Item 1A. Risk Factors 46
Item 1B. Unresolved Staff Comments 72
Item 2. Properties 72
Item 3. Legal Proceedings 73
Item 4. Mine Safety Disclosures 73
PART II
Item 6. Reserved 73
Item 7A. Quantitative and Qualitative Disclosures about Market Risk 87
Item 8. Financial Statements and Supplementary Data F-1 – F-32
Item 9A. Controls and Procedures 88
Item 9B. Other Information 89
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 89
PART III
Item 10. Directors, Executive Officers and Corporate Governance 89
Item 11. Executive Compensation 95
Item 14. Principal Accounting Fees and Services 104
PART IV
Item 15. Exhibits, Financial Statement Schedules 105
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 discovering, licensing, acquiring and developing therapeutics and diagnostics to treat and prevent human disease and
alleviate suffering. We are building capabilities in synthetic biology, precision medicine, protein engineering and vaccine manufacturing
through internal efforts as well as through collaborations with academic institutions and contract research organizations. Our therapeutics
under development include both small molecules and biologics. All of our drug, biologic and diagnostic candidates are still in development.
Tonix’s portfolio is primarily
composed of immunology, central nervous system, or CNS, and infectious disease product candidates. Tonix’s immunology portfolio
includes biologics to address organ transplant rejection, autoimmune diseases and cancer. The CNS portfolio includes small molecules and
biologics to treat pain, neurologic, psychiatric and addiction conditions. Tonix’s infectious disease portfolio of product candidates
includes next-generation vaccines to prevent COVID-19, an antiviral to treat COVID-19, and a potential treatment for Long COVID. The infectious
disease portfolio also includes a vaccine in development to prevent smallpox and monkeypox.
Tonix’s lead candidate within
its immunology pipeline is TNX-1500*, a humanized monoclonal antibody, or mAb, directed against CD40-ligand,
or CD40L, engineered to modulate binding to Fc receptors, that is being developed as a prophylaxis against organ transplant rejection
as well as to treat autoimmune conditions. In experiments at the Massachusetts General Hospital, a teaching hospital of Harvard Medical
School, TNX-1500 is being studied as monotherapy or in combination with other immunosuppressive agents in heart and kidney organ transplants
in non-human primates. Preliminary results from an ongoing experiment in heart transplants indicate that TNX-1500 appears to have comparable
efficacy to historical experiments using the chimeric mouse/human IgG1 version (5c8H1) of the anti-CD40L mAb 5c8. First generation anti-CD40L
mAb were associated with an increased risk of blood clots or thrombosis. In the non-human primate studies with TNX-1500, no evidence of
thrombosis has been observed so far. We expect to start a Phase 1 study of TNX-1500 in the second half of 2022.
Among the CNS candidates
in development is TNX-1300* (double-mutant cocaine esterase) which is in Phase 2 for the treatment of life-threatening cocaine intoxication.
TNX-1300 has been granted Breakthrough Therapy designation, or BTD, by the U.S. Food and Drug Administration, or FDA. TNX-1300 was licensed
from Columbia University in 2019 after a Phase 2 study showed that it rapidly and efficiently disintegrates cocaine in the blood of volunteers
who received intravenous, or i.v., cocaine. We expect to initiate a Phase 2 open-label safety study of TNX-1300 in an emergency room setting
in the first half of 2022.
3
Our latest stage CNS product candidate is TNX-102 SL*, a proprietary sublingual
tablet formulation of CBP, designed for bedtime administration. TNX-102 SL has active INDs for fibromyalgia, or FM, posttraumatic
stress disorder, or PTSD, agitation in Alzheimer’s disease, or AAD, and alcohol use disorder, or AUD. We also intend to develop
TNX-102 SL as a treatment for Long COVID, which is also known as post-acute sequelae of COVID-19, or PASC.
TNX-102 SL is in mid-Phase
3 development for the management of FM, a pain disorder characterized by chronic widespread pain, non-restorative sleep, fatigue and impaired
cognition. In December 2020, we reported positive results from the Phase 3 RELIEF study of TNX-102 SL 5.6 mg for the management of FM.
