 2030 | |||
| 10201406930U | Methods for treatment of pain | Singapore | July 27, 2030 | |||
| 201200584 | Methods for treatment of pain | South Africa | July 27, 2030 | |||
| 2,769,347 | Methods for treatment of pain | Canada | July 27, 2030 | |||
| 413642 | Methods for treatment of pain | India | July 27, 2030 |
Tianeptine Hemioxalate – Salts and Crystalline Forms
| Patent No. | Title | Country / Region | Expiration Date | |||
| 10,449,203 | Tianeptine Oxalate Salts and Polymorphs | U.S.A. | December 28, 2037 | |||
| 10,946,027 | Tianeptine Oxalate Salts and Polymorphs | U.S.A. | December 28, 2037 | |||
| 2019/04185 | Tianeptine Oxalate Salts and Polymorphs | South Africa | December 28, 2037 | |||
| 2017385958 | Tianeptine Oxalate Salts and Polymorphs | Australia | December 28, 2037 | |||
| IDP000082485 | Tianeptine Oxalate Salts and Polymorphs | Indonesia | December 28, 2037 | |||
| 754797 | Tianeptine Oxalate Salts and Polymorphs | New Zealand | December 28, 2037 |
Tianeptine – Neurocognitive Dysfunction
| Patent No. | Title | Country / Region | Expiration Date | |||
| 9,314,469 | Method for Treating Neurocognitive Dysfunction | U.S.A. | September 24, 2030 | |||
| 2723688 | Method for Treating Neurodegenerative Dysfunction | Canada | April 30, 2029 | |||
| 2299822 (602009047361.1 in Germany and E911827 in Austria) | Method for Treating Neurodegenerative Dysfunction | European Patent Office – Austria, Belgium, Switzerland, Germany, Spain, France, United Kingdom, Ireland, Luxembourg, Monaco, Portugal | April 30, 2029 | |||
| 3246031 (602009057284.9 in Germany) | Method for Treating Neurocognitive Dysfunction | European Patent Office – Austria, Belgium, Switzerland, Germany, Spain, France, United Kingdom, Ireland, Luxembourg, Monaco, Portugal | April 30, 2029 |
Triple reuptake inhibitor therapeutics
| Patent No. | Title | Country / Region | Expiration Date | |||
| 7,915,433 | Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives | U.S.A |
March 10, 2028
| |||
| 8,017,791 | Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives | U.S.A. | April 14, 2024 | |||
| 8,519,159 | Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives | U.S.A | December 7, 2025 | |||
| 8,841,464 | Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives | U.S.A | April 15, 2025 | |||
| 8,937,189 | Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives | U.S.A | January 12, 2027 | |||
| 9,458,124 | Substituted Pyran Derivatives | U.S.A | February 6, 2034 |
25
TFF2 therapeutics
| Patent No. | Title | Country / Region | Expiration Date | |||
| 10,124,037 | Trefoil family factor proteins and uses thereof | U.S.A | April 2, 2033 | |||
| 11,167,010 | Trefoil family factor proteins and uses thereof | U.S.A | April 2, 2033 |
Synthetic Chimeric Poxviruses
| Patent No. | Title | Country / Region | Expiration Date | |||
| 11,345,896 | Synthetic Chimeric Poxviruses | U.S.A | November 2, 2037 | |||
| 397516 | Synthetic Chimeric Poxviruses | Mexico | November 2, 2037 | |||
| 2019/02868 | Synthetic Chimeric Poxviruses | South Africa | November 2, 2037 |
Radioprotection therapeutics
| Patent No. | Title | Country / Region | Expiration Date | |||
| 11,566,032 | Radio-Protective and Chemo-Protective Substituted Thiols | U.S.A | May 7, 2041 |
Pending Patent Applications
Our current pending patent applications are as follows:
CD40 and anti-CD154 Therapeutics
| Application No. | Title | Country / Region | ||
| 17/623,710 | Anti-CD154 antibodies and uses thereof | U.S.A. | ||
| 2020300002 | Anti-CD154 antibodies and uses thereof | Australia | ||
| BR112021026410-8 | Anti-CD154 antibodies and uses thereof | Brazil | ||
| 3145453 | Anti-CD154 antibodies and uses thereof | Canada | ||
| 202080059891.1 | Anti-CD154 antibodies and uses thereof | China | ||
| 20764933.6 | Anti-CD154 antibodies and uses thereof | European Patent Office | ||
| 202217004870 | Anti-CD154 antibodies and uses thereof | India | ||
| P00202200763 |
Anti-CD154 antibodies and uses thereof |
Indonesia | ||
| 289354 | Anti-CD154 antibodies and uses thereof | Israel | ||
| 2021-578262 | Anti-CD154 antibodies and uses thereof | Japan | ||
| PI 2021007835 | Anti-CD154 antibodies and uses thereof | Malaysia | ||
| MX/a/2022/000133 | Anti-CD154 antibodies and uses thereof | Mexico | ||
| 784548 | Anti-CD154 antibodies and uses thereof | New Zealand | ||
| 11202114433Y | Anti-CD154 antibodies and uses thereof | Singapore | ||
| 2022/01378 | Anti-CD154 antibodies and uses thereof | South Africa | ||
| 62022063693.5 | Anti-CD154 antibodies and uses thereof | Hong Kong | ||
| 62022062573.0 | Anti-CD154 antibodies and uses thereof | Hong Kong | ||
| PCT/US2022/011404 | Methods of Inducing Immune Tolerance with Modified Anti-CD154 Antibodies | PCT | ||
| 3136725 | Inhibitors of CD40-CD154 Binding | Canada | ||
| 20787970.1 | Inhibitors of CD40-CD154 Binding | European Patent Office | ||
| 2021-560713 | Inhibitors of CD40-CD154 Binding | Japan | ||
| 17/603,260 | Inhibitors of CD40-CD154 Binding | U.S.A. | ||
| 202080033531.4 | Inhibitors of CD40-CD154 Binding | China |
CBP/Amitriptyline Eutectic Formulations
| Application No. | Title | Country / Region | ||
| 17/121,547 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | U.S.A. | ||
| 17/082,949 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | U.S.A. | ||
| 2020289838 | Eutectic Formulations of Cyclobenzaprine Hydrochloride (Allowed) | Australia | ||
| BR112017005231-8 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Brazil | ||
| BR122020020968-2 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Brazil | ||
| 2,961,822 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Canada | ||
| 3,119,755 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Canada | ||
|
201910263541.6 |
Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | China | ||
| 202011576351.9 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | China | ||
| 15841528.1 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | European Patent Office | ||
| 19214535.7 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | European Patent Office | ||
| 18101200.4 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Hong Kong | ||
| 42020003105.2 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Hong Kong | ||
| 42020019748.1 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Hong Kong | ||
| 42021036749.6 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Hong Kong | ||
| 3392/KOLNP/2015 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | India | ||
| 2021-105582 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Japan | ||
| 2021-169539 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Japan |
26
| Application No. | Title | Country / Region | ||
| PI 2015703142 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Malaysia | ||
| PI 20233000078 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Malaysia | ||
| 730379 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | New Zealand | ||
| 768064 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | New Zealand | ||
| 517381123 | Eutectic Formulations of Cyclobenzaprine Hydrochloride | Saudi Arabia | ||
|
10201707528W 10201902203V |
Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride Eutectic Formulations of Cyclobenzaprine Hydrochloride |
Singapore Singapore | ||
| 2014-000391 | Eutectic Formulations of Cyclobenzaprine Hydrochloride and Amitriptyline Hydrochloride | Venezuela |
Sublingual CBP/Amitriptyline
| Application No. | Title | Country / Region | ||
| 13/918,692 | Compositions and Methods for Transmucosal Absorption | U.S.A. | ||
| P20130102101 | Compositions and Methods for Transmucosal Absorption | Argentina | ||
| Not Yet Assigned | Compositions and Methods for Transmucosal Absorption | Argentina | ||
| BR122019024508-8 | Compositions and Methods for Transmucosal Absorption |
Brazil | ||
| 3,118,913 | Compositions and Methods for Transmucosal Absorption | Canada | ||
| 202010024102.2 | Compositions and Methods for Transmucosal Absorption | China | ||
|
2013/24661 2013/37088 |
Compositions and Methods for Transmucosal Absorption Compositions and Methods for Transmucosal Absorption |
Gulf Cooperation Council Gulf Cooperation Council | ||
| 2013/40660 | Compositions and Methods for Transmucosal Absorption | Gulf Cooperation Council | ||
| 42020020336.2 | Compositions and Methods for Transmucosal Absorption | Hong Kong | ||
| P-00 2021 01421 | Compositions and Methods for Transmucosal Absorption | Indonesia | ||
| 2021-100154 | Compositions and Methods for Transmucosal Absorption | Japan | ||
| 10201605407T | Compositions and Methods for Transmucosal Absorption | Singapore | ||
CBP – PTSD
| Application No. | Title | Country / Region | ||
| 17/951,723 | Methods and Compositions for Treating Symptoms Associated with Post-Traumatic Stress Disorder Using Cyclobenzaprine | U.S.A. |
Assessing Clinical Response – PTSD
| Application No. | Title | Country / Region | ||
| PCT/US2022/015327 | An Improved Method of Assessing Clinical Response in the Treatment of PTSD Symptoms | PCT |
CBP – Fatigue
| Application No. | Title | Country / Region | ||
| 16/903,965 | Methods and Compositions for Treating Fatigue Associated with Disordered Sleep Using Very Low Dose Cyclobenzaprine | U.S.A. |
27
CBP – Agitation in Neurodegenerative Condition
| Application No. | Title | Country / Region | ||
| 16/215,952 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | U.S.A. | ||
| 2018383098 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | Australia | ||
| BR112020011345-0 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | Brazil | ||
| 3,083,341 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | Canada | ||
| 201880079917.1 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | China | ||
| 18847270.8 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | European Patent Office | ||
| P00202004178 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | Indonesia | ||
| 275289 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | Israel | ||
| 202017023747 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | India | ||
| 2020-531611 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | Japan | ||
| MX/a/2020/006140 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | Mexico | ||
| PI2020002800 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | Malaysia | ||
| 765792 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | New Zealand | ||
| 520412146 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | Saudi Arabia | ||
