Item 1A. Risk Factors 37
Item 1B. Unresolved Staff Comments 57
Item 2. Properties 57
Item 3. Legal Proceedings 57
Item 4. Mine Safety Disclosures 57
PART II
Item 6. Reserved 58
Item 7A. Quantitative and Qualitative Disclosures about Market Risk 69
Item 8. Financial Statements and Supplementary Data F-1 – F-24
Item 9A. Controls and Procedures 70
Item 9B. Other Information 70
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 70
PART III
Item 10. Directors, Executive Officers and Corporate Governance 71
Item 11. Executive Compensation 75
Item 14. Principal Accounting Fees and Services 84
PART IV
Item 15. Exhibits, Financial Statement Schedules 85
Signatures 88
2
PART
I
ITEM
1 - BUSINESS
This
Annual Report on Form 10-K (including the section regarding Management’s Discussion and Analysis of Financial Condition and Results
of Operations) contains forward-looking statements regarding our business, financial condition, results of operations and prospects. Words
such as “expects,” “anticipates,” “intends,” “plans,” “believes,” “seeks,”
“estimates” and similar expressions or variations of such words are intended to identify forward-looking statements, but are
not deemed to represent an all-inclusive means of identifying forward-looking statements as denoted in this Annual Report on Form 10-K. Additionally,
statements concerning future matters are forward-looking statements.
Although
forward-looking statements in this Annual Report on Form 10-K reflect the good faith judgment of our Management, such statements can only
be based on facts and factors currently known by us. Consequently, forward-looking statements are inherently subject to risks and uncertainties
and actual results and outcomes may differ materially from the results and outcomes discussed in or anticipated by the forward-looking
statements. Factors that could cause or contribute to such differences in results and outcomes include, without limitation, those specifically
addressed under the heading “Risks Factors” below, as well as those discussed elsewhere in this Annual Report on Form 10-K.
Readers are urged not to place undue reliance on these forward-looking statements, which speak only as of the date of this Annual Report
on Form 10-K. We file reports with the Securities and Exchange Commission (“SEC”). You can read and copy any materials we
file or will file with the SEC, which, among other places, can be found on the SEC’s website at http://www.sec.gov, as well as on
our corporate website at www.tonixpharma.com).
We
undertake no obligation to revise or update any forward-looking statements in order to reflect any event or circumstance that may arise
after the date of this Annual Report on Form 10-K. Readers are urged to carefully review and consider the various disclosures made throughout
the entirety of this Annual Report, which attempt to advise interested parties of the risks and factors that may affect our business,
financial condition, results of operations and prospects.
Tonix
Pharmaceuticals®, Tonmya®, ProtecticTM, Angstro-TechnologyTM and other trademarks and intellectual
property of ours appearing in this report are our property. This report contains additional trade names and trademarks of other companies.
We do not intend our use or display of other companies’ trade names or trademarks to imply an endorsement or sponsorship of
us by such companies, or any relationship with any of these companies.
Business
Overview
We are a clinical-stage biopharmaceutical
company focused on developing therapeutics and vaccines to treat and prevent human disease and alleviate suffering. We have a rich pipeline
of products in development that has been curated from internal discovery, as well as licenses, acquisitions and collaborations with academic
institutions and contract research organizations. We continue to build capabilities in synthetic biology, precision medicine, protein
engineering, medicinal chemistry, molecular biology, pharmacogenomics and clinical-scale manufacturing. Our therapeutics under development
include both small molecules and biologics.
Our portfolio consists of central nervous system, or CNS, rare disease,
immunology, and infectious disease product candidates. The CNS portfolio includes small molecules and biologics to treat pain, neurologic,
psychiatric and addiction conditions. Our rare disease portfolio focuses on developing novel therapies for patients with rare diseases,
including those caused by genetic disorders which are characterized by complex symptoms and for which no drug is approved. Our immunology
portfolio includes biologics to address organ transplant rejection, autoimmune diseases and cancer. Our infectious disease portfolio includes
a vaccine in development to prevent smallpox and mpox (formerly known as monkeypox), next-generation vaccines to prevent COVID-19, a platform
to make fully human monoclonal antibodies, or mAbs, to treat COVID-19 and humanized anti-SARS-CoV-2 mAbs. Our vaccine in development to
prevent smallpox and mpox also serves as the live virus vaccine platform or recombinant pox vaccine (RPV) platform for other infectious
diseases.
Our
latest stage CNS product candidate is TNX-102 SL*, a proprietary sublingual tablet formulation of cyclobenzaprine (CBP) designed for
bedtime administration. TNX-102 SL has active INDs for fibromyalgia, or FM, FM-type Long COVID or PASC (post-acute sequelae of
SARS-CoV-2 infection), posttraumatic stress disorder, or PTSD, agitation in Alzheimer’s disease, or AAD, and alcohol use
disorder, or AUD.
TNX-102
SL is in mid-Phase 3 development for the management of FM, a pain disorder characterized by chronic widespread pain, non-restorative
sleep, fatigue and impaired cognition. In December 2020, we reported positive results from the Phase 3 RELIEF study of TNX-102 SL
5.6 mg for the management of FM. In July 2021, we reported pre-planned interim analysis results from a second Phase 3 study, RALLY.
Based on the recommendation from the independent data monitoring committee (IDMC) that the RALLY trial was unlikely to demonstrate a
statistically significant improvement in the primary endpoint, we stopped enrollment of new participants but allowed those
participants who were already enrolled to complete the study. We reported topline data from the completed study in March of 2022. As
expected, based on interim analysis results, TNX-102 SL did not achieve statistical significance over placebo on the primary endpoint
of reduction in daily pain, and relative to the previous positive Phase 3 Study (RELIEF), RALLY had an unexpected increase in study
participant adverse event-related discontinuations in both drug and placebo groups. In April 2022, we started a new potentially
confirmatory Phase 3 study of TNX-102 SL in FM, RESILIENT. Interim analysis results are expected in the second quarter of 2023 and
topline results are expected in the fourth quarter of 2023. Following a positive outcome of the RESILIENT study, Tonix believes we
would be positioned to file a New Drug Application (NDA) for TNX-102 SL for the management of FM.