In July 2021, we reported pre-planned interim analysis results from a second Phase 3 study, RALLY. Based on the recommendation from the
independent data monitoring committee that the RALLY trial was unlikely to demonstrate a statistically significant improvement in the
primary endpoint, we stopped enrollment of new participants but allowed those participants who were already enrolled to complete the study.
We expect to report topline data from the completed study in the first quarter of 2022. We expect to analyze the RALLY results to improve
the design of subsequent Phase 3 studies. In addition, we plan to employ pharmacogenomic techniques to compare the RALLY and RELIEF study
populations, which may provide a path to precision medicine-based companion diagnostics for TNX-102 SL in FM. We intend to start a new
Phase 3 study of TNX-102 SL in FM in the first half of 2022.
TNX-102 SL is also being developed as a potential treatment for Long COVID.
We met with the FDA in the third quarter of 2021 to seek agreement on the design of a Phase 2 potential pivotal study and the overall
clinical development plan to qualify TNX-102 SL as an indicated treatment for Long COVID. We intend to focus our clinical development
on the subgroup of Long COVID patients whose symptoms overlap with FM, particularly with respect to widespread pain. We received the official
minutes from this meeting in the third quarter of 2021 and intend to initiate a Phase 2 study in the first half of 2022.
For
TNX-102 SL in PTSD, we completed the Phase 3 RECOVERY trial and reported topline results in the fourth quarter of 2020 in which
TNX-102 SL did not meet the primary efficacy endpoint. PTSD is a serious psychiatric condition that develops in response to experiencing
a traumatic event. We subsequently completed a meeting with the FDA to discuss potential new endpoints for the indication of treatment
of PTSD, and we expect to begin enrolling a Phase 2 study of TNX-102 SL in police in Kenya in the first half of 2022. The AAD
program is Phase 2 ready with an active IND and FDA Fast Track designation. AAD, which includes emotional lability, restlessness,
irritability, and aggression, is one of the most distressing and debilitating of the behavioral complications of Alzheimer’s
disease. Tonix does not have any near-term plans to start a Phase 2 study in AAD. The AUD program is also Phase 2 ready with an
active IND. AUD is a chronic relapsing brain disease characterized by compulsive alcohol use, loss of control over alcohol intake,
and a negative emotional state when not using alcohol. Tonix does not have any near-term plans to start a Phase 2 study in AUD.
TNX-1900* (intranasal potentiated oxytocin) is in development for prophylaxis
of chronic migraine and for the treatment of craniofacial pain, insulin resistance and related conditions as well binge eating disorder,
or BED. TNX-1900 was acquired from Trigemina, Inc. and licensed from Stanford University in 2020. The potentiated formulation includes
magnesium, which has been shown in animals to potentiate binding of oxytocin to the oxytocin receptor in the trigeminal ganglion. We received
IND clearance from the FDA in the fourth quarter of 2021 and intend to initiate a Phase 2 study in migraine in the second half of 2022.
Tonix also licensed technology to use TNX-1900 for the treatment of insulin resistance from the University of Geneva. TNX-1900 will be
studied as a potential treatment for BED in an investigator-initiated Phase 2 clinical trial. The Phase 2 clinical trial is expected to
start in the second half of 2022. In March 2022, we announced an agreement with Massachusetts General Hospital, a teaching hospital of
Harvard Medical School, to conduct this study. Tonix does not own an IND for BED.
TNX-2900* is another intranasal oxytocin-based therapeutic in development
for the treatment of Prader-Willi syndrome, or PWS. The technology for TNX-2900 was licensed from Inserm, the French National Institute
of Health and Medical Research. PWS, an orphan condition, is a rare genetic disorder of failure to thrive in infancy, associated with
uncontrolled appetite beginning in childhood with complications of obesity and diabetes. We have sponsored a research program at the Inserm
to study oxytocin on suckling behavior in mice that have been engineered to express one of the Prader-Willi genes. TNX-2900 has been granted
Orphan-Drug Designation for the treatment of PWS.