| 11202004799T | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | Singapore | ||
| 2020/03243 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | South Africa | ||
| 6202002246.2 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | Hong Kong | ||
| 62021029558.5 | Cyclobenzaprine Treatment for Agitation, Psychosis and Cognitive Decline in Dementia and Neurodegenerative Conditions | Hong Kong |
CBP – Depression
| Application No. | Title | Country / Region | ||
| 13/412,571 | Methods and Compositions for Treating Depression Using Cyclobenzaprine | U.S.A. | ||
| 19214568.8 | Methods and Compositions for Treating Depression Using Cyclobenzaprine | European Patent Office |
Analogs of CBP
| Application No. | Title | Country / Region | ||
|
16/630,832 CA3069699 201880050758.2 EP18831505.5 |
Analogs of Cyclobenzaprine and Amitriptyline Analogs of Cyclobenzaprine and Amitriptyline Analogs of Cyclobenzaprine and Amitriptyline Analogs of Cyclobenzaprine and Amitriptyline Analogs of Cyclobenzaprine and Amitriptyline |
U.S.A. Canada China European Patent Office | ||
| 2020-526592 | Analogs of Cyclobenzaprine and Amitriptyline | Japan | ||
CBP – ASD and PTSD
| Application No. | Title | Country / Region | ||
| 2019/38140 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | Gulf Cooperation Council | ||
| 108129709 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | Taiwan R.O.C. | ||
| 17/269,106 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | U.S.A. | ||
| 2019323764 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | Australia | ||
| PI2021000802 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | Malaysia | ||
| 772889 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | New Zealand | ||
| BR112021003107-3 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | Brazil | ||
| 3109258 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | Canada | ||
| 201980062283.3 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | China | ||
| 19802247.7 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | European Patent Office | ||
| 62021045278.0 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | Hong Kong | ||
| 62022046260.5 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | Hong Kong | ||
| 202117011223 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | India | ||
| P00202101716 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | Indonesia | ||
| 280921 | Cyclobenzaprine or Amitriptyline Containing Compositions for Use in Treating Stress Disorders | Israel | ||
| 2021-509201 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | Japan | ||
| MX/a/2021/002012 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | Mexico | ||
| 11202101443W | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | Singapore | ||
| 2021/01121 | Methods of Treating Acute Stress Disorder and Posttraumatic Stress Disorder | South Africa | ||
CBP – Fibromyalgia
| Application No. | Title | Country / Region | ||
| PCT/US2021/062244 | Cyclobenzaprine Treatment for Fibromyalgia | PCT |
28
CBP – Alcohol Use Disorder
| Application No. | Title | Country / Region | ||
| PCT/US2021/060011 | Cyclobenzaprine Treatment for Alcohol Use Disorder | PCT |
CBP – Sexual dysfunction
| Application No. | Title | Country / Region | ||
| PCT/US2022/045791 | Cyclobenzaprine Treatment for Sexual Dysfunction | PCT | ||
| 17/226,058 | Cyclobenzaprine Treatment for Sexual Dysfunction | U.S.A | ||
| 2021253592 | Cyclobenzaprine Treatment for Sexual Dysfunction | Australia | ||
| 3179754 | Cyclobenzaprine Treatment for Sexual Dysfunction | Canada | ||
| 202180040673.8 | Cyclobenzaprine Treatment for Sexual Dysfunction | China | ||
| 21721779.3 | Cyclobenzaprine Treatment for Sexual Dysfunction | European Patent Office | ||
| 2022-562023 | Cyclobenzaprine Treatment for Sexual Dysfunction | Japan |
CBP – Post-Acute Sequelae of SARS-CoV-2 (PASC)
| Application No. | Title | Country / Region | ||
| 63/354,215 | Cyclobenzaprine Treatment for Post-Acute Sequelae of (SARS)-CoV-2 Infection (PASC) | U.S.A. |
Oxytocin therapeutics
| Application No. | Title | Country / Region | ||
| 2020286221 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Australia | ||
| BR1120170145456 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Brazil | ||
| 2972975 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Canada | ||
| 16735422.4 | Magnesium-Containing Oxytocin Formulations and Methods of Use | European Patent Office | ||
| 18112297.5 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Hong Kong | ||
| 2021-179295 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Japan | ||
| 1020177021998 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Republic of Korea | ||
| 734097 | Magnesium-Containing Oxytocin Formulations and Methods of Use | New Zealand | ||
| 771693 | Magnesium-Containing Oxytocin Formulations and Methods of Use | New Zealand | ||
| 201705176 | Magnesium-Containing Oxytocin Formulations and Methods of Use (Allowed) | South Africa | ||
| 16/976,912 | Labeled Oxytocin and Method of Manufacture and Use | U.S.A. | ||
| 19710979.6 | Labeled Oxytocin and Method of Manufacture and Use | European Patent Office | ||
| 2020-545532 | Labeled Oxytocin and Method of Manufacture and Use | Japan | ||
| 16/093,104 | Magnesium-Containing Oxytocin Formulations and Methods of Use | U.S.A. | ||
| 2017250505 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Australia | ||
| 3,020,179 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Canada | ||
| 2017800361853 | Magnesium-Containing Oxytocin Formulations and Methods of Use (Allowed) | China | ||
| 2023100344997 | Magnesium-Containing Oxytocin Formulations and Methods of Use | China | ||
| 17783080.9 | Magnesium-Containing Oxytocin Formulations and Methods of Use | European Patent Office | ||
| 19128645.9 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Hong Kong | ||
| 2022-60727 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Japan | ||
| MX/a/2018/012351 | Magnesium-Containing Oxytocin Formulations and Methods of Use | Mexico | ||
| 747221 | Magnesium-Containing Oxytocin Formulations and Methods of Use | New Zealand | ||
| 787097 | Magnesium-Containing Oxytocin Formulations and Methods of Use | New Zealand |
Nociceptin/Orphanin FQ therapeutics
| Application No. | Title | Country / Region | ||
| BR122021007932-3 | Methods for Treatment of Pain | Brazil |
Tianeptine Hemioxalate – Salts and Crystalline Forms
| Application No. | Title | Country / Region | ||
| BR112019013244-9 | Tianeptine Oxalate Salts and Polymorphs | Brazil | ||
| 3,048,324 | Tianeptine Oxalate Salts and Polymorphs | Canada | ||
| 201780085697.9 | Tianeptine Oxalate Salts and Polymorphs | China | ||
| 17844642.3 | Tianeptine Oxalate Salts and Polymorphs | European Patent Office | ||
| 62020006380.3 | Tianeptine Oxalate Salts and Polymorphs | Hong Kong | ||
| 62020006381.1 | Tianeptine Oxalate Salts and Polymorphs | Hong Kong | ||
| 267708 | Tianeptine Oxalate Salts and Polymorphs, Compositions Comprising Same and Uses Thereof | Israel | ||
| 201917029300 | Tianeptine Oxalate Salts and Polymorphs | India | ||
|
2019-535330 2022-180549 MX/a/2019/007891 PI2019003711 519402021 11201905974W |
Tianeptine Oxalate Salts and Polymorphs Tianeptine Oxalate Salts and Polymorphs Tianeptine Oxalate Salts and Polymorphs Tianeptine Oxalate Salts and Polymorphs Tianeptine Oxalate Salts and Polymorphs Tianeptine Oxalate Salts and Polymorphs |
Japan Japan Mexico Malaysia Saudi Arabia Singapore |
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Tianeptine and Naloxone – Major Depressive Disorder
| Application No. | Title | Country / Region | ||
| PCT/US2022/020406 | Tianeptine Oxalate and Naloxone Treatment for Major Depressive Disorder | PCT |
Synthetic Chimeric Poxviruses
| Application No. | Title | Country / Region | ||
| 17/827,320 | Synthetic Chimeric Poxviruses | U.S.A. | ||
| P 20170103043 | Synthetic Chimeric Poxviruses | Argentina | ||
| 2017/34209 | Synthetic Chimeric Poxviruses | Gulf Cooperation Council | ||
| 2017/41626 | Synthetic Chimeric Poxviruses | Gulf Cooperation Council | ||
| 106137976 | Synthetic Chimeric Poxviruses | Taiwan R.O.C. | ||
| 2017353868 | Synthetic Chimeric Poxviruses | Australia | ||
| BR112019008781-8 | Synthetic Chimeric Poxviruses | Brazil | ||
| BR122023000373-0 | Synthetic Chimeric Poxviruses | Brazil | ||
| 3,042,694 | Synthetic Chimeric Poxviruses | Canada | ||
| 201780078546.0 | Synthetic Chimeric Poxviruses | China | ||
| 17868045.0 | Synthetic Chimeric Poxviruses | European Patent Office | ||
|
201917021814 PID201904682 |
Synthetic Chimeric Poxviruses Synthetic Chimeric Poxviruses |
India Indonesia | ||
|
266399 2019-545700 |
Synthetic Chimeric Poxviruses Synthetic Chimeric Poxviruses |
Israel Japan | ||
| 2022-140113 | Synthetic Chimeric Poxviruses | Japan | ||
| PI2019002462 | Synthetic Chimeric Poxviruses | Malaysia | ||
|
752893 11201903893P |
Synthetic Chimeric Poxviruses Synthetic Chimeric Poxviruses |
New Zealand Singapore | ||
| 2022/04981 | Synthetic Chimeric Poxviruses | South Africa | ||
| 2017-000418 | Synthetic Chimeric Poxviruses | Venezuela | ||
| 62020003684.1 | Synthetic Chimeric Poxviruses | Hong Kong | ||
| 62020003675.9 | Synthetic Chimeric Poxviruses | Hong Kong |
Synthetic Vaccinia Virus
| Application No. | Title | Country / Region | ||
| 2019/37492 | Synthetic Chimeric Vaccinia Virus | Gulf Cooperation Council | ||
| 2019/41458 | Synthetic Chimeric Vaccinia Virus | Gulf Cooperation Council | ||
| 20190101165 | Synthetic Chimeric Vaccinia Virus | Argentina | ||
| 108115290 | Synthetic Chimeric Vaccinia Virus | Taiwan R.O.C. | ||
| 17/050,946 | Synthetic Chimeric Vaccinia Virus | U.S.A. | ||
| 2019262149 | Synthetic Chimeric Vaccinia Virus | Australia | ||
| BR112020022181-3 | Synthetic Chimeric Vaccinia Virus | Brazil | ||
| 3099330 | Synthetic Chimeric Vaccinia Virus | Canada | ||
| 201980029677.9 | Synthetic Chimeric Vaccinia Virus | China | ||
| 19796145.1 | Synthetic Chimeric Vaccinia Virus | European Patent Office | ||
| 202017052398 | Synthetic Chimeric Vaccinia Virus | India | ||
| P00202008694 | Synthetic Chimeric Vaccinia Virus | Indonesia | ||
| 278419 | Synthetic Chimeric Vaccinia Virus | Israel | ||
| 2020-560920 | Synthetic Chimeric Vaccinia Virus | Japan | ||
| PI 2020005696 | Synthetic Chimeric Vaccinia Virus | Malaysia | ||
| MX/a/2020/011586 | Synthetic Chimeric Vaccinia Virus | Mexico | ||
| 768999 | Synthetic Chimeric Vaccinia Virus | New Zealand | ||