TNX-102 SL is also
being developed as a potential treatment for a type of Long COVID, the symptoms of which overlap with FM, that we term FM-type
Long COVID. We initiated enrollment in the Phase 2 study PREVAIL, in August 2022. The primary endpoint is a change in daily pain
scores from baseline.
For TNX-102 SL in PTSD,
we completed the Phase 3 RECOVERY trial and reported topline results in the fourth quarter of 2020 in which TNX-102 SL did not
meet the primary efficacy endpoint. PTSD is a serious psychiatric condition that develops in response to experiencing a traumatic
event. We subsequently completed a meeting with the FDA to discuss potential new endpoints going forward for the indication of
treatment of PTSD. Future studies will employ the one month look-back CAPS-5 as the primary endpoint rather than the one week look-back
as used in prior studies.
3
The
AAD program is Phase 2 ready with an active IND and FDA Fast Track designation. AAD, which includes emotional lability, restlessness,
irritability, and aggression, is one of the most distressing and debilitating of the behavioral complications of Alzheimer’s disease.
Tonix does not have any near-term plans to start a Phase 2 study in AAD.
The
AUD program is also Phase 2 ready with an active IND. AUD is a chronic relapsing brain disease characterized by compulsive alcohol use,
loss of control over alcohol intake, and a negative emotional state when not using alcohol. Tonix does not have any near-term plans to
start a Phase 2 study in AUD.
TNX-1900* (intranasal
potentiated oxytocin) is in development for the treatment of chronic migraine and obesity-associated binge eating disorder, or BED.
TNX-1900 was acquired from Trigemina, Inc. and licensed from Stanford University in 2020. The potentiated formulation includes
magnesium, which has been shown in animal studies to potentiate binding of oxytocin to the oxytocin receptor. We received IND
clearance from the FDA in the fourth quarter of 2021 to study TNX-1900 in chronic migraine and we initiated a Phase 2 study in
migraine in the first quarter of 2023. We expect interim analysis results from the first 50 percent of patients enrolled in the
fourth quarter of 2023. In March 2022, we announced an agreement with Massachusetts General Hospital, a teaching hospital of Harvard
Medical School, to conduct an investigator-initiated Phase 2 clinical trial to study TNX-1900 in BED. The Phase 2 clinical trial is
expected to start in the second quarter of 2023. We do not own an IND for BED. We also licensed technology to use TNX-1900 for the
treatment of insulin resistance from the University of Geneva and also have rights to develop it as a treatment for craniofacial
pain, but we are not imminently pursuing clinical trials in either of these indications at this time.
TNX-601 ER* (tianeptine hemioxalate extended-release tablets) is a CNS
product candidate in development as a treatment for major depressive disorder, or depression, and with possible additional indications
of PTSD, and neurocognitive dysfunction associated with corticosteroid use. TNX-601 ER represents a novel approach to treating depression
in the U.S., since the active ingredient tianeptine induces a neuroprotective and resilient phenotype in both neurons and microglia under
conditions of stress in animals. The dramatic and unique effects of tianeptine are illustrated in animal models by the restoration of
dendritic arborization of pyramidal neurons of CA3 region of hippocampus and the dentate gyrus region new neuron formation and integration
into hippocampal networks. In contrast, antidepressants that are marketed in the U.S. act by modulating the levels or receptor binding
of neurotransmitters in the synapse. We have completed a Phase 1 trial for formulation development outside of the U.S. We expect to initiate
a potentially pivotal Phase 2 study in the first quarter of 2023 for the treatment of major depressive disorder and we expect interim
analysis results from the first 50 percent of patients enrolled in the fourth quarter of 2023.
Another CNS candidate in development
is TNX-1300* (double-mutant cocaine esterase) which is in Phase 2 for the treatment of life-threatening cocaine intoxication. TNX-1300
has been granted Breakthrough Therapy designation, or BTD, by the U.S. Food and Drug Administration, or FDA. TNX-1300 was licensed from
Columbia University in 2019 after a Phase 2 study showed that it rapidly and efficiently disintegrates cocaine in the blood of volunteers
who received intravenous, or i.v., cocaine. In August of 2022, we received a Federal Grant from the National Institute on Drug Abuse (NIDA)
to advance the development of TNX-1300 as a treatment for cocaine intoxication. We expect to initiate a potentially pivotal Phase 2 study
of TNX-1300 in emergency rooms in the second quarter of 2023.
Finally,
our CNS pipeline includes TNX-1600*, an inhibitor of the reuptake of neurotransmitters serotonin, norepinephrine and dopamine, or a triple
reuptake inhibitor. TNX-1600 was licensed from Wayne State University in 2019 and is expected to be developed as a treatment for PTSD,
depression and attention-deficit/hyperactivity disorder, or ADHD. TNX-1600 is in the preclinical stage of development.
Our rare disease portfolio
consists of TNX-2900*, another magnesium-potentiated intranasal oxytocin-based therapeutic in development for the treatment of Prader-Willi
syndrome, or PWS. The technology for TNX-2900 was licensed from Inserm, the French National Institute of Health and Medical Research.
PWS, an orphan condition, is a rare genetic disorder of failure to thrive in infancy, associated with uncontrolled appetite beginning
in childhood with complications of obesity and diabetes. We have sponsored a research program at Inserm to study oxytocin on suckling
behavior in mice that have been engineered to express one of the Prader-Willi genes. TNX-2900 has been granted Orphan-Drug Designation
for the treatment of PWS and is in the pre-IND stage of development.
Our lead candidate
in the immunology pipeline is TNX-1500*, a humanized mAb, directed against CD40-ligand, or CD40L (also
known as CD154), engineered to modulate binding to Fc receptors, that is being developed as a prophylaxis against organ transplant
rejection as well as to treat autoimmune conditions. In experiments at the Massachusetts General Hospital or MGH, a teaching hospital
of Harvard Medical School, TNX-1500 is being studied as monotherapy or in combination with other immunosuppressive agents in heart
and kidney allogeneic organ transplants in non-human primates. Preliminary results from ongoing experiments in kidney and heart
transplants indicate that TNX-1500 appears to have comparable efficacy to historical experiments using the chimeric mouse/human
IgG1 version (5c8H1) of the anti-CD40L mAb 5c8. First generation anti-CD40L mAb therapies were associated with an increased risk
of blood clots or thrombosis. In the non-human primate studies with TNX-1500 for the prevention of rejection in allogeneic organ
transplants, no evidence of thrombosis has been observed so far. We expect to start a Phase 1 study of TNX-1500 in the second quarter
of 2023. TNX-1500 also is being studied in combination with other immunosuppressive agents in xenogeneic organ transplants in non-human
primates at MGH and at the University of Maryland at Baltimore or UMB. In experiments at UMB, TNX-1500 is being studied to prevent
rejection of xenogeneic hearts from genetically engineered pigs developed by the Revivicor division of United Therapeutics Corporation.