TNX-601 CR* (tianeptine oxalate and naloxone controlled-release tablets)
is a CNS product candidate in development as a treatment for major depressive disorder, or depression, for PTSD, and for neurocognitive
dysfunction associated with corticosteroid use. We completed a Phase 1 trial for formulation development outside of the U.S. Based on
official minutes from a pre-IND meeting with the FDA, we expect to initiate a pharmacokinetic study in the third quarter of 2022, and
a Phase 2 study in the first quarter of 2023.
Tonix’s
infectious disease portfolio includes vaccines based on Tonix’s recombinant pox vaccine, or “RPV” technology platform.
RPV vaccines are believed to protect against negative outcomes of infectious diseases by eliciting T cell responses in addition to antibody
responses. TNX-801* is an RPV live horsepox virus vaccine for percutaneous administration in the pre-IND stage of development to protect
against smallpox and monkeypox. TNX-801 vaccinated non-human primates were protected from monkeypox in studies reported in the first
quarter of 2020.
TNX-1800*
is a live virus vaccine that expresses the SARS-CoV-2 spike protein from the ancestral Wuhan strain, which has shown encouraging results
in non-human primates. Because the subsequent omicron variant has out-competed the ancestral Wuhan strain, we are now planning new vaccine
versions, TNX-1840* and TNX-1850*, that are designed to express spike protein from the omicron variant and from the BA.2 variant, respectively.
The COVID-19 vaccines that are approved for use, or have emergency use authorization, or EUA, in the U.S. have provided significant health
benefits to the vaccinated population; however, they are showing limitations in the durability of protection conferred and, in their ability,
to block forward transmission. Live virus vaccines that protect against other viral diseases by eliciting T cell responses have shown
durability of protection that lasts years to decades and some live virus vaccines have significantly inhibited forward transmission. With
respect to TNX-1800 vaccination, we reported positive efficacy data from animal challenge studies using live SARS-CoV-2 in the first quarter
of 2021. In this study, TNX-1800 vaccinated, SARS-CoV-2 challenged animals had undetectable SARS-CoV-2 in the upper airways, which we
believe relates to potential inhibition of forward transmission of this respiratory pathogen.
4
TNX-3500*
(sangivamycin) is an antiviral inhibitor of SARS-CoV-2 which has demonstrated broad-spectrum activity in laboratory-based assays against
the coronaviruses SARS-CoV-2 and MERS-CoV. Tonix licensed this technology from OyaGen, Inc. and intends to develop it as a treatment for
COVID-19 and potentially other viral diseases. The active ingredient of TNX-3500 has been studied for safety in humans in prior studies
with cancer patients at the U.S. National Cancer Institute but has not been approved for marketing in any jurisdiction. Tonix intends
to conduct further animal studies in preparation for filing an IND.
TNX-3600* refers to a series of
fully human mAbs generated by a human-human hybridomas from COVID-19 convalescent volunteers. Tonix is collaborating with Columbia University
to produce these fully human mAbs to SARS-CoV-2 spike proteins from variants such as delta and omicron and to other viral targets. The
initial focus is to develop COVID-19 therapeutic mAbs. Tonix plans to seek indications similar to current EUA therapeutic mAbs for treating
individuals with mild-to-moderate COVID-19 who are at high risk for progression to severe disease. TNX-3600 mAbs may also be used in combination
therapy with other COVID-19 therapeutic mAbs. Combination therapies with other anti-SARS-CoV-2 mAbs may reduce the emergence of resistant
viral strains. Given the unpredictable trajectory of the SARS-CoV-2 virus and new variants, we seek to contribute to a broad set of mAbs
from a variety of patients, that can be scaled up quickly and potentially combined with other mAbs. We envision the future of mAb therapy
for COVID-19 to be cocktails of mAbs with specificity to variants of concern. TNX-3600 is in the preclinical stage of development.
Tonix intends to study inhibition of SARS-CoV-2 variants in tissue culture and initiate animal studies in the first half of 2022.