| 11202010272P | Synthetic Chimeric Vaccinia Virus | Singapore | ||
| 2020/06350 | Synthetic Chimeric Vaccinia Virus | South Africa | ||
| 62021036744.2 | Synthetic Chimeric Vaccinia Virus | Hong Kong | ||
| 62021038254.0 | Synthetic Chimeric Vaccinia Virus | Hong Kong |
Stem cells-scPV treatment
| Application No. | Title | Country / Region | ||
| 2019/37505 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | Gulf Cooperation Council | ||
| 2019/41460 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | Gulf Cooperation Council | ||
| 20190101166 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | Argentina | ||
| 108115294 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | Taiwan R.O.C. | ||
| 17/049,741 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | U.S.A. | ||
| 2019262150 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | Australia | ||
| 3098145 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | Canada | ||
| 201980029672.6 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | China | ||
| 19797026.2 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | European Patent Office | ||
| 278420 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | Israel | ||
| 2020-561064 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | Japan | ||
| 62021038255.7 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | Hong Kong | ||
| 62021031667.0 | Stem Cells Comprising Synthetic Chimeric Vaccinia Virus and Methods of Using Them | Hong Kong | ||
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Poxvirus vaccine against COVID-19
| Application No. | Title | Country / Region | ||
| 17/187,678 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | U.S.A. | ||
| 110107179 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Taiwan | ||
| 20210100512 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Argentina | ||
| 63/315,520 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | U.S.A. | ||
| 1202200348 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | African Intellectual Property Organization | ||
| AP/P/2022/014318 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | African Regional Intellectual Property Organization | ||
| 2021226592 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Australia | ||
| BR112022016992-2 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Brazil | ||
| 3173996 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Canada | ||
| 202180027983.6 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | China | ||
| 202292431 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Eurasian Patent Office | ||
| 21715007.7 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | European Patent Office | ||
| 202217053476 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | India | ||
| P00202210244 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Indonesia | ||
| 295925 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Israel | ||
| 2022-551297 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Japan | ||
| PI 2022004613 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Malaysia | ||
| MX/a/2022/010588 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Mexico | ||
| 791924 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | New Zealand | ||
| 10-2022-7033014 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Republic of Korea | ||
| 522440323 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | Saudi Arabia | ||
| 2022/09895 | Recombinant Poxvirus Based Vaccine against SARS-CoV-2 virus | South Africa | ||
Salts of glutathione
| Application No. | Title | Country / Region | ||
| 17/442,258 | Salt forms of S-(N, N-diethylcarbamolyl) glutathione | U.S.A. | ||
| 2020249868 | Salt forms of S-(N, N-diethylcarbamolyl) glutathione | Australia | ||
| 3,134,875 | Salt forms of S-(N, N-diethylcarbamolyl) glutathione | Canada | ||
| 202080034626.8 | Salt forms of S-(N, N-diethylcarbamolyl) glutathione | China | ||
| 20727359.0 | Salt forms of S-(N, N-diethylcarbamolyl) glutathione | European Patent Office | ||
| 286730 | Salt forms of S-(N, N-diethylcarbamolyl) glutathione | Israel | ||
| 2021-557223 | Salt forms of S-(N, N-diethylcarbamolyl) glutathione | Japan | ||
| 62022054457.6 | Salt forms of S-(N, N-diethylcarbamolyl) glutathione | Hong Kong | ||
| 62022057646.1 | Salt forms of S-(N, N-diethylcarbamolyl) glutathione | Hong Kong |
TFF2 therapeutics
| Application No. | Title | Country / Region | ||
| 17/638,761 | Modified TFF2 polypeptides | U.S.A. | ||
| 2020338947 | Modified TFF2 polypeptides | Australia | ||
| 3152665 | Modified TFF2 polypeptides | Canada | ||
| 202080071768.1 | Modified TFF2 polypeptides | China | ||
| 20781063.1 | Modified TFF2 polypeptides | European Patent Office | ||
| 202217016249 | Modified TFF2 polypeptides | India | ||
| 290910 | Modified TFF2 polypeptides | Israel | ||
| 2022-513154 | Modified TFF2 polypeptides | Japan | ||
| MX/a/2022/002337 | Modified TFF2 polypeptides | Mexico | ||
| 786004 | Modified TFF2 polypeptides | New Zealand | ||
| 2022/03355 | Modified TFF2 polypeptides | South Africa | ||
| 62023066535.3 | Modified TFF2 polypeptides | Hong Kong | ||
| 62023066928.0 | Modified TFF2 polypeptides | Hong Kong |
Radioprotection therapeutics
| Application No. | Title | Country / Region | ||
| 17/991,292 | Radio-Protective and Chemo-Protective Substituted Thiols | U.S.A. | ||
| 17/923,831 | Radio-and Chemo-Protective Compounds | U.S.A. | ||
| 2021269125 | Radio-and Chemo-Protective Compounds | Australia | ||
| 3182014 | Radio-and Chemo-Protective Compounds | Canada |
| Not Yet Assigned | Radio-and Chemo-Protective Compounds | China | ||
| 21728771.3 | Radio-and Chemo-Protective Compounds | European Patent Office | ||
| 202217070148 | Radio-and Chemo-Protective Compounds | India | ||
| 298025 | Radio-and Chemo-Protective Compounds | Israel | ||
| 2022-567802 | Radio-and Chemo-Protective Compounds | Japan | ||
| 793900 | Radio-and Chemo-Protective Compounds | New Zealand | ||
| 522441204 | Radio-and Chemo-Protective Compounds | Saudi Arabia | ||
| 11202254727V | Radio-and Chemo-Protective Compounds | Singapore |
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Clinical data statistical analysis
| Application No. | Title | Country / Region | ||
| PCT/US2021/056213 | Randomization Honoring Methods to Assess the Significance of Interventions on Outcomes in Disorders | PCT | ||
| 17/508,182 | Randomization Honoring Methods to Assess the Significance of Interventions on Outcomes in Disorders | U.S.A. |
Monoclonal Antibodies – anti-SARS-CoV-2 Spike
| Application No. | Title | Country / Region | ||
| 63/421,137 | Anti-SARS-CoV-2-Spike Monoclonal Antibodies and Antigen-Binding Fragments Thereof and Use in Treating SARS-CoV-2 Infection | U.S.A. | ||
| 63/421,138 | Anti-SARS-CoV-2-Spike Monoclonal Antibodies and Antigen-Binding Fragments Thereof and Use in Treating SARS-CoV-2 Infection | U.S.A. | ||
| 63/421,141 | Anti-SARS-CoV-2-Spike Monoclonal Antibodies and Antigen-Binding Fragments Thereof and Use in Treating SARS-CoV-2 Infection | U.S.A. |
Nanoparticles – T cell Immune Response
| Application No. | Title | Country / Region | ||
| 63/338,217 | Nanoparticles for Inducing a TH1 T Cell Immune Response | U.S.A. |
Nanoparticles – mRNA vaccine
| Application No. | Title | Country / Region | ||
| PCT/US2022/070739 | RNA Stabilizing Nanoparticles | PCT | ||
| PCT/US2022/075944 | mRNA Vaccine Formulations and Methods of Using the Same | PCT |
Virus Vaccine – Bovine Parainfluenza Virus Vaccine
| Application No. | Title | Country / Region | ||
| 17/755,359 | Broadly Protective Bovine Parainfluenza 3 Virus and Bovine Viral Diarrhea Virus Vaccine | U.S.A. | ||
| PCT/US2022/072433 | SARS-Coronavirus 2 (SARS-CoV-2) Spike Protein Subunit Vaccines | PCT |
Antiviral Drugs – Cathepsin Inhibitors
| Application No. | Title | Country / Region | ||
| 63/327,431 | Therapeutic Agents and Combinations for Treating Viral Diseases | U.S.A. | ||
| 18/055,596 | Compositions and Methods for Increasing Efficacy of a Drug | U.S.A. | ||
| 2021271806 | Compositions and Methods for Increasing Efficacy of a Drug | Australia | ||
| 21803283.7 | Compositions and Methods for Increasing Efficacy of a Drug | European Patent Office | ||
| 2022-569505 | Compositions and Methods for Increasing Efficacy of a Drug | Japan | ||
| 202217072271 | Compositions and Methods for Increasing Efficacy of a Drug | India | ||
| PCT/US2021/052664 | Methods and Compositions for the Treatment of Viral Diseases | PCT |
Trademarks and Service Marks
We seek trademark and service mark protection in the United States and outside of the United States where available and when appropriate. We are the owner of the following U.S. federally registered marks: TONIX PHARMACEUTICALS (Reg. No. 4656463, issued December 16, 2014).
We are the owner of the following marks for which applications for U.S. federal registration are currently pending: FYMRALIN (Serial No. 97/458017, filed June 14, 2022), MODALTIN (Serial No. 97/424052, filed May 23, 2022), RAPONTIS (Serial No. 97/424058, filed May 23, 2022), PROTECTIC (Serial No. 97/424071, filed May 23, 2022), TONIX PHARMACEUTICALS (Serial No. 88/896150, filed April 30, 2020), and ANGSTRO-TECHNOLOGY (Serial No. 88/690384, filed November 13, 2019) and TONMYA (Serial No. 97/185424, filed December 22, 2021).
Research and Development
We have approximately 94 employees dedicated to research and development. Our research and development operations are located in Chatham, NJ, Dartmouth, MA, Frederick, Maryland, San Diego, CA, Dublin, Ireland and Montreal, Canada. We have used, and expect to continue to use, third parties to conduct our nonclinical and clinical studies. We acquired the RDC in Frederick, Maryland consisting of two buildings totaling approximately 48,000 square feet. The acquisition closed in October 2021 and is operational.
Manufacturing
We have contracted with a third-party cGMP-compliant contract manufacturer organization, or CMOs, for the manufacture of TNX-102 SL drug substances and drug products for investigational purposes, including nonclinical and clinical testing. For TNX-102 SL, we have engaged a cGMP facility for manufacturing of to-be-marketed product for Phase 3 clinical and commercial. Our manufacturing operations are managed and controlled in Dublin, Ireland.
All of our small molecules drug candidates are synthesized using industry standard processes, and our drug products are formulated using commercially available pharmaceutical grade excipients.