Our immunology pipeline
also includes TNX-1700*, a recombinant Trefoil Factor Family 2, or rTFF2, fusion protein that was licensed from Columbia University
in 2019. TNX-1700 consists of TFF2 fused to human serum albumin or HSA and is a biologic being developed to treat gastric and colorectal
cancers by an immune-oncology mechanism, in combination with PD1 blockers, and is in the preclinical stage of development. We recently
presented data that show a murine version of TNX-1700 consisting of a fusion protein with murine serum albumin or MSA was able
to evoke anti-tumor immunity in the MC38 mouse model of colorectal cancer as monotherapy and that TNX-1700 augmented the efficacy
of anti-PD1 therapy in both the MC38 model and the CT26.wt mouse models of colorectal cancer.
Our infectious disease
portfolio includes vaccines based on our live virus vaccine or recombinant pox vaccine, “RPV” platform. Live virus
vaccines are believed to protect against poor clinical outcomes of infectious diseases by eliciting T cell responses in addition
to antibody responses. TNX-801*, a live attenuated vaccine based on synthesized horsepox, is in the pre-IND stage of development
to protect against smallpox and mpox. Non-human primates vaccinated with TNX-801 were protected from mpox in studies reported in
the first quarter of 2020. A Phase 1 study of TNX-801 in humans is expected to start in the second half of 2023. TNX-801 also
serves as the live virus vaccine platform for other infectious diseases for which subsequent products will be designed by expressing
other viral antigens in the horsepox vector.
TNX-1850* is a live
virus vaccine that expresses the SARS-CoV-2 spike protein from the BA.2 strain that has not yet been tested in animals. TNX-1800*
is a live virus vaccine that expresses the SARS-CoV-2 spike protein from the ancestral Wuhan strain, which has shown encouraging
results in non-human primates. Because the subsequent omicron variant out-competed the ancestral Wuhan strain, we began work on
new vaccine versions, TNX-1840* and TNX-1850*, that are designed to express spike protein from the omicron variant and from the
BA.2 variant, respectively. Of those, based on the trajectory of COVID-19, the focus is now on TNX-1850. The COVID-19 vaccines
that are approved for use, or have emergency use authorization, or EUA, in the U.S. have provided significant health benefits to
the vaccinated population; however, they have shown limitations in the durability of protection conferred and in their ability
to block forward transmission. Live virus vaccines that protect against other viral diseases by eliciting T cell responses have
shown durability of protection that lasts years to decades and some live virus vaccines have significantly inhibited forward transmission.
With respect to TNX-1800 vaccination, we reported positive efficacy data from animal challenge studies using live SARS-CoV-2 in
the first quarter of 2021. In this study, TNX-1800 vaccinated, SARS-CoV-2 challenged animals had undetectable SARS-CoV-2 in the
upper airways, which we believe relates to potential inhibition of forward transmission of this respiratory pathogen.
4
TNX-2300* is a live
virus vaccine based on bovine parainfluenza virus in development to protect against COVID-19. In April 2022, Tonix extended a sponsored
research agreement with Kansas State University to develop a vaccine candidate, TNX-2300, for the prevention of COVID-19 that utilizes
a novel live virus vaccine vector platform based on bovine parainfluenza virus. The efficacy of co-expression of the CD40-ligand,
also known as CD154, to stimulate T cell immunity will also be tested. Attenuated bovine parainfluenza virus has previously been
shown to be an effective antigen delivery vector in humans. Previous work by others has shown that attenuated BPI3V is well tolerated
and immunogenic in non-human primates and human infants and children. We believe the vector is well suited for mucosal immunization
using a nasal atomizer, and can also be delivered parenterally. TNX-2300 is in the preclinical stage of development.
TNX-3600* and TNX-3800*
are mAbs directed against SARS-CoV-2 which are in development as potential therapeutic or preventative agents for COVID-19. Given
the unpredictable trajectory of the SARS-CoV-2 virus and new variants, we seek to contribute a broad set of anti-SARS-CoV-2 mAbs,
that can be scaled up quickly and potentially combined with other mAbs. We envision the future of mAb therapy for COVID-19 to be
cocktails of mAbs with specificity to variants of concern. TNX-3600 refers to a series of fully human mAbs generated by
human-human hybridomas from COVID-19 convalescent volunteers. We are collaborating with Columbia University to produce these fully
human mAbs to SARS-CoV-2 spike proteins from variants such as delta, omicron and XBB1.5 and to other viral targets. TNX-3800 refers
to three humanized murine mAbs which we licensed exclusively in December 2022 from Curia Global, Inc. for the treatment or prophylaxis
of SARS-CoV-2 infection. The initial focus is to develop COVID-19 therapeutic mAbs. We plan to seek indications similar to previously
EUA-approved therapeutic mAbs for treating individuals with mild-to-moderate COVID-19 who are at high risk for progression to severe
disease or for prophylaxis in individuals with compromised immune systems who are at high risk for severe COVID-19 disease.
None of the previously EUA-approved therapeutic or preventative mAbs are still available, because each has become obsolete since
the SARS-CoV-2 virus has mutated to evade their binding. TNX-3600 and TNX-3800 mAbs may also be used in combination therapy with
other COVID-19 therapeutic mAbs. Combination therapies with other anti-SARS-CoV-2 mAbs may reduce the emergence of resistant viral
strains. TNX-3600 and TNX-3800 are in the preclinical stage of development.