Tonix also
is collaborating with Columbia University to better understand immune responses to SARS-CoV-2 in healthy individuals who have recovered
from COVID-19, which is expected to provide a foundation for tailoring therapeutics to appropriate individuals using precision medicine.
TNX-3700*
is a COVID-19 mRNA vaccine candidate employing a zinc nanoparticle (ZNP) formulation. In collaboration with Kansas State University, Tonix
is developing this ZNP technology as a potential replacement for the lipid nanoparticle (LNP) technology used in current mRNA vaccines.
ZNP technology potentially allows for improved stability which facilitates shipping and storage and addresses the limitations in current
mRNA vaccines which require ultra-cold storage and shipping. This current requirement limits the use of mRNA vaccines in less developed
countries. We plan to seek initial indications as a booster, similar to the current FDA approved mRNA vaccines. Tonix intends to conduct
research with Kansas State University on ZNP SARS-CoV-2 spike based vaccines in tissue culture and animals in the first half of 2022.
TNX-2100*
is an in vivo diagnostic skin test we are developing to measure SARS-CoV-2 exposure and T cell immunity. T cell immunity is more
durable than antibody immunity since serum antibodies wane between six months and one year after vaccination. TNX-2100 is a potential
test to measure delayed-type hypersensitivity (DTH) response to SARS-CoV-2. The DTH response for other pathogens, notably tuberculosis,
can serve as an in vivo measure of functional T cell immunity. TNX-2100 is comprised of GMP peptides designed to mimic SARS-CoV-2
proteins and stimulate SARS-CoV-2 specific T cells. We initiated a first-in-human, dose-finding clinical study in the first quarter of
2022 and expect study results in the first half of 2022.
Our immunology pipeline also includes TNX-1700*. TNX-1700
is a recombinant modified form of Trefoil Family Factor 2, or rTFF2, that was licensed from Columbia University in 2019. TNX-1700 is a
biologic being developed to treat gastric and colorectal cancers by an immune-oncology mechanism and is in the preclinical stage of development.
Our biodefense
pipeline includes TNX-701*, an undisclosed small molecule technology being developed to prevent deleterious effects of radiation exposure
which has the potential to be used as a medical countermeasure to improve biodefense. TNX-701 is in the preclinical stage of development.
5
Finally,
our CNS pipeline includes TNX-1600*, an inhibitor of the reuptake of neurotransmitters serotonin, norepinephrine and dopamine, or a triple
reuptake inhibitor. TNX-1600 was licensed from Wayne State University in 2019 and is being developed as a treatment for PTSD, depression
and attention-deficit/hyperactivity disorder, or ADHD. TNX-1600 is in the preclinical stage of development.
Relating
to our COVID-19 and other infectious disease development programs, we are developing the resources necessary to enable internal research,
development and manufacturing capabilities necessary to meet the goal of producing new vaccine candidates within 100 days of recognition
and new diagnostics within weeks of obtaining sequence information. As articulated in the American Pandemic Preparedness Plan, or AP3,
released by the U.S. Office of Science and Technology Policy, this 100-day goal for vaccines is a key component of preparedness for future
pandemics. We intend to establish the infrastructure necessary to support the pandemic preparedness goals established in the AP3, specifically
with respect to our RPV vaccine and skin test platforms and potentially to other vaccine, diagnostic and therapeutic platforms. This infrastructure
consists of (i) our infectious disease R&D Center, or “RDC”, (ii) our Advanced Development Center, or ADC, and (iii) our
Commercial Manufacturing Center, or CMC. We acquired the infectious disease RDC in Frederick, Maryland consisting of two buildings totaling
approximately 48,000 square feet. The acquisition closed in October 2021 and was operational at closing, but as of December 31, 2021,
the facility was not ready for its intended use. It is our intention to have the facility ready for use in the first half of 2022. The
RDC facility will focus on our development of vaccines and antiviral drugs against SARS-CoV-2, its variants, and other infectious diseases.