Our smallpox- and mpox-preventing vaccine candidate is a biologic and employs a live form of horsepox. Both the drug substance (HPVX and the cell bank) and the drug product (vaccine) will be manufactured by contract cGMP-compliant facilities capable of manufacturing for nonclinical/clinical testing and licensed product.
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On September 28, 2020, we completed the purchase of our 45,000 square foot facility in Massachusetts, to house our new Advanced Development Center for accelerated development and manufacturing of vaccines and biologics. As of October 1, 2022, the facility was ready for its intended use and is operational.
On December 23, 2020, we completed the purchase of our approximately 44-acre site in Hamilton, Montana, for the construction of a vaccine development and commercial scale manufacturing facility. As of December 31, 2022, the facility was not ready for its intended use.
Government Regulations
The FDA and other federal, state, local and foreign regulatory agencies impose substantial requirements upon the clinical development, approval, labeling, manufacture, marketing and distribution of drug products. These agencies regulate, among other things, research and development activities and the testing, approval, manufacture, quality control, safety, effectiveness, labeling, storage, record keeping, advertising and promotion of our product candidates. The regulatory approval process is generally lengthy and expensive, with no guarantee of a positive result. Moreover, failure to comply with applicable requirements by the FDA or other requirements may result in civil or criminal penalties, recall or seizure of products, injunctive relief including partial or total suspension of production, or withdrawal of a product from the market.
The FDA regulates, among other things, the research, manufacture, promotion and distribution of drugs in the U.S. under the FDCA and other statutes and implementing regulations. The process required by the FDA before prescription drug product candidates may be marketed in the U.S. generally involves the following:
| ● | completion of extensive nonclinical laboratory tests, animal studies and formulation studies, all performed in accordance with the FDA’s Good Laboratory Practice regulations; |
| ● | submission to the FDA of an IND, which must become effective before human clinical trials may begin; |
| ● | performance of adequate and well-controlled human clinical trials in accordance with the FDA’s regulations, including Good Clinical Practices, to establish the safety and efficacy of the product candidate for each proposed indication; |
| ● | submission to the FDA of an NDA for drug products, or a Biologics License Application, or BLA, for biologic products; |
| ● | satisfactory completion of a preapproval inspection by the FDA of the manufacturing facilities at which the product is produced to assess compliance with cGMP regulations; and |
| ● | the FDA’s review and approval of the NDA or BLA prior to any commercial marketing, sale or shipment of the drug. |
The testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for our product candidates will be granted on a timely basis, if at all.
Nonclinical tests include laboratory evaluations of product chemistry, formulation and stability, as well as studies to evaluate toxicity in animals and other animal studies. The results of nonclinical tests, together with manufacturing information and analytical data, are submitted as part of an IND to the FDA. Some nonclinical testing may continue even after an IND is submitted. The IND also includes one or more protocols for the initial clinical trial or trials and an investigator’s brochure. An IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises concerns or questions relating to the proposed clinical trials as outlined in the IND and places the clinical trial on a clinical hold. In such cases, the IND sponsor and the FDA must resolve any outstanding concerns or questions before any clinical trials can begin. Clinical trial holds also may be imposed at any time before or during studies due to safety concerns or non-compliance with regulatory requirements. An independent Institutional Review Board, or IRB, at each of the clinical centers proposing to conduct the clinical trial must review and approve the plan for any clinical trial before it commences at that center. An IRB considers, among other things, whether the risks to individuals participating in the trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the consent form signed by the trial participants and must monitor the study until completed.
Clinical Trials
Clinical trials involve the administration of the product candidate to human subjects under the supervision of qualified medical investigators according to approved protocols that detail the objectives of the study, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor participant safety. Each protocol for a U.S. study is submitted to the FDA as part of the IND.
Human clinical trials are typically conducted in three sequential phases, but the phases may overlap, or be combined.
| ● | Phase 1 clinical trials typically involve the initial introduction of the product candidate into healthy human volunteers. In Phase 1 clinical trials, the product candidate is typically tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and pharmacodynamics. |
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Phase 2 clinical trials are generally conducted in a limited patient population to gather evidence about the efficacy of the product candidate for specific, targeted indications; to determine dosage tolerance and optimal dosage; and to identify possible adverse effects and safety risks. Phase 2 clinical trials, in particular Phase 2b trials, can be undertaken to evaluate clinical efficacy and to test for safety in an expanded patient population at geographically dispersed clinical trial sites. |
| ● | Phase 3 clinical trials are undertaken to evaluate clinical efficacy and to test for safety in an expanded patient population at geographically dispersed clinical trial sites. The size of Phase 3 clinical trials depends upon clinical and statistical considerations for the product candidate and disease. Phase 3 clinical trials are intended to establish the overall risk-benefit ratio of the product candidate and provide an adequate basis for product labeling. |
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Post-approval clinical trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial approval. These clinical trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow-up.
Clinical testing must satisfy the extensive regulations of the FDA. Reports detailing the results of the clinical trials must be submitted at least annually to the FDA and safety reports must be submitted for serious and unexpected adverse events. Success in early-stage clinical trials does not assure success in later-stage clinical trials. The FDA, an IRB or we may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.
New Drug Applications
Assuming successful completion of the required clinical trials, the results of product development, nonclinical studies and clinical trials are submitted to the FDA as part of an NDA (or BLA, in the case of a biologic product). An NDA or BLA also must contain extensive manufacturing information, as well as proposed labeling for the finished product. An NDA or BLA applicant must develop information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the product in accordance with cGMP. The manufacturing process must be capable of consistently producing quality product within specifications approved by the FDA. The manufacturer must develop methods for testing the quality, purity and potency of the final product. In addition, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product does not undergo unacceptable deterioration over its shelf life. Prior to approval, the FDA will conduct an inspection of the manufacturing facilities to assess compliance with cGMP.
The FDA reviews all NDAs and BLAs submitted before it accepts them for filing. The FDA may request additional information rather than accept an NDA for filing. In this event, the NDA or BLA must be resubmitted with the additional information and is subject to review before the FDA accepts it for filing. After an application is filed, the FDA may refer the NDA or BLA to an advisory committee for review, evaluation and recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers them carefully when making decisions. The FDA may deny approval of an NDA or BLA if the applicable regulatory criteria are not satisfied. Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data.
The FDA may issue a complete response letter, which may require additional clinical or other data or impose other conditions that must be met in order to secure final approval of the NDA or BLA. If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product. In addition, the FDA may require us to conduct Phase 4 testing which involves clinical trials designed to further assess a drug’s safety and effectiveness after NDA or BLA approval, and may require surveillance programs to monitor the safety of approved products which have been commercialized. Once issued, the FDA may withdraw product approval if ongoing regulatory requirements are not met or if safety or efficacy questions are raised after the product reaches the market.
Section 505(b) NDAs
There are two types of NDAs: the Section 505(b)(1) NDA, or full NDA, and the Section 505(b)(2) NDA. We intend to file Section 505(b)(2) NDAs for TNX-102 SL for FM, Long COVID and PTSD, for TNX-1900 for chronic migraine and TNX-2900 for Prader Willi Syndrome and for certain other products, that might, if accepted by the FDA, save time and expense in the development and testing of our product candidates. We may need to file a Section 505(b)(1) NDA for certain other products in the future. A full NDA is submitted under Section 505(b)(1) of the FDCA, and must contain full reports of investigations conducted by the applicant to demonstrate the safety and effectiveness of the drug. A Section 505(b)(2) NDA may be submitted for a drug for which one or more of the investigations relied upon by the applicant was not conducted by or for the applicant and for which the applicant has no right of reference from the person by or for whom the investigations were conducted. A Section 505(b)(2) NDA may be submitted based in whole or in part on published literature or on the FDA’s finding of safety and efficacy of one or more previously approved drugs, which are known as reference drugs. Thus, the filing of a Section 505(b)(2) NDA may result in approval of a drug based on fewer clinical or nonclinical studies than would be required under a full NDA. The number and size of studies that need to be conducted by the sponsor depends on the amount and quality of data pertaining to the reference drug that are publicly available, and on the similarity of and differences between the applicant’s drug and the reference drug. In some cases, extensive, time-consuming, and costly clinical and nonclinical studies may still be required for approval of a Section 505(b)(2) NDA.
Our drug approval strategy for our new formulations of approved chemical entities is to submit Section 505(b)(2) NDAs to the FDA. As such, we plan to submit an NDA under Section 505(b)(2) for TNX-102 SL for FM, Long COVID and PTSD; TNX-1900 for chronic migraine, and TNX-2900 for Prader Willi Syndrome. The FDA may not agree that these product candidates are approvable as a Section 505(b)(2) NDA. If the FDA determines that a Section 505(b)(2) NDA is not appropriate and that a full NDA is required, the time and financial resources required to obtain FDA approval could substantially and materially increase and be less likely to be approved. If the FDA requires a full NDA or requires more extensive testing and development for some other reason, our ability to compete with alternative products that arrive on the market more quickly than our product candidates would be adversely impacted. If reference listed products are withdrawn from the market by the FDA for a safety reason, we may not be able to reference such products to support our anticipated 505(b)(2) NDAs, and we may be required to follow the requirements of Section 505(b)(1).
Patent Protections
An applicant submitting a Section 505(b)(2) NDA must certify to the FDA with respect to the patent status of the reference drug upon which the applicant relies in support of approval of its drug. With respect to every patent listed in the FDA’s Orange Book, which is the FDA’s list of approved drug products, as claiming the reference drug or an approved method of use of the reference drug, the Section 505(b)(2) applicant must certify that: (1) there is no patent information listed in the orange book for the reference drug; (2) the listed patent has expired; (3) the listed patent has not expired, but will expire on a particular date; (4) the listed patent is invalid or will not be infringed by the manufacture, use, or sale of the product in the Section 505(b)(2) NDA; or (5) if the patent is a use patent, that the applicant does not seek approval for a use claimed by the patent. If the applicant files a certification to the effect of clause (1), (2) or (5), FDA approval of the Section 505(b)(2) NDA may be made effective immediately upon successful FDA review of the application, in the absence of marketing exclusivity delays, which are discussed below. If the applicant files a certification to the effect of clause (3), the Section 505(b)(2) NDA approval may not be made effective until the expiration of the relevant patent and the expiration of any marketing exclusivity delays.