TNX-3700* is a COVID-19
mRNA vaccine candidate employing a zinc nanoparticle (ZNP) formulation. In collaboration with Kansas State University, we are developing
this ZNP technology as a potential replacement for the lipid nanoparticle (LNP) technology used in current mRNA vaccines. ZNP technology
potentially allows for improved stability which facilitates shipping and storage and addresses the limitations in current mRNA
vaccines which require ultra-cold storage and shipping. This current requirement limits the use of mRNA vaccines in less developed
countries. We plan to seek initial indications as a booster, similar to the current FDA approved mRNA vaccines for COVID-19. We
intend to conduct research with Kansas State University on ZNP SARS-CoV-2 spike based vaccines in tissue culture and animals in
the first half of 2023. TNX-3700 is in the preclinical stage of development.
Relating to our COVID-19 and other infectious disease development programs,
we are developing the resources necessary to enable internal research, development and manufacturing capabilities necessary to meet the
goal of producing new vaccine candidates within 100 days of recognition within weeks of obtaining sequence information from a novel pathogen.
We seek to be a leader in the movement to re-build domestic U.S. research, development and manufacturing capabilities. Because this movement
follows a protracted period when domestic research, development and manufacturing were moved out of the U.S., or “off-shore”
by other companies to save on labor and other costs, the movement to reverse that trend has been described as “on-shoring”
or “re-domestication”. The COVID-19 pandemic taught that national borders may close during a health emergency. Therefore,
domestic capabilities are essential for the health security of the U.S., which has also been described as pandemic preparedness and biodefense.
As articulated in the American Pandemic Preparedness Plan, or AP3, released by the U.S. Office of Science and Technology Policy, this
100-day goal for vaccines is a key component of preparedness for future pandemics. We believe we have established the infrastructure necessary
to support the pandemic preparedness goals established in the AP3, specifically with respect to our RPV vaccine and potentially to other
vaccine and therapeutic platforms. This infrastructure consists of (i) our R&D Center, or “RDC”, (ii) our Advanced Development
Center, or “ADC”, and (iii) our Commercial Manufacturing Center, or “CMC”. We acquired the RDC in Frederick, Maryland
consisting of one building totaling approximately 48,000 square feet. The acquisition closed in October 2021 and the facility is operational.
The RDC facility focuses on our development of vaccines and antiviral drugs against SARS-CoV-2, its variants, and other infectious diseases.
The RDC also conducts research on central nervous systema and immunology drugs. The RDC facility is mostly biosafety level 2 (BSL-2),
with some components designated BSL-3. We completed the substantial renovation of the ADC located in the New Bedford business park in
Dartmouth, Massachusetts, which became operational as of the fourth quarter 2022. This approximately 45,000 square foot BSL-2 facility
is intended to accelerate development and clinical scale manufacturing of live-virus vaccines and biologics to support clinical trials.
We also plan to build the CMC in Hamilton, Montana, where we purchased approximately 44 acres of land and have built a field office to
manage construction of the facility. The CMC will focus on developing and manufacturing commercial scale live-virus vaccines and biologics
and is also intended to be BSL-2. Site enabling work is expected to be initiated for the CMC in 2023. Together, we expect these facilities
may qualify the RPV vaccine platform for programs that are designed to carry out the goals of AP3.
*All
of our product candidates are investigational new drugs or biologics and have not been approved for any indication.
We
are led by a management team with significant industry experience in drug development. We complement our management team with a network
of scientific, clinical, and regulatory advisors that includes recognized experts in their respective fields.
Corporate
Information
We were incorporated on November 16, 2007 under the laws of the State of
Nevada as Tamandare Explorations Inc. On October 11, 2011, we changed our name to Tonix Pharmaceuticals Holding Corp. Our common stock
is listed on The NASDAQ Capital Market under the symbol “TNXP”. Our principal executive offices are located at 26 Main Street,
Suite 101, Chatham, New Jersey 07928, and our telephone number is (862) 799-8599. Our website address is www.tonixpharma.com.
5
Our
Strategy
Our
strategy is to use our integrated development engine to advance innovative programs across multiple therapeutic areas into the clinic
while maximizing asset potential, with the objective of developing and commercializing our product candidates. The principal components
of our strategy are to:
Disease
and Market Overview
Our
product candidates address disorders that are not well served by currently available therapies or have no approved treatment which represent
large potential commercial market opportunities. Background information on the disorders and related commercial markets that may be addressed
by our product candidates in or nearing the clinical-stage is set forth below.
Central
Nervous System
Fibromyalgia
(FM)
FM
is a chronic syndrome characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. The peak
incidence of FM occurs between 20-50 years of age, and 80-90% of diagnosed patients are female. FM may have a substantial negative impact
on social and occupational function, including disrupted relationships with family and friends, social isolation, reduced activities of
daily living and leisure activities, avoidance of physical activity, and loss of career or inability to advance in career or education.
According to the American Chronic Pain Association, an estimated six to twelve million adults in the U.S. have FM.
According
to a report by Frost and Sullivan that we commissioned, despite the availability of approved medications, the majority of patients fail
therapy due to either insufficient efficacy, poor tolerability, or both. Prescription pain and sleep medications are frequently prescribed
off-label for symptomatic relief, despite the lack of evidence that such medications provide a meaningful or durable therapeutic benefit,
and many of these medications carry significant safety risks and risk of dependence. For example, approximately 30% of patients diagnosed
with FM take chronic opioids, despite the lack of evidence for their effectiveness and the risk of addiction and toxicity, including overdose.
Long
COVID
Long COVID, or PASC, is a condition that some survivors of COVID-19 infection
experience in varying degrees of severity. It is a chronic disabling condition that is expected to result in a significant global health
and economic burden. We are focusing development of TNX-102 SL on FM-type Long COVID. The symptoms include intense fatigue, sleep
problems, multi-site pain, and cognitive issues (“brain fog”). The proposed indication is for the management of multi-site
pain associated with PASC.
6
Post
infection, many patients experience one or many of the symptoms of Long COVID: some patients have initial symptoms that become prolonged;
others manifest entirely new syndromes that impact more than one system or organ. According to a 2021 publication in the Journal of American
Medical Association (JAMA), over 1 in 10 healthcare workers who had recovered from COVID-19 were still coping with at least one moderate
to severe symptom eight months later. Research shows that Long COVID occurs in approximately 13% of recovered COVID-19 patients. There
is currently no approved drug for the treatment of Long COVID.