The RDC facility is currently biosafety level 2 (BSL-2), but we intend to upgrade components to BSL-3. We are in the process of a substantial
renovation of the ADC located in the New Bedford business park in Dartmouth, Massachusetts. This facility is intended to accelerate development
and clinical scale manufacturing of live-virus vaccines to support Phase 1 and Phase 2 clinical trials. It is currently under construction
and will be an approximately 45,000 square foot BSL-2 facility once completed. It is expected to be partially operational in the first
half of 2022. We also plan to build the CMC in Hamilton, Montana, where we purchased approximately 44 acres of land. The CMC will focus
on developing and manufacturing commercial scale live-virus vaccines and is also intended to be BSL-2. Site enabling work is expected
to be initiated for the CMC in 2022. Together, we expect these facilities may qualify the RPV vaccine and skin test platforms for
programs that are designed to carry out the goals of AP3.
*All
of Tonix’s product candidates are investigational new drugs or biologics and have not been approved for any indication.
We are led by a management team with significant industry experience in
drug development. We complement our management team with a network of scientific, clinical, and regulatory advisors that includes recognized
experts in their respective fields.
Corporate Information
We were incorporated on November
16, 2007 under the laws of the State of Nevada as Tamandare Explorations Inc. On October 11, 2011, we changed our name to Tonix Pharmaceuticals
Holding Corp. Our common stock is listed on The NASDAQ Capital Market under the symbol “TNXP”. Our principal executive offices
are located at 26 Main Street, Suite 101, Chatham, New Jersey 07928, and our telephone number is (862) 799-8599. Our website addresses
are www.tonixpharma.com, www.tonix.com, and www.krele.com.
Our Strategy
Our objective is to develop and commercialize our
product candidates. The principal components of our strategy are to:
6
Disease
and Market Overview
Our
product candidates address disorders that are not well served by currently available therapies or have no approved treatment which
represent large potential commercial market opportunities. Background information on the disorders and related commercial markets
that may be addressed by our product candidates in or nearing the clinical-stage is set forth below.
Immunology
Organ Transplant Rejection
Organ transplant
rejection occurs when the immune system of the organ recipient attacks the new organ as if it was an infection or tumor. Often transplantation
is the last resort for most end-stage organ failure patients, affecting either kidneys, liver, heart, lungs, and/or pancreas. Genetic
disparity between organ donor and recipient is often at the root of the rejection. Mismatched or not closely matched organs triggers
an immune reaction that leads to rejection. Overcoming this difficulty is paramount to a patient’s survival as organ donations
are in limited supply.
Gastric
and Colorectal cancers
Gastric
or stomach cancer is a disease in which malignant cancer cells line the inner lumen of the stomach. Development of this form of cancer
is often influenced by age, diet and other stomach disease. This type of cancer begins to form in the mucosa, the surface of the lumen
that is in direct contact with the contents of the stomach, and spreads through the outer layers of the stomach as the tumor grows.
Currently,
per the National Cancer Institute, the 5-year relative survival for stomach cancer is 32.4%. The lifetime risk of developing stomach
cancer is higher in men (about 1 in 96) than in women (about 1 in 152).2 In 2018, there were an estimated 120,301 people living
with stomach cancer in the United States.
7
Colorectal
cancer includes cancers in the colon and the rectum, organs that are crucial to absorption of water by the body and the elimination of
food-waste. Most colorectal cancers start as a growth or polyp on the inner lining of the colon or rectum. Some types of polyps can change
into cancer over time (usually many years), but not all polyps become cancer. Adenomatous polyps are the ones that turn malignant with
time. Similar to gastric cancer, the malignancy begins in the mucosal layer and spreads outwards.
The
5-year relative survival rate is 64.7%. Overall, the lifetime risk of developing colorectal cancer is about 1 in 23 (4.3%) for men and
1 in 25 (4.0%) for women. In 2018, there were an estimated 1,365,135 people living with colorectal cancer in the United States.