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If the Section 505(b)(2) NDA applicant provides a certification to the effect of clause (4), referred to as a paragraph IV certification, the applicant also must send notice of the certification to the patent owner and the holder of the NDA for the reference drug. The filing of a patent infringement lawsuit within 45 days of the receipt of the notification may prevent the FDA from approving the Section 505(b)(2) NDA for 30 months from the date of the receipt of the notification unless the court determines that a longer or shorter period is appropriate because either party to the action failed to reasonably cooperate in expediting the action. However, the FDA may approve the Section 505(b)(2) NDA before the 30 months have expired if a court decides that the patent is invalid or not infringed, or if a court enters a settlement order or consent decree stating the patent is invalid or not infringed.
Notwithstanding the approval of many products by the FDA pursuant to Section 505(b)(2), over the last few years certain brand-name pharmaceutical companies and others have objected to the FDA’s interpretation of Section 505(b)(2). If the FDA’s interpretation of Section 505(b)(2) is successfully challenged in court, the FDA may be required to change its interpretation of Section 505(b)(2) which could delay or even prevent the FDA from approving any Section 505(b)(2) NDA that we submit. The pharmaceutical industry is highly competitive, and it is not uncommon for a manufacturer of an approved product to file a citizen petition with the FDA seeking to delay approval of, or impose additional approval requirements for, pending competing products. If successful, such petitions can significantly delay, or even prevent, the approval of the new product. Moreover, even if the FDA ultimately denies such a petition, the FDA may substantially delay approval while it considers and responds to the petition.
Marketing Exclusivity
Market exclusivity provisions under the FDCA can delay the submission or the approval of Section 505(b)(2) NDAs, thereby delaying a Section 505(b)(2) product from entering the market. The FDCA provides five-year marketing exclusivity to the first applicant to gain approval of an NDA for an NCE, meaning that the FDA has not previously approved any other drug containing the same active moiety. This exclusivity prohibits the submission of a Section 505(b)(2) NDA for any drug product containing the active ingredient during the five-year exclusivity period. However, submission of a Section 505(b)(2) NDA that certifies that a listed patent is invalid, unenforceable, or will not be infringed, as discussed above, is permitted after four years, but if a patent infringement lawsuit is brought within 45 days after such certification, FDA approval of the Section 505(b)(2) NDA may automatically be stayed until 7½ years after the NCE approval date. The FDCA also provides three years of marketing exclusivity for the approval of new and supplemental NDAs for product changes, including, among other things, new indications, dosage forms, routes of administration or strengths of an existing drug, or for a new use, if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by FDA to be essential to the approval of the application.
Five-year and three-year exclusivity will not delay the submission or approval of another full NDA; however, as discussed above, an applicant submitting a full NDA under Section 505(b)(1) would be required to conduct or obtain a right of reference to all of the nonclinical and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.
Other types of exclusivity in the United States include orphan drug exclusivity and pediatric exclusivity. The FDA may grant orphan drug designation to a drug intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for this type of disease or condition will be recovered from sales in the United States for that drug. Seven-year orphan drug exclusivity is available to a product that has orphan drug designation and that receives the first FDA approval for the indication for which the drug has such designation. Orphan drug exclusivity prevents approval of another application for the same drug for the same orphan indication, for a period of seven years, regardless of whether the application is a full NDA or a Section 505(b)(2) NDA, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity. Pediatric exclusivity, if granted, provides an additional six months to an existing exclusivity or statutory delay in approval resulting from a patent certification. This six-month exclusivity, which runs from the end of other exclusivity protection or patent delay, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.
Section 505(b)(2) NDAs are similar to full NDAs filed under Section 505(b)(1) in that they are entitled to any of these forms of exclusivity if they meet the qualifying criteria. They also are entitled to the patent protections described above, based on patents that are listed in the FDA’s Orange Book in the same manner as patents claiming drugs and uses approved for NDAs submitted as full NDAs.
Breakthrough Therapy Designation
The Food and Drug Administration Safety and Innovation Act, or FDASIA, Section 902 provides for Breakthrough Therapy designation. A Breakthrough Therapy is a drug:
| ● | intended alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition; and |
| ● | preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. |
Fast Track Designation
A Fast Track is a designation by the FDA of an investigational drug which:
| ● | intended alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition; and |
| ● | non-clinical or clinical data demonstrate the potential to address an unmet medical need |
Fast track is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. The benefits of a Fast Track designation include rolling submission of portions of the NDA for the drug candidate and eligibility for priority review of the NDA. Additionally, more frequent meetings and written communication with the FDA regarding the development plan and trial design for the drug candidate are encouraged throughout the entire drug development and review process, with the goal of having earlier drug approval and access for patients.
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Material Threat Medical Countermeasures
In 2016, the 21st Century Cures Act, or Act, was signed into law to support ongoing biomedical innovation. One part of the Act, Section 3086, is aimed at “Encouraging Treatments for Agents that Present a National Security Threat.” The Act created a new priority review voucher program for approved “material threat medical countermeasure applications.” The Act defines such countermeasures as drug or biological products, including vaccines intended to treat biological, chemical, radiological, or nuclear agents that present a national security threat or to treat harm from a condition that may be caused by administering a drug or biological product against such an agent. The Department of Homeland Security has identified 13 such threats, including anthrax, smallpox, Ebola/Marburg, tularemia, botulinum toxin, and pandemic influenza, which includes the SARS coronavirus 2, known as SARS-CoV-2.
Other Regulatory Requirements
Maintaining substantial compliance with appropriate federal, state and local statutes and regulations requires the expenditure of substantial time and financial resources. Drug manufacturers are required to register their establishments with the FDA and certain state agencies, and after approval, the FDA and these state agencies conduct periodic unannounced inspections to ensure continued compliance with ongoing regulatory requirements, including cGMPs. In addition, after approval, some types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further FDA review and approval. The FDA may require post-approval testing and surveillance programs to monitor safety and the effectiveness of approved products that have been commercialized. Any drug products manufactured or distributed by us pursuant to FDA approvals are subject to continuing regulation by the FDA, including:
| ● | record-keeping requirements; |
| ● | reporting of adverse experiences with the drug; |
| ● | providing the FDA with updated safety and efficacy information; |
| ● | reporting on advertisements and promotional labeling; |
| ● | drug sampling and distribution requirements; and |
| ● | complying with electronic record and signature requirements. |
In addition, the FDA strictly regulates labeling, advertising, promotion and other types of information on products that are placed on the market. There are numerous regulations and policies that govern various means for disseminating information to health-care professionals as well as consumers, including to industry sponsored scientific and educational activities, information provided to the media and information provided over the Internet. Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved label.
The FDA has very broad enforcement authority and the failure to comply with applicable regulatory requirements can result in administrative or judicial sanctions being imposed on us or on the manufacturers and distributors of our approved products, including warning letters, refusals of government contracts, clinical holds, civil penalties, injunctions, restitution and disgorgement of profits, recall or seizure of products, total or partial suspension of production or distribution, withdrawal of approvals, refusal to approve pending applications, and criminal prosecution resulting in fines and incarceration. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability. In addition, even after regulatory approval is obtained, later discovery of previously unknown problems with a product may result in restrictions on the product or even complete withdrawal of the product from the market.
Coverage and Reimbursement
Sales of our product candidates, if approved, will depend, in part, on the extent to which such products will be covered by third-party payors, such as government health care programs, commercial insurance and managed healthcare organizations. These third-party payors are increasingly limiting coverage or reducing reimbursements for medical products and services. In addition, the U.S. government, state legislatures and foreign governments have continued implementing cost-containment programs, including price controls, restrictions on reimbursement and requirements for substitution of generic products. Third-party payors decide which therapies they will pay for and establish reimbursement levels. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own coverage and reimbursement policies. However, decisions regarding the extent of coverage and amount of reimbursement to be provided for any drug candidates that we develop will be made on a payor-by-payor basis. Each payor determines whether or not it will provide coverage for a therapy, what amount it will pay the manufacturer for the therapy, and on what tier of its formulary it will be placed. The position on a payor’s list of covered drugs, or formulary, generally determines the co-payment that a patient will need to make to obtain the therapy and can strongly influence the adoption of such therapy by patients and physicians. Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit our net revenue and results. Decreases in third-party reimbursement for our product candidates or a decision by a third-party payor to not cover our product candidates could reduce physician usage of our product candidates, once approved, and have a material adverse effect on our sales, results of operations and financial condition.
Other Healthcare Laws
Because of our current and future arrangements with healthcare professionals, principal investigators, consultants, customers and third-party payors, we will also be subject to healthcare regulation and enforcement by the federal government and the states and foreign governments in which we will conduct our business, including our clinical research, proposed sales, marketing and educational programs. Failure to comply with these laws, where applicable, can result in the imposition of significant civil penalties, criminal penalties, or both.
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The U.S. laws that may affect our ability to operate, among others, include: the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information; certain state laws governing the privacy and security of health information in certain circumstances, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts; the federal healthcare programs’ Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, in exchange for or to induce either the referral of an individual for, or the purchase, order or recommendation of, any good or service for which payment may be made under federal healthcare programs such as the Medicare and Medicaid programs; federal false claims laws which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid, or other third-party payors that are false or fraudulent; federal criminal laws that prohibit executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters; the Physician Payments Sunshine Act, which requires manufacturers of drugs, devices, biologics, and medical supplies to report annually to the U.S. Department of Health and Human Services information related to payments and other transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members; and state law equivalents of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items or services reimbursed by any third-party payor, including commercial insurers.
In addition, many states have similar laws and regulations, such as anti-kickback and false claims laws that may be broader in scope and may apply regardless of payor, in addition to items and services reimbursed under Medicaid and other state programs. Additionally, to the extent that our product is sold in a foreign country, we may be subject to similar foreign laws.
The Impact of New Legislation and Amendments to Existing Laws
The FDCA is subject to routine legislative amendments with a broad range of downstream effects. In addition to new legislation, such as the FDA Reauthorization Act of 2017 or the FDASIA in 2012, Congress introduces amendments to reauthorize drug user fees and address emerging concerns every five years. We cannot predict the impact of these new legislative acts and their implementation of regulations on our business. The programs established or to be established under the legislation may have adverse effects upon us, including increased regulation of our industry. Compliance with such regulation may increase our costs and limit our ability to pursue business opportunities. In addition, the FDA’s regulations, policies and guidance are often revised or reinterpreted by the agency or the courts in ways that may significantly affect our business and our products.
We expect that additional federal and state, as well as foreign, healthcare reform measures will be adopted in the future, any of which could result in reduced demand for our products or additional pricing pressure.
Human Capital Resources
As of March 13, 2023, we had 117 full-time employees, of whom 19 hold M.D. or Ph.D. degrees. We have 94 employees dedicated to research and development. None of our employees are represented by a collective bargaining agreement. We believe that the skills, experience and industry knowledge of our key employees significantly benefit our operations and performance. Our research and development operations are located in Chatham, NJ, San Diego, CA, Dartmouth, MA, Frederick, Maryland, Dublin, Ireland and Montreal, Canada. We have used, and expect to continue to use, third parties to conduct our nonclinical and clinical studies as well as part-time employees.