Migraine
Headaches
Migraine
is a primary headache disorder characterized by recurrent headaches that are moderate to severe. Typically, episodes affect one side of
the head, are pulsating in nature, and last from a few hours to three days. Associated symptoms may include nausea, vomiting, and sensitivity
to light, sound, or smell. The pain is generally made worse by physical activity, although regular exercise may have prophylactic effects.
Up to one-third of people affected have aura, typically a short period of visual disturbance that signals that the headache will soon
occur. Occasionally, aura can occur with little or no headache following it. Approximately one billion individuals worldwide suffer from
migraine (~14% of the population). Migraine is the second leading cause of years lived with disability. Chronic migraine (≥ 15 headache/migraine
days per month) affects about 1-2% of individuals (~75-150 million individuals worldwide; 3-7 million in the U.S.). CGRP antibodies are
the only migraine specific prophylaxis drugs approved in decades, but they require parenteral administration and there are long term safety
concerns with prolonged systemic blockade of CGRP or its receptor.
Major
Depressive Disorder
According to the Substance Abuse and Mental Health Services Administration,
an estimated 21.0 million adults in the U.S. in 2020 experienced at least one major depressive episode, representing 8.4% of all U.S.
adults. According
to the National Institute of Mental Health, depression affects approximately 17 million adults in the U.S., with approximately 2.5 million
adults treated with adjunctive therapy. Depression is a condition characterized by symptoms such as a depressed mood or loss of interest
or pleasure in daily activities most of the time for two weeks or more, accompanied by appetite changes, sleep disturbances, motor restlessness
or retardation, loss of energy, feelings of worthlessness or excessive guilt, poor concentration, and suicidal thoughts and behaviors.
These symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The
majority of people who suffer from depression do not respond adequately to initial antidepressant therapy.
Cocaine
Intoxication
Cocaine is an illegal
recreational drug taken for its pleasurable effects and associated euphoria. Pharmacologically, cocaine blocks the reuptake of the
neurotransmitter dopamine from central nervous system synapses, resulting in the accumulation of dopamine within the synapse and an
amplification of dopamine signaling that is related to its role in creating positive feeling. With the continued use of cocaine,
however, intense cocaine cravings occur resulting in a high potential for abuse and addiction, or dependence, as well as the risk of
cocaine intoxication. Cocaine intoxication refers to the deleterious effects on other parts of the body, especially those involving
the cardiovascular system. Common symptoms of cocaine intoxication include tachyarrhythmias and elevated blood pressure,
either of which can be life-threatening. As a result, individuals with known or suspected cocaine intoxication are sent
immediately to the emergency department, preferably by ambulance in case cardiac arrest occurs during transit. There are
approximately 505,000 emergency room visits for cocaine abuse each year in the U.S., of which 61,000 require detoxification
services. According to the National Institute on Drug Abuse, cocaine-involved deaths rose nearly 54% from 2019 to 2021,
resulting in over 24,486 deaths total.
Posttraumatic Stress Disorder, or PTSD
PTSD is a chronic condition that
may develop after a person is exposed to one or more traumatic events, such as warfare, sexual assault, serious injury, or threat of imminent
death. The core symptom clusters of PTSD are avoidance, emotional numbing, hyperarousal, and intrusion, where the triggering traumatic
event is commonly re-experienced by the individual through intrusive, recurrent recollections, flashbacks, and nightmares. People with
PTSD suffer significant impairment in their daily functioning, including occupational activities and social relations, and are at elevated
risk for impulsive violent behaviors toward others and themselves, including suicide. Of those who experience a significant trauma, approximately
20% of women and 8% of men develop PTSD. An estimated 12 million adults annually in the U.S. suffer from PTSD. According to the U.S. Department
of Veterans Affairs, the prevalence rate of PTSD in the military population is higher than that among civilians.
Many patients fail to adequately
respond to the medications approved for PTSD and approved medications show little evidence of a treatment effect in men, lack evidence
of efficacy in those for whom the traumatic event was combat-related, and carry suicidality warnings. Sleep disturbances are central features
of PTSD and are predictive of disease severity, depression, substance abuse, and suicidal ideation, yet are resistant to the approved
medications and present a difficult therapeutic challenge. Current PTSD treatments include off-label use of anxiolytics, sedative-hypnotics,
and antipsychotics, many of which lack reliable evidence of efficacy, and several have significant safety liabilities and dependence risk.
Rare
Disease
Prader-Willi
Syndrome
Prader-Willi
syndrome (PWS) is recognized as the most common genetic cause of life-threatening childhood obesity and affects males and females
with equal frequency and all races and ethnicities. The hallmarks of PWS are lack of suckling in infants and, in children and
adults, severe hyperphagia, an overriding physiological drive to eat, leading to severe obesity and other complications associated
with significant morbidity and mortality. PWS is an orphan disease that occurs in approximately one in 15,000 births. There is
currently no approved treatment for obesity and hyperphagia in adults and older children associated with PWS.
Immunology
Organ
Transplant Rejection
Organ
transplant rejection occurs when the immune system of the organ recipient attacks the new organ as if it was an infection or tumor. Often
transplantation is the last resort for most end-stage organ failure patients, affecting either kidneys, liver, heart, lungs, and/or pancreas.
Genetic disparity between organ donor and recipient is often at the root of the rejection. Mismatched or not closely matched organs triggers
an immune reaction that leads to rejection. Overcoming this difficulty is paramount to a patient’s survival as organ donations are
in limited supply.
7
Gastric
and Colorectal cancers
Gastric or stomach cancer is a
disease in which malignant cancer cells line the inner lumen of the stomach. Development of this form of cancer is often influenced by
age, diet and other stomach diseases. This type of cancer begins to form in the mucosa, the surface of the lumen that is in direct contact
with the contents of the stomach, and spreads through the outer layers of the stomach as the tumor grows.
Currently, per the National Cancer
Institute, the 5-year relative survival for stomach cancer is 33.3%. According to 2017-2019 data, approximately 0.8 percent of men and
women will be diagnosed with stomach cancer during their lifetime. In 2019, there were an estimated 123,920 people living with stomach
cancer in the U.S.
Colorectal cancer includes cancers
in the colon and the rectum, organs that are crucial to absorption of water by the body and the elimination of food-waste. Most colorectal
cancers start as a growth or polyp on the inner lining of the colon or rectum. Some types of polyps can change into cancer over time (usually
many years), but not all polyps become cancer. Adenomatous polyps are the ones that turn malignant with time. Similar to gastric cancer,
the malignancy begins in the mucosal layer and spreads outwards.