Central
Nervous System
Cocaine
Intoxication
Cocaine
is an illegal recreational drug taken for its pleasurable effects and associated euphoria. Pharmacologically, cocaine blocks the
reuptake of the neurotransmitter dopamine from central nervous system synapses, resulting in the accumulation of dopamine within
the synapse and an amplification of dopamine signaling that is related to its role in creating positive feeling. With the continued
use of cocaine, however, intense cocaine cravings occur resulting in a high potential for abuse and addiction, or dependence,
as well as the risk of cocaine intoxication. Cocaine intoxication refers to the deleterious effects on other parts of the body,
especially those involving the cardiovascular system. Common symptoms of cocaine intoxication include tachyarrhythmias and
elevated blood pressure, either of which can be life-threatening. As a result, individuals with known or suspected cocaine
intoxication are sent immediately to the emergency department, preferably by ambulance in case cardiac arrest occurs during transit.
There are approximately 505,000 emergency room visits for cocaine abuse each year in the U.S., of which 61,000 require detoxification
services. According to the National Institute on Drug Abuse, over 15,883 individuals died of cocaine overdose in 2019.
Fibromyalgia
(FM)
FM
is a chronic syndrome characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues.
The peak incidence of FM occurs between 20-50 years of age, and 80-90% of diagnosed patients are female. FM may have a substantial
negative impact on social and occupational function, including disrupted relationships with family and friends, social isolation,
reduced activities of daily living and leisure activities, avoidance of physical activity, and loss of career or inability to
advance in career or education. According to the American Chronic Pain Association, an estimated six to twelve million adults
in the U.S. have FM.
According
to a report by Frost and Sullivan that we commissioned, despite the availability of approved medications, the majority of patients
fail therapy due to either insufficient efficacy, poor tolerability, or both. Prescription pain and sleep medications are frequently
prescribed off-label for symptomatic relief, despite the lack of evidence that such medications provide a meaningful or durable
therapeutic benefit, and many of these medications carry significant safety risks and risk of dependence. For example, approximately
30% of patients diagnosed with FM take chronic opioids, despite the lack of evidence for their effectiveness and the risk of addiction
and toxicity, including overdose.
Long
COVID
Long
COVID, or PASC, is a condition that some survivors of COVID-19 infection experience in varying degrees
of severity. It is a chronic disabling condition that is expected to result in a significant global health and economic burden. The symptoms
include intense fatigue, fevers, sleep problems, pain, and cognitive issues (“brain fog”). Post infection, many patients
experience one or many of the symptoms of Long COVID: some patients have initial symptoms that become prolonged; others manifest entirely
new syndromes that impact more than one system or organ. According to a recent publication in the Journal of American Medical Association
(JAMA), over 1 in 10 healthcare workers who had recovered from COVID-19 were still coping with at least one moderate to severe symptom
eight months later. Several cohort studies have reported that persistence of symptoms following SARS-CoV-2 infection occurs in more than
30% of patients. There is currently no approved drug for the treatment of Long COVID.
8
Posttraumatic
Stress Disorder, or PTSD
PTSD
is a chronic condition that may develop after a person is exposed to one or more traumatic events, such as warfare, sexual assault,
serious injury, or threat of imminent death. The core symptom clusters of PTSD are avoidance, emotional numbing, hyperarousal,
and intrusion, where the triggering traumatic event is commonly re-experienced by the individual through intrusive, recurrent
recollections, flashbacks, and nightmares. People with PTSD suffer significant impairment in their daily functioning, including
occupational activities and social relations, and are at elevated risk for impulsive violent behaviors toward others and themselves,
including suicide. Of those who experience a significant trauma, approximately 20% of women and 8% of men develop PTSD. An estimated
12 million adults annually in the U.S. suffer from PTSD. According to the U.S. Department of Veterans Affairs, the prevalence
rate of PTSD in the military population is higher than that among civilians. As of 2012, there were approximately 638,000 veterans
receiving treatment for PTSD in the Veterans Health Administration, or VHA. Based on March 2015 VHA data, more than 19% of military
veterans involved in recent conflicts in Iraq and Afghanistan were seen at VHA facilities for potential or provisional PTSD.