Employee health and safety in the workplace is one of our core values. The COVID-19 pandemic has underscored for us the importance of keeping our employees safe and healthy. In response to the pandemic, we have taken actions aligned with the World Health Organization and the Centers for Disease Control and Prevention in an effort to protect our workforce so they can more safely and effectively perform their work.
Employee levels are managed to align with the pace of business and management believes it has sufficient human capital to operate its business successfully.
Corporate Information
We lease the space for our principal executive offices, which are located at 26 Main Street, Suite 101, Chatham, New Jersey 07928, and our telephone number is (862) 799 8599. Our website address is www.tonixpharma.com. We do not incorporate the information on our websites into this annual report, and you should not consider such information part of this annual report.
We were incorporated on November 16, 2007 under the laws of the State of Nevada as Tamandare Explorations Inc. On October 11, 2011, we changed our name to Tonix Pharmaceuticals Holding Corp.
Item 1A. Risk Factors
Summary of Risk Factors
| ● | We have a history of operating losses and may never generate revenues or achieve profitability. |
| ● | We expect our operating results to fluctuate, which may make it difficult to predict our future performance. |
| ● | Our product candidates are novel and still in development. |
| ● | We do not expect to generate any revenues from product sales in the foreseeable future, if at all. |
| ● | We are largely dependent on the success of our product candidates and cannot be certain that our product candidates will receive regulatory approval or be successfully commercialized. |
| ● | Clinical studies required for our product candidates are expensive and time-consuming, and their outcome is uncertain. |
| ● | We are subject to extensive and costly government regulation. |
| ● |
We have never submitted an NDA before, and may be unable to do so for our product candidates we are developing. |
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| ● | Our product candidates may cause serious adverse events or undesirable side effects which may delay or prevent marketing approval, or, if approval is received, require them to be taken off the market, require them to include safety warnings or otherwise limit their sales. |
| ● | We may be unable to meet our anticipated development and commercialization timelines for approval of any of our product candidates. |
| ● | Any breakthrough, fast track or orphan drug designation or grant of priority review status by the FDA may not actually lead to a faster development or regulatory review or approval process, nor assure FDA approval of our product candidates. |
| ● | Even if approved, our products may not be accepted by the market. | |
| ● | We may use our financial and human resources to pursue a particular research program or product candidate and fail to capitalize on programs or product candidates that may be more profitable or for which there is a greater likelihood of success. |
| ● | Our independent registered public accounting firm has included an explanatory paragraph relating to our ability to continue as a going concern in its report on our audited financial statements. We may be unable to continue to operate without the threat of liquidation for the foreseeable future. |
| ● | We will need additional capital. If additional capital is not available or is available at unattractive terms, we may be forced to delay, reduce the scope of or eliminate our research and development programs, reduce our commercialization efforts or curtail our operations. |
| ● | Outbreaks of communicable diseases may materially and adversely affect our business, financial condition and results of operations. |
| ● | Competition and technological change may make our product candidates and technologies less attractive or obsolete. |
| ● | If we fail to protect our intellectual property rights, our ability to pursue the development of our technologies and products would be negatively affected. |
| ● | We may be involved in lawsuits to protect or enforce our patents, which could be expensive and time consuming. |
| ● | If we infringe the rights of third parties we could be prevented from selling products, forced to pay damages, and defend against litigation. |
| ● | We rely on third parties to conduct, supervise and monitor our clinical studies, and if those third parties perform in an unsatisfactory manner, it may harm our business. |
| ● | We will need to expand our operations and increase the size of our company, and we may experience difficulties in managing growth. |
| ● | Our executive officers and other key personnel are critical to our business, and our future success depends on our ability to retain them. |
| ● | If we are unable to hire additional qualified personnel, our ability to grow our business may be harmed. |
| ● | We rely on third parties to manufacture the compounds used in our studies, and we intend to rely on them for the manufacture of any approved products for commercial sale. If these third parties do not manufacture our product candidates in sufficient quantities and at an acceptable cost, clinical development and commercialization of our product candidates could be delayed, prevented or impaired. |
| ● | Failure by our third-party manufacturers to comply with the regulatory guidelines set forth by the FDA with respect to our product candidates could delay or prevent the completion of clinical studies, the approval of any product candidates or the commercialization of our products. | |
| ● | Adverse global conditions, including economic uncertainty, may negatively impact our financial results. | |
| ● | Our internal computer systems, or those of our CRO’s or other contractors or consultants, may fail or suffer security breaches, which could result in a material disruption of our product development programs. |
| ● | Corporate and academic collaborators may take actions to delay, prevent, or undermine the success of our products. |
| ● | Data provided by collaborators and others upon which we rely that has not been independently verified could turn out to be false, misleading, or incomplete. |
| ● | Our product candidates may face competition sooner than expected. |
| ● | If we fail to establish marketing, sales and distribution capabilities, or fail to enter into arrangements with third parties, we will not be able to create a market for our product candidates. |
| ● | Our relationships with customers, physicians, and third-party payors will be subject, directly or indirectly, to federal and state healthcare fraud and abuse laws, false claims laws, health information privacy and security laws, and other healthcare laws and regulations. If we are unable to comply, or have not fully complied, with such laws, we could face substantial penalties. |
| ● | Coverage and adequate reimbursement may not be available for our current or any future drug candidates, which could make it difficult for us to sell profitably, if approved. |
| ● | Healthcare legislative reform measures may have a negative impact on our business and results of operations. |
| ● | If we obtain approval to commercialize any approved products outside of the United States, a variety of risks associated with international operations could materially adversely affect our business. |
| ● | We face the risk of product liability claims and may not be able to obtain insurance. |
| ● | We use hazardous chemicals in our business. Potential claims relating to improper handling, storage or disposal of these chemicals could affect us and be time consuming and costly. |
| ● | If we retain collaborative partners and our partners do not satisfy their obligations, we will be unable to develop our partnered product candidates. |
| ● | We may be unsuccessful in obtaining a priority review voucher for material threat medical countermeasures. |
| ● | Government entities may take actions that directly or indirectly have the effect of limiting opportunities for our vaccines for COVID-19. |
| ● | If technology developed for the purposes of developing new medicines or vaccines can be applied to the creation or development of biological weapons, then our technology may be considered “dual use” technology and be subject to limitations on public disclosure or export. |
| ● | We face risks in connection with existing and future collaborations with respect to the development, manufacture, and commercialization of our product candidates. |
| ● | We face risks in connection with the testing, production and storage of our vaccine product candidates. |
| ● | An active trading market for our common stock may not be sustained. |
| ● | The market price of our common stock has been extremely volatile and may continue to be volatile due to numerous circumstances beyond our control. |
| ● | We could be delisted from Nasdaq, which could seriously harm the liquidity of our stock and our ability to raise capital. |
| ● | We do not anticipate paying dividends on our common stock and, accordingly, shareholders must rely on stock appreciation for any return on their investment. | |
| ● | We expect that our quarterly results of operations will fluctuate, and this fluctuation could cause our stock price to decline. |
| ● | If we fail to comply with the rules under the Sarbanes-Oxley Act of 2002 related to accounting controls and procedures, or if we discover material weaknesses and deficiencies in our internal control and accounting procedures, our stock price could decline significantly and raising capital could be more difficult. |
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| ● | If securities or industry analysts do not publish research or reports about our business, or if they change their recommendations regarding our stock adversely, our stock price and trading volume could decline. |
| ● | Other companies may have difficulty acquiring us, even if doing so would benefit our stockholders, due to provisions under our corporate charter and bylaws, as well as Nevada law. |
| ● | Other companies may have difficulty acquiring us, even if doing so would benefit our stockholders, due to provisions under our corporate charter and bylaws, as well as Nevada law. |
| ● | Our bylaws designate the Eighth Judicial District Court of Clark County, Nevada as the sole and exclusive forum for certain types of actions and proceedings that may be initiated by our stockholders, which could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, officers, employees or agents. |
RISKS RELATED TO OUR BUSINESS
We have a history of operating losses and expect to incur losses for the foreseeable future. We may never generate revenues or, if we are able to generate revenues, achieve profitability.
We are focused on product development, and we have not generated any revenues to date. We have incurred losses in each year of our operations, and we expect to continue to incur operating losses for the foreseeable future. These operating losses have adversely affected and are likely to continue to adversely affect our working capital, total assets and shareholders’ equity.
We and our prospects should be examined in light of the risks and difficulties frequently encountered by new and early-stage companies in new and rapidly evolving markets. These risks include, among other things, the speed at which we can scale up operations, our complete dependence upon development of our product candidates that currently have no market acceptance, our ability to establish and expand our brand name, our ability to expand our operations to meet the commercial demand of our clients, our development of and reliance on strategic and customer relationships and our ability to minimize fraud and other security risks.
The process of developing our products requires significant clinical, nonclinical and CMC development, laboratory testing and clinical studies. In addition, commercialization of our product candidates will require that we obtain necessary regulatory approvals and establish sales, marketing and manufacturing capabilities, either through internal hiring or through contractual relationships with others. We expect to incur substantial losses for the foreseeable future as a result of anticipated increases in our research and development costs, including costs associated with conducting preclinical and nonclinical testing and clinical studies, and regulatory compliance activities.
We expect to incur substantial additional operating expenses over the next several years as our research, development, preclinical and nonclinical testing, and clinical study activities increase, and if and when we acquire rights to additional product candidates. The amount of future losses and when, if ever, we will achieve profitability are uncertain. We have no products that have generated any commercial revenue, do not expect to generate revenues from the commercial sale of products in the near future, and might never generate revenues from the sale of products. Our ability to generate revenue and achieve profitability will depend on, among other things, successful completion of the development of our product candidates; obtaining necessary regulatory approvals from the FDA; establishing manufacturing, sales, and marketing arrangements with third parties; successfully commercializing our products; establishing a favorable competitive position; and raising sufficient funds to finance our activities. Many of these factors will depend on circumstances beyond our control. We might not succeed at any of these undertakings. If we are unsuccessful at some or all of these undertakings, our business, prospects, and results of operations may be materially adversely affected.
We expect a number of factors to cause our operating results to fluctuate on a quarterly and annual basis, which may make it difficult to predict our future performance.