The 5-year relative survival rate
is 65.1%, per the National Cancer Institute. According to 2017-2019 data, approximately 4.1 percent of men and women will be diagnosed
with colorectal cancer during their lifetime. In 2019, there were an estimated 1,369,005 people living with colorectal cancer in the United
States.
Infectious
Diseases
Smallpox
and Mpox
Smallpox is an acute contagious disease caused by the variola virus, or
VARV, which is a member of the orthopoxvirus family. Smallpox was declared eradicated in 1980 following a global immunization campaign.
Smallpox is transmitted from person to person by infective droplets during close contact with infected symptomatic people. Mpox is an
acute contagious disease caused by the monkeypox virus or MPXV, which is also a member of the orthopoxvirus family. Mpox symptoms are
similar to those of smallpox, although less severe. Mpox is emerging as an important zoonotic infection in humans in Central and West
Africa. Until 2022, only a few cases of mpox had been reported outside of Africa in patients who had been infected while in Africa. Starting
in May of 2022, mpox cases spread rapidly in the U.S. and other countries. More than 30,000 cases in the U.S. have been reported according
to the U.S. Centers for Disease Control and Prevention.
Smallpox was eradicated by a World
Health Organization program that vaccinated individuals with live replicating vaccinia vaccines wherever smallpox appeared. In the 1970s,
vaccination of civilians to protect against smallpox was discontinued in the U.S.; however, smallpox remains a material threat to national
security and a proportion of military personnel, including members of the Global Response Force continue to be vaccinated. Vaccines for
smallpox and mpox are stockpiled by the U.S. government in the strategic national stockpile and for potential widespread immunization
in the event of malicious reintroduction of VARV.
COVID-19
SARS-CoV-2
is a contagious virus causing the disease COVID-19 that became a global pandemic in 2019 and has resulted in more than three million deaths.
While the infection and mortality rates have slowed in regions of the world with high vaccination rates, the struggle with the pathogen
is ongoing and evolving since SARS-CoV-2 is mutating into new variants. COVID-19 is characterized by fever, sore throat, acute shortness
of breath, cough, and oxygen desaturation in the blood. At least three major variants have swept across the world in successive waves
and overwhelmed healthcare systems during these waves. With new variants of the virus emerging, therapeutic research is addressing the
challenge of keeping up with this rapidly mutating virus. The early vaccines have been effective in limiting the severity of disease in
vaccinated individuals. Vaccines that elicit strong T cell responses are believed to have the potential to provide long-term or durable
protection.
Lead
Product Candidates
We
believe that our product candidates offer innovative therapeutic approaches and may provide significant advantages relative to available
therapies. We have worldwide commercialization rights to all of our product candidates listed below. The following table summarizes our
later stage product candidates that are in or nearing the clinic:
Product Candidate Indication Stage of Development
TNX-102 SL Fibromyalgia Mid-Phase 3, >50% enrolled
TNX-102 SL FM-type Long COVID Phase 2 enrolling
TNX-1900 Chronic migraine Phase 2, enrolling
TNX-601 ER Depression Phase 2, targeted 1Q 2023 start
TNX-1300 Cocaine Intoxication Mid-Phase 2, targeted 2Q 2023 start
TNX-1500 Kidney Transplant Rejection Phase 1, targeted 2Q 2023 start
TNX-801 Smallpox and Mpox vaccine Phase 1, targeted 2H 2023 start
TNX-2900 Prader-Willi Syndrome Phase 1
TNX-102
SL
Overview
TNX-102
SL, in clinical development for registration in five indications. TNX-102 SL is a proprietary sublingual tablet formulation of CBP that
efficiently delivers CBP across the oral mucosal membrane into the systemic circulation. We are developing TNX-102 SL as a bedtime treatment
for FM, PTSD, PASC or Long Covid, AAD and AUD. We own all rights to TNX-102 SL in all geographies, and we bear no obligations to third-parties
for any future development or commercialization. Excipients used in TNX-102 SL are approved for pharmaceutical use. Some of the excipients
were specially selected to promote a local oral environment that facilitates mucosal absorption of cyclobenzaprine or CBP.
8
The
current TNX-102 SL sublingual tablets contain 2.8 mg of CBP. For the treatment of FM, TNX-102 SL 5.6 mg (two 2.8 mg tablets) at bedtime
is in Phase 3 development. We selected this dose with the goal of providing a balance of efficacy, safety, and tolerability that would
be acceptable as a first-line therapy and for long-term use, and in-patient populations characterized by burdensome symptoms and sensitivity
to medications.
The
active ingredient in TNX-102 SL, is CBP, a serotonin-2A and alpha-1 adrenergic receptor antagonist as well as an inhibitor of serotonin
and norepinephrine reuptake. In addition, TNX-102 SL acts upon other receptors in the central nervous system including muscarinic M1 and
histaminergic H1 receptors.
CBP
is the active ingredient of two products that are approved in the U.S. for the treatment of muscle spasm: Flexeril® (5 mg and
10 mg oral immediate-release, or IR, tablet) and Amrix® (15 mg and 30 mg oral extended-release capsule). The Flexeril
brand of CBP IR tablet has been discontinued since May 2013. There are numerous generic versions of CBP IR tablets on the market. CBP-containing
products are approved for short term use (two to three weeks) only as an adjunct to rest and physical therapy for relief of muscle spasm
associated with acute, painful musculoskeletal conditions. CBP IR tablets are recommended for three times per day dosing, which results
in relatively stable blood levels of CBP after several days of treatment. Extended-release CBP capsules taken once a day mimic, and flatten,
the pharmacokinetic profile of three times per day CBP IR tablets.
We
designed TNX-102 SL to be administered once-daily at bedtime and with the intention for long-term use. We believe the selected dose of
TNX-102 SL and its unique pharmacokinetic profile will enable it to achieve a desirable balance of efficacy, safety, and tolerability.
Our Phase 1 comparative trials showed that, on a dose-adjusted basis, TNX-102 SL results in faster systemic absorption and significantly
higher plasma levels of CBP in the first hour following sublingual administration relative to oral IR CBP tablets. It also showed that
the sublingual route of administration, which largely bypasses the “first pass” hepatic metabolism that swallowed medications
undergo, results in a higher plasma ratio of CBP to its main active metabolite, norcyclobenzaprine. In clinical studies, TNX-102 SL 2.8
mg and TNX-102 SL 5.6 mg were generally well-tolerated, with no drug-related serious and unexpected adverse reactions reported in these
studies. Some subjects experienced transient numbness of the tongue after TNX-102 SL administration.
We have successfully completed
the pivotal exposure bridging study with TNX-102 SL compared to Amrix. Results from this study support the approval of TNX-102 SL
under Section 505(b)(2) of the Federal Food, Drug and Cosmetic Act, or FDCA, with Amrix as the reference listed drug, or RLD. In general,
the development timeline for a 505(b)(2) NDA is shorter and less expensive than an NDA developed under Section 505(b)(1), which is for
new chemical entities, or NCEs, that have never been approved in the U.S. We believe that TNX-102 SL has the potential to provide clinical
benefit to FM, Long COVID, and PTSD patients and possibly other CNS (central nervous system) indications that are underserved by currently
marketed products or have no approved treatment.
TNX-102
SL – FM program
We
are developing TNX-102 SL as a bedtime treatment for FM under an active IND application. The potential approval of TNX-102 SL for FM is
expected to be under Section 505(b)(2) of the FDCA.
Clinical
Development Plan
Phase
3 RESILIENT (F307)
The first patient was enrolled in the potentially pivotal Phase 3 RESILIENT
study in April 2022. The RESILIENT study is a double-blind, randomized, placebo-controlled adaptive design trial designed to evaluate
the efficacy and safety of TNX-102 SL in FM. The two-arm trial is expected to enroll approximately 470 participants in the U.S. and was
50% enrolled as of December 2022. The first two weeks of treatment consist of a run-in period in which participants start on TNX-102 SL
2.8 mg (1 tablet) or placebo. Thereafter, all participants increase their dose to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo
tablets for the remaining 12 weeks. The primary endpoint is the daily diary pain severity score change (TNX-102 SL 5.6 mg vs. placebo)
from baseline to Week 14 (using the weekly averages of the daily numerical rating scale scores), analyzed by mixed model repeated measures
with multiple imputation. An interim analysis by an IDMC will be conducted on the primary endpoint based on the first 50% of enrolled
participants for a potential sample size adjustment or early stop for futility. Interim data is expected in the second quarter of 2023.
Topline data is expected in the fourth quarter of 2023.
Completed
Phase 3 RALLY Study (F306)
We reported pre-planned interim analysis results from a Phase 3 study,
RALLY (F306), in July 2021. Based on the recommendation from the independent data monitoring committee that the RALLY trial was unlikely
to demonstrate a statistically significant improvement in the primary endpoint, we stopped enrollment of new participants but allowed
those participants who were already enrolled to complete the study. We reported topline data from the completed study in March of 2022.
As expected based on interim analysis results, TNX-102 SL did not achieve statistical significance over placebo on the primary endpoint
of reduction in daily pain, and relative to the previous positive Phase 3 Study (RELIEF), RALLY had an unexpected increase in study participant
adverse event-related discontinuations in both drug and placebo groups. The RALLY study was a double-blind, randomized, placebo-controlled
adaptive design trial intended to evaluate the efficacy and safety of TNX-102 SL in FM. The trial was expected to enroll approximately
670 patients across approximately 40 U.S. sites. For the first two weeks of treatment, there was a run-in period in which patients started
on TNX-102 SL 2.8 mg (1 tablet) or placebo. After the first two weeks, all patients had the dose increased to TNX-102 SL 5.6 mg (2 x 2.8
mg tablets) or two placebo tablets for 12 weeks. The primary endpoint was daily diary pain severity score change from baseline to Week
14 (using the weekly averages of the daily numerical rating scale scores), analyzed by mixed model repeated measures with multiple imputation.
Completed
Phase 3 RELIEF Study (F304)
In
the fourth quarter of 2020, we announced the results of a randomized, double-blind, placebo-controlled, 12-week Phase 3 study of TNX-102
SL in 503 participants with FM, which we refer to as the RELIEF study. The primary objective of this study was to evaluate the potential
clinical benefit of using TNX-102 SL to treat FM at a dose of 5.6 mg, administered sublingually once daily at bedtime for 12 weeks. The
primary endpoint of the RELIEF trial was the daily diary pain severity score change from baseline to Week 14 (using the weekly averages
of the daily numerical rating scale scores), analyzed by mixed model repeated measures with multiple imputation. The RELIEF study achieved
statistical significance on the primary efficacy endpoint: change from baseline in the weekly average of daily diary pain severity numerical
rating scale (NRS) scores for TNX-102 SL 5.6 mg (LS mean [SE]: -1.9 [0.12] units) versus placebo (-1.5 [0.12] units), analyzed by mixed
model repeated measures with multiple imputation (LS mean [SE] difference: -0.4 [0.16] units, p=0.010).
9
The
statistically significant improvement in pain is further substantiated when diary pain was analyzed by another standard statistical approach,
a 30 percent responder analysis, with 46.8% on active and 34.9% on placebo having a 30 percent or greater reduction in pain (logistic
regression; odds ratio [95% CI]: 1.67 [1.16, 2.40]; p=0.006). Consistent with the proposed mechanism that TNX-102 SL acts in fibromyalgia
through improving sleep quality, TNX-102 SL showed nominal improvement of sleep by several measures. For daily diary sleep quality ratings,
TNX-102 SL (-2.0 [0.12] units) compared to placebo (-1.5 [0.12] units) was nominally significant (LS mean difference: -0.6 [0.17] units;
p<0.001). For the PROMIS Sleep Disturbance instrument, TNX-102 SL was also nominally significant over placebo on T-scores (LS mean
difference: -2.9 [0.82] units; p<0.001). The effect sizes on the diary sleep ratings and PROMIS Sleep Disturbance instrument were 0.31
and 0.32, respectively.