We are a development-stage biopharmaceutical and our operations to date have been primarily limited to developing our technology and undertaking preclinical and nonclinical testing and clinical studies of our latest stage product candidate, TNX-102 SL for FM, Long COVID and potentially other CNS conditions. We have not yet obtained regulatory approvals for TNX-102 SL or any of our other product candidates. Consequently, any predictions made about our future success or viability may not be as accurate as they could be if we had a longer operating history or commercialized products. Our financial condition has varied significantly in the past and will continue to fluctuate from quarter-to-quarter or year-to-year due to a variety of factors, many of which are beyond our control. Factors relating to our business that may contribute to these fluctuations include other factors described elsewhere in this annual report and also include, among other things:
| ● | our ability to obtain additional funding to develop our product candidates; |
| ● | delays in the commencement, enrollment and timing of clinical studies; |
| ● | the success of our clinical studies through all phases of clinical development, including studies of our most advanced product candidate, TNX-102 SL for FM, Long COVID and potentially other CNS indications; |
| ● | any delays in regulatory review and approval of product candidates in clinical development; |
| ● | our ability to obtain and maintain regulatory approval for our product candidate TNX-102 SL for FM and Long COVID, TNX-1900 for chronic migraine, TNX-601 ER for depression or any of our other product candidates in the United States and foreign jurisdictions; |
| ● | potential nonclinical toxicity and/or side effects of our product candidates that could delay or prevent commercialization, limit the indications for any approved drug, require the establishment of REMS, or cause an approved drug to be taken off the market; |
| ● | our ability to establish or maintain collaborations, licensing or other arrangements; |
| ● | market acceptance of our product candidates; |
| ● | competition from existing products or new products that may emerge; |
| ● | the ability of patients or healthcare providers to obtain coverage of or sufficient reimbursement for our products; |
| ● | our ability to leverage our proprietary technology platform to discover and develop additional product candidates; |
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| ● | our ability and our licensors’ abilities to successfully obtain, maintain, defend and enforce intellectual property rights important to our business; and |
| ● | potential product liability claims; |
Accordingly, the results of any quarterly or annual periods should not be relied upon as indications of future operating performance.
RISKS RELATED TO PRODUCT DEVELOPMENT, REGULATORY APPROVAL, MANUFACTURING AND COMMERCILAIZATION
Our product candidates are novel and still in development.
We are a clinical-stage pharmaceutical company focused on the development of drug product candidates, all of which are still in development. Our drug development methods may not lead to commercially viable drugs for any of several reasons. For example, we may fail to identify appropriate targets or compounds, our drug candidates may fail to be safe and effective in clinical studies, or we may have inadequate financial or other resources to pursue development efforts for our drug candidates. Our drug candidates will require significant additional development, clinical studies, regulatory clearances and additional investment by us or our collaborators before they can be commercialized.
Further, we and our product candidates are subject to extensive regulation by the FDA and comparable regulatory authorities in other countries governing, among other things, research, testing, clinical studies, manufacturing, labeling, promotion, selling, adverse event reporting and recordkeeping. We are not permitted to market any of our product candidates in the United States until we receive approval of an NDA for a product candidate from the FDA or the equivalent approval from a foreign regulatory authority. Obtaining FDA approval is a lengthy, expensive and uncertain process. We currently have one product candidate, TNX-102 SL, in Phase 3 development for the treatment of FM and Phase 2 development for the treatment of Long COVID, and we have three other products in Phase 2 development for the treatment of chronic migraine, depression and cocaine intoxication. The success of our business currently depends on the successful development, approval and commercialization of our product candidates and TNX-102 SL. Any projected sales or future revenue predictions are predicated upon FDA approval and market acceptance. If projected sales do not materialize for any reason, it would have a material adverse effect on our business and our ability to continue operations.
As we have no approved products on the market, we do not expect to generate any revenues from product sales in the foreseeable future, if at all.
To date, we have no approved product on the market and have generated no product revenues. We have funded our operations primarily from sales of our securities. We have not received, and do not expect to receive for at least the next couple of years, if at all, any revenues from the commercialization of our product candidates.
To obtain revenues from sales of our product candidates, we must succeed, either alone or with third parties, in developing, obtaining regulatory approval for, manufacturing and marketing drugs with commercial potential. We may never succeed in these activities, and we may not generate sufficient revenues to continue our business operations or achieve profitability.
We are largely dependent on the success of our lead product candidates, and we cannot be certain that these product candidates will receive regulatory approval or be successfully commercialized.
We have not yet submitted an NDA or foreign equivalent or received marketing approval for our lead product candidates anywhere in the world. The clinical development programs may not lead to commercial products for a number of reasons, including if we fail to obtain necessary approvals from the FDA or foreign regulatory authorities because our clinical studies fail to demonstrate to their satisfaction that this product candidate is safe and effective or a clinical program may be put on hold due to unexpected safety issues. We may also fail to obtain the necessary approvals if we have inadequate financial or other resources to advance our product candidates through the clinical study process. Any failure or delay in completing clinical studies or obtaining regulatory approvals for our lead product candidates in a timely manner would have a material adverse impact on our business and our stock price.
We may not commence or advance clinical trials for COVID-related products if the COVID-19 disease outbreak subsides.
Disease outbreaks are unpredictable. For example, the SARS virus disappeared just four months after it caused a global panic. In the event that COVID-19 has a similar disease cycle, we may be forced to abandon or delay the development of our COVID-related products due to a lack of patients or government funding.
Successful development of our products is uncertain.
Our development of current and future product candidates is subject to the risks of failure and delay inherent in the development of new pharmaceutical products, including: delays in product development, clinical testing, or manufacturing; unplanned expenditures in product development, clinical testing, or manufacturing; failure to receive regulatory approvals; emergence of superior or equivalent products; inability to manufacture on its own, or through any others, product candidates on a commercial scale; and failure to achieve market acceptance.
Because of these risks, our research and development efforts may not result in any commercially viable products. If a significant portion of these development efforts are not successfully completed, required regulatory approvals are not obtained or any approved products are not commercially successfully, our business, financial condition, and results of operations may be materially harmed.
Clinical studies required for our product candidates are expensive and time-consuming, and their outcome is uncertain.
In order to obtain FDA approval to market a new pharmaceutical product, we must demonstrate proof of safety and effectiveness in humans. To meet these requirements, we must conduct “adequate and well controlled” clinical studies. Conducting clinical studies is a lengthy, time-consuming, and expensive process. The length of time may vary substantially according to the type, complexity, novelty, and intended use of the product candidate, and often can be several years or more per study. Delays associated with products for which we are directly conducting clinical studies may cause us to incur additional operating expenses. The commencement and rate of completion of clinical studies may be delayed by many factors, including, for example: inability to manufacture sufficient quantities of stable and qualified materials under cGMP, for use in clinical studies; slower than expected rates of patient recruitment; failure to recruit a sufficient number of patients; modification of clinical study protocols; changes in regulatory requirements for clinical studies; the lack of effectiveness during clinical studies; the emergence of unforeseen safety issues; delays, suspension, or termination of the clinical studies due to the IRB responsible for overseeing the study at a particular study site; and government or regulatory delays or “clinical holds” requiring suspension or termination of the studies.
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The results from early clinical studies are not necessarily predictive of results obtained in later clinical studies. Accordingly, even if we obtain positive results from early clinical studies, we may not be able to confirm the results in future clinical studies. In addition, clinical studies may not demonstrate sufficient safety and effectiveness to obtain the requisite regulatory approvals for product candidates.
Our clinical studies may be conducted in patients with CNS conditions, and in some cases, our product candidates are expected to be used in combination with approved therapies that themselves have significant adverse event profiles. During the course of treatment, these patients could suffer adverse medical events or die for reasons that may or may not be related to our product candidates. We cannot ensure that safety issues will not arise with respect to our product candidates in clinical development.
The failure of clinical studies to demonstrate safety and effectiveness for the desired indications could harm the development of that product candidate and other product candidates. This failure could cause us to abandon a product candidate and could delay development of other product candidates. Any delay in, or termination of, our clinical studies would delay the filing of our NDAs with the FDA and, ultimately, our ability to commercialize our product candidates and generate product revenues. Any change in, or termination of, our clinical studies could materially harm our business, financial condition, and results of operations.
We are subject to extensive and costly government regulation.
Product candidates employing our technology are subject to extensive and rigorous domestic government regulation including regulation by the FDA, the Centers for Medicare and Medicaid Services, other divisions of the United States Department of Health and Human Services, the United States Department of Justice, state and local governments, and their respective foreign equivalents. The FDA regulates the research, development, preclinical and nonclinical testing and clinical studies, manufacture, safety, effectiveness, record-keeping, reporting, labeling, storage, approval, advertising, promotion, sale, distribution, import, and export of biopharmaceutical products. The FDA regulates small molecule chemical entities as drugs, subject to an NDA under the FDCA. The FDA applies the same standards for biologics, requiring an IND application, followed by a Biologic License Application, or BLA, prior to licensure. Other products, such as vaccines, are also regulated under the Public Health Service Act. FDA has conflated the standards for approval of NDAs and BLAs so that they require the same types of information on safety, effectiveness, and CMCs. If products employing our technologies are marketed abroad, they will also be subject to extensive regulation by foreign governments, whether or not they have obtained FDA approval for a given product and its uses. Such foreign regulation may be equally or more demanding than corresponding United States regulation.
Government regulation substantially increases the cost and risk of researching, developing, manufacturing, and selling our products. The regulatory review and approval process, which includes preclinical and nonclinical testing and clinical studies of each product candidate, is lengthy, expensive, and uncertain. We or our collaborators must obtain and maintain regulatory authorization to conduct clinical studies. We or our collaborators must obtain regulatory approval for each product we intend to market, and the manufacturing facilities used for the products must be inspected and meet legal requirements. Securing regulatory approval requires the submission of extensive preclinical, nonclinical and clinical data and other supporting information for each proposed therapeutic indication in order to establish the product’s safety and efficacy, and in the case of biologics also potency and purity, for each intended use. The development and approval process takes many years, requires substantial resources, and may never lead to the approval of a product.
Even if we are able to obtain regulatory approval for a particular product, the approval may limit the indicated medical uses for the product, may otherwise limit our ability to promote, sell, and distribute the product, may require that we conduct costly post-marketing surveillance, and/or may require that we conduct ongoing post-marketing studies. Material changes to an approved product, such as, for example, manufacturing changes or revised labeling, may require further regulatory review and approval. Once obtained, any approvals may be withdrawn, including, for example, if there is a later discovery of previously unknown problems with the product, such as a previously unknown safety issue.