In the RELIEF study, TNX-102 SL was similarly well tolerated as in the
Phase 2 BESTFIT and Phase 3 AFFIRM studies, which both studied TNX-102 SL at a lower dose of 2.8 mg daily. There were no new safety signals
observed in the RELIEF study at the 5.6 mg daily dose. Among participants randomized to the TNX-102 SL and placebo arms, 82.3% and 83.5%,
respectively, completed the 14-week dosing period. As expected, based on prior TNX-102 SL studies, administration site reactions are the
most commonly reported adverse events and were higher in the TNX-102 SL treatment group, including rates of oral numbness (17.3% vs. 0.8%),
oral pain/discomfort (11.7% v. 2.0%), taste impairment (6.5% vs. 0.4%), and oral tingling (5.6% v. 0.4%). Oral numbness or tingling and
taste impairment were local administration site effects nearly always temporally related to dose administration and transiently expressed
(<60 minutes) in almost all occurrences. The only systemic treatment-emergent adverse events that occurred at a rate of 5.0% or greater
in either arm was somnolence/sedation at 5.6% in the TNX-102 SL arm vs. 1.2% in placebo, which was consistent with known side effects
of marketed oral cyclobenzaprine. Adverse events resulted in premature study discontinuation in 8.9% of those who received TNX-102 SL
compared with 3.9% of placebo recipients. There was a total of seven serious adverse events reported during the study, none of which were
deemed related to investigational product; five in placebo arm, and two in TNX-102 SL arm. Of the two in the TNX-102 SL arm, one was a
motor vehicle accident with multiple bone fractures, and the other was a pneumonia secondary to an infection.
Completed
Phase 3 AFFIRM Study (F301)
In
the third quarter of 2016, we announced the results of a randomized, double-blind, placebo-controlled, 12-week Phase 3 study of TNX-102
SL in 519 participants with FM, which we refer to as the AFFIRM study. The primary objective of this study was to evaluate the potential
clinical benefit of using TNX-102 SL to treat FM at a dose of 2.8 mg, administered sublingually once daily at bedtime for 12 weeks. The
primary endpoint of the AFFIRM trial was the 30% pain responder analysis in which a responder is defined as a subject for whom pain intensity
was reduced by at least 30% at Week 12 as compared to baseline. AFFIRM did not achieve statistical significance at the primary endpoint
(p=0.095). Yet, statistical significance was achieved when pain was analyzed instead as a continuous variable, either by MMRM (p<0.001)
or by MMRM with multiple imputation for missing data (p=0.005), a generally accepted approach to pain data. TNX-102 SL also showed
statistically significant improvements in the declared secondary analyses of the Patient Global Impression of Change, or PGIC (p=0.038)
and the Fibromyalgia Impact Questionnaire-Revised, or FIQ-R (p<0.001). The study also showed statistically significant improvement
with TNX-102 SL on measures of sleep quality, including the Patient-Reported Outcomes Measurement Information System, or PROMIS, Sleep
Disturbance instrument (p<0.001).
TNX-102
SL was well tolerated in the AFFIRM trial. Among patients randomized to the active and control arms, 78% and 86%, respectively, completed
the 12-week dosing period. The most common adverse events were local in nature, with transient tongue or mouth numbness occurring in 40%
of participants on TNX-102 SL vs. 1% on placebo. These local adverse events did not appear to affect either rates of retention of study
participants or their compliance with taking TNX-102 SL. Systemic adverse events were similar between TNX-102 SL and placebo. No serious
adverse events were reported.
Other
NDA Requirements
The
Agreed Initial Pediatric Study Plan, or Agreed iPSP, was accepted by the FDA in September 2015. An amendment to the Agreed iPSP will be
submitted for FDA agreement prior to marketing application.
Based
on our discussions with the FDA and the FDA official meeting minutes, we will not have to conduct special populations, such as geriatric
and renal/hepatic impaired patients, drug-drug interaction or cardiovascular safety studies to support the TNX-102 SL NDA filing since
the pivotal systemic exposure bridging study using Amrix as the reference listed drug, or RLD, has been successfully completed. Due to
the well-established safety profile of CBP at much higher doses than we proposed for FM and the long-term safety data in PTSD, up to 15
months, on TNX-102 SL 5.6 mg, the FDA has not requested a risk management plan or medication guide for this product.
Phase
1 Bioequivalence, Bridging PK, Food-Effect and Dose-Proportionality Studies
We
have completed the required Phase 1 bioequivalence, multi-dose bridging pharmacokinetic, and food effect and dose-proportionality studies.
Cyclobenzaprine
Hydrochloride Nonclinical Development
In October 2016, we completed
the six-month repeated-dose toxicology study of the active ingredient, CBP, in rats and a nine-month repeated-dose toxicology study in
dogs required for the NDA filing. These chronic toxicity studies were requested by the FDA to augment the nonclinical information in the
AMRIX prescribing information, or labeling, which is necessary to support the TNX-102 SL labeling for long-term use. Due to the lack of
evidence of potential abuse in clinical studies of TNX-102 SL, the FDA agreed that nonclinical study to assess CBP abuse potential is
not required to support the TNX-102 SL NDA filing.
We are planning to develop TNX-102 SL for the treatment of FM in Japan.
Cyclobenzaprine, the active ingredient of TNX-102 SL, has not been approved in Japan, and is considered a NCE (new chemical entity). In
February 2022, we held an End of Phase 2 Consultation with the Pharmaceuticals and Medical Devices Agency, or PMDA, an independent administrative
institution responsible for ensuring the safety, efficacy and quality of pharmaceuticals and medical devices in Japan, to discuss the
Japan development plan. Agreement was reached on the design of a Phase 1 bridging study (TNX-CY-F108/F108) in ethnic Japanese healthy
volunteers to enable clinical studies of TNX-102 SL in Japan. PMDA also provided guidance on the overall nonclinical package to support
a Japan NDA filing for TNX-102 SL for the treatment of FM.
10
The F108 Phase 1 study was initiated
in March 2022 and the clinical phase was completed in May 2022 and we are awaiting the final study report at the time of this filing.
We are completing nonclinical safety, pharmacology and embryo-fetal development
toxicology studies as part of the agreed IND-enabling nonclinical data package to support clinical studies of TNX-102 SL in Japan.
TNX
102 SL – FM-type Long COVID Program
We
are developing TNX-102 SL as a bedtime treatment for FM-type Long COVID. The potential approval of TNX-102 SL for Long COVID is expected
to be under Section 505(b)(2) of the FDCA.
Phase
2 PREVAIL Study (PA201)