If we, our collaborators, or our CMOs fail to comply with applicable regulatory requirements at any stage during the regulatory process, such noncompliance could result in, among other things delays in the approval of applications or supplements to approved applications; refusal of a regulatory authority, including the FDA, to review pending market approval applications or supplements to approved applications; warning letters; fines; import and/or export restrictions; product recalls or seizures; injunctions; total or partial suspension of production; civil penalties; withdrawals of previously approved marketing applications or licenses; recommendations by the FDA or other regulatory authorities against governmental contracts; and/or criminal prosecutions.
We do not have, and may never obtain, the regulatory approvals we need to market our product candidates.
Following completion of clinical studies, the results are evaluated and, depending on the outcome, submitted to the FDA in the form of an NDA or BLA in order to obtain FDA approval of the product and authorization to commence commercial marketing. In responding to an NDA, the FDA may require additional testing or information, may require that the product labeling be modified, may impose post-approval study and other commitments or reporting requirements or other restrictions on product distribution, or may deny the application. The FDA has established performance goals for review of NDAs or BLAs: six months for priority applications and ten months for standard applications. However, the FDA is not required to complete its review within these time periods. The timing of final FDA review and action varies greatly but can take years in some cases and may involve the input of an FDA advisory committee of outside experts. Product sales in the United States may commence only when an NDA or BLA is approved.
To date, we have not applied for or received the regulatory approvals required for the commercial sale of any of our products in the United States or in any foreign jurisdiction. None of our product candidates have been determined to be safe and effective, and we have not submitted an NDA or BLA to the FDA or an equivalent application to any foreign regulatory authorities for any of our product candidates.
It is possible that none of our product candidates will be approved for marketing. Failure to obtain regulatory approvals, or delays in obtaining regulatory approvals, may adversely affect the successful commercialization of any drugs or biologics that we or our partners develop, may impose additional costs on us or our collaborators, may diminish any competitive advantages that we or our partners may attain, and/or may adversely affect our receipt of revenues or royalties.
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We have never submitted an NDA before, and may be unable to do so for our product candidates we are developing.
The conduct of pivotal clinical studies and the submission of a successful NDA is a complicated process. Although members of our management team have extensive industry experience, including in the development and clinical testing of drug candidates and the commercialization of drug, have limited experience in preparing, submitting and prosecuting regulatory filings, and have not submitted an NDA before. Consequently, we may be unable to successfully and efficiently execute and complete this planned clinical study in a way that leads to NDA submission and approval of our product candidates we are developing. We may require more time and incur greater costs than our competitors and may not succeed in obtaining regulatory approvals of product candidates that we develop. Failure to commence or complete, or delays in, our planned clinical studies would prevent or delay commercialization of TNX-102 SL and other product candidates we are developing.
Our product candidates may cause serious adverse events, or SAEs, or undesirable side effects which may delay or prevent marketing approval, or, if approval is received, require them to be taken off the market, require them to include safety warnings or otherwise limit their sales.
SAEs or undesirable side effects from any of our other product candidates could arise either during clinical development or, if approved, after the approved product has been marketed. The results of future clinical studies may show that our product candidates cause SAEs or undesirable side effects, which could interrupt, delay or halt clinical studies, resulting in delay of, or failure to obtain, marketing approval from the FDA and other regulatory authorities.
If any of our other product candidates cause SAEs or undesirable side effects or suffer from quality control issues:
| ● | regulatory authorities may impose a clinical hold or risk evaluation and mitigation strategies, or REMS, which could result in substantial delays, significantly increase the cost of development, and/or adversely impact our ability to continue development of the product; |
| ● | regulatory authorities may require the addition of statements, specific warnings, or contraindications to the product label, or restrict the product’s indication to a smaller potential treatment population; |
| ● | we may be required to change the way the product is administered or conduct additional clinical studies; |
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we may be required to implement a risk minimization action plan, which could result in substantial cost increases and have a negative impact on our ability to commercialize the product;
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we may be required to limit the participants who can receive the product; |
| ● | we may be subject to limitations on how we promote the product; |
| ● | we may, voluntarily or involuntarily, initiate field alerts for product recall, which may result in shortages; |
| ● | sales of the product may decrease significantly; |
| ● | regulatory authorities may require us to take our approved product off the market; |
| ● | we may be subject to litigation or product liability claims; and |
| ● | our reputation may suffer. |
Any of these events could prevent us from achieving or maintaining market acceptance of the affected product or could substantially increase commercialization costs and expenses, which in turn could delay or prevent us from generating significant revenues from the sale of our products.
If we are unable to file for approval of TNX-102 SL under Section 505(b)(2) of the FDCA or if we are required to generate additional data related to safety and efficacy in order to obtain approval under Section 505(b)(2), we may be unable to meet our anticipated development and commercialization timelines.
Our current plans for filing NDAs for our most advanced product candidate, TNX-102 SL, include efforts to minimize the data we will be required to generate in order to obtain marketing approval and therefore reduce the development time. We intend to file Section 505(b)(2) NDAs for TNX-102 SL for FM, Long COVID and for other proposed indications, that might, if accepted by the FDA, save time and expense in the development and testing of TNX-102 SL.
TNX-102 SL for FM and other CNS indications is our most advanced development product candidate which is in mid-Phase 3 for FM. The timeline for filing and review of our NDA for TNX-102 SL for FM is based on our plan to submit this NDA under Section 505(b)(2) of the FDCA, which would enable us to rely in part on data in the public domain or elsewhere. We have not yet filed an NDA under Section 505(b)(2) for any of our product candidates. Depending on the data that may be required by the FDA for approval, some of the data may be related to products already approved by the FDA. If the data relied upon is related to products already approved by the FDA and covered by third-party patents, we would be required to certify that we do not infringe the listed patents or that such patents are invalid or unenforceable. As a result of the certification, the third-party would have 45 days from notification of our certification to initiate an action against us. In the event that an action is brought in response to such a certification, the approval of our NDA could be subject to a stay of up to 30 months or more while we defend against such a suit. Approval of our product candidates under Section 505(b)(2) may therefore be delayed until patent exclusivity expires or until we successfully challenge the applicability of those patents to our product candidates. Alternatively, we may elect to generate sufficient additional clinical data so that we no longer rely on data which triggers a potential stay of the approval of our product candidates. Even if no exclusivity periods apply to our applications under Section 505(b)(2), the FDA has broad discretion to require us to generate additional data on the safety and efficacy of our product candidates to supplement third-party data on which we may be permitted to rely. In either event, we could be required, before obtaining marketing approval for any of our product candidates, to conduct substantial new research and development activities beyond those we currently plan to engage in order to obtain approval of our product candidates. Such additional new research and development activities would be costly and time-consuming.
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We may not be able to realize a shortened development timeline for TNX-102 SL for FM, Long COVID (or other proposed indications under TNX-102 SL), and the FDA may not approve our NDA based on their review of the submitted data. If cyclobenzaprine-containing products are withdrawn from the market by the FDA for any safety reason, we may not be able to reference such products to support a 505(b)(2) NDA for TNX-102 SL, and we may need to fulfill the more extensive requirements of Section 505(b)(1). If we are required to generate additional data to support approval, we may be unable to meet our anticipated development and commercialization timelines, may be unable to generate the additional data at a reasonable cost, or at all, and may be unable to obtain marketing approval of our lead product candidate.
Any breakthrough, fast track or orphan drug designation or grant of priority review status by the FDA may not actually lead to a faster development or regulatory review or approval process, nor will it assure FDA approval of our product candidates. Additionally, our product candidates may treat indications that do not qualify for priority review vouchers.
If a product candidate offers major advances in treatment, the FDA may designate it eligible for priority review. The FDA has broad discretion whether or not to grant these designations, so even if we believe a particular product candidate is eligible for these designations, we cannot assure you that the FDA would decide to grant them. Even if we do receive fast track designation or priority review, we may not experience a faster development process, review or approval compared to conventional FDA procedures. The FDA may withdraw fast track designation if it believes that the designation is no longer supported by data from our clinical development program.
Even if approved, our products will be subject to extensive post-approval regulation.
Once a product is approved, numerous post-approval requirements apply. Among other things, the holder of an approved NDA is subject to periodic and other FDA monitoring and reporting obligations, including obligations to monitor and report adverse events and instances of the failure of a product to meet the specifications in the NDA. Application holders must submit new or supplemental applications and obtain FDA approval for certain changes to the approved product, product labeling, or manufacturing process. Application holders must also submit advertising and other promotional material to the FDA and report on ongoing clinical studies.
Depending on the circumstances, failure to meet these post-approval requirements can result in criminal prosecution, fines, injunctions, recall or seizure of products, total or partial suspension of production, denial or withdrawal of pre-marketing product approvals, or refusal to allow us to enter into supply contracts, including government contracts. In addition, even if we comply with FDA and other requirements, new information regarding the safety or effectiveness of a product could lead the FDA to modify or withdraw product approval.
Even if we obtain regulatory approval to market our product candidates, our product candidates may not be accepted by the market.
Even if the FDA approves one or more of our product candidates, physicians and patients may not accept it or use it. Even if physicians and patients would like to use our products, our products may not gain market acceptance among healthcare payors such as managed care formularies, insurance companies or government programs such as Medicare or Medicaid. Acceptance and use of our products will depend upon a number of factors including: perceptions by members of the health care community, including physicians, about the safety and effectiveness of our drug or device product; cost-effectiveness of our product relative to competing products; availability of reimbursement for our product from government or other healthcare payors; and effectiveness of marketing and distribution efforts by us and our licensees and distributors, if any.
The degree of market acceptance of any pharmaceutical product that we develop will depend on a number of factors, including:
| ● | cost-effectiveness; | |
| ● | the safety and effectiveness of our products, including any significant potential side effects (including drowsiness and dry mouth), as compared to alternative products or treatment methods; | |
| ● | the timing of market entry as compared to competitive products; | |
| ● | the rate of adoption of our products by doctors and nurses; | |
| ● | product labeling or product insert required by the FDA for each of our products; | |
| ● | reimbursement policies of government and third-party payors; | |
| ● | effectiveness of our sales, marketing and distribution capabilities and the effectiveness of such capabilities of our collaborative partners, if any; and | |
| ● | unfavorable publicity concerning our products or any similar products. |
Because we expect sales of our current product candidates, if approved, to generate substantially all of our product revenues for the foreseeable future, the failure of these products to find market acceptance would harm our business and could require us to seek additional financing.
We may use our financial and human resources to pursue a particular research program or product candidate and fail to capitalize on programs or product candidates that may be more profitable or for which there is a greater likelihood of success.
Because we have limited financial and human resources, we are currently focusing on development of our lead product candidates. As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on existing and future product candidates for specific indications may not yield any commercially viable products. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rig