Many
patients fail to adequately respond to the medications approved for PTSD and approved medications show little evidence of a treatment
effect in men, lack evidence of efficacy in those for whom the traumatic event was combat-related, and carry suicidality warnings.
Sleep disturbances are central features of PTSD and are predictive of disease severity, depression, substance abuse, and suicidal
ideation, yet are resistant to the approved medications and present a difficult therapeutic challenge. Current PTSD treatments
include off-label use of anxiolytics, sedative-hypnotics, and antipsychotics, many of which lack reliable evidence of efficacy,
and several have significant safety liabilities and dependence risk.
Migraine
Headaches
Migraine
is a primary headache disorder characterized by recurrent headaches that are moderate to severe. Typically, episodes affect one
side of the head, are pulsating in nature, and last from a few hours to three days. Associated symptoms may include nausea, vomiting,
and sensitivity to light, sound, or smell. The pain is generally made worse by physical activity, although regular exercise may
have prophylactic effects. Up to one-third of people affected have aura, typically a short period of visual disturbance that signals
that the headache will soon occur. Occasionally, aura can occur with little or no headache following it. Approximately one billion
individuals worldwide suffer from migraine (~14% of the population). Migraine is the second leading cause of years lived with
disability. Chronic migraine (≥ 15 headache/migraine days per month) affects about 1-2% of individuals (~75-150 million individuals
worldwide; 3-7 million in the U.S.). CGRP antibodies are the only migraine specific prophylaxis drugs approved in decades, but
they require parenteral administration and there are long term safety concerns with prolonged systemic blockade of CGRP receptor.
Prader-Willi Syndrome
Prader-Willi syndrome (PWS) is
recognized as the most common genetic cause of life-threatening childhood obesity and affects males and females with equal frequency and
all races and ethnicities. The hallmarks of PWS are lack of suckling in infants and, in children and adults, severe hyperphagia, an overriding
physiological drive to eat, leading to severe obesity and other complications associated with significant mortality. PWS is an orphan
disease that occurs in approximately one in 15,000 births. There is currently no approved treatment for the obesity and hyperphagia in
adults and older children associated with PWS.
Major Depressive Disorder
According to the National Institute
of Mental Health, depression affects approximately 17 million adults in the U.S., with approximately 2.5 million adults treated with adjunctive
therapy. Depression is a condition characterized by symptoms such as a depressed mood or loss of interest or pleasure in daily activities
most of the time for two weeks or more, accompanied by appetite changes, sleep disturbances, motor restlessness or retardation, loss of
energy, feelings of worthlessness or excessive guilt, poor concentration, and suicidal thoughts and behaviors. These symptoms cause clinically
significant distress or impairment in social, occupational, or other important areas of functioning. The majority of people who suffer
from depression do not respond adequately to initial antidepressant therapy.
9
Infectious Diseases
COVID-19
SARS-CoV-2 is a contagious virus
causing the disease COVID-19 that became a global pandemic in 2019 and has resulted in more than three million deaths. While the infection
and mortality rates have slowed in regions of the world with high vaccination rates, the struggle with the pathogen is ongoing and evolving
since SARS-CoV-2 is mutating into new variants. COVID-19 is characterized by fever, sore throat, acute shortness of breath, cough, and
oxygen desaturation in the blood. At least three major variants have swept across the world in successive waves and overwhelmed healthcare
systems during these waves. With new variants of the virus emerging, therapeutic research is addressing the challenge of keeping up with
this rapidly mutating virus. The early vaccines have been effective in limiting the severity of disease in vaccinated individuals. Vaccines
that elicit strong T cell responses are believed to have the potential to provide long-term or durable protection.
Smallpox and Monkeypox
Smallpox is an acute contagious
disease caused by the variola virus, or VARV, which is a member of the orthopoxvirus family. Smallpox was declared eradicated in 1980
following a global immunization campaign. Smallpox is transmitted from person to person by infective droplets during close contact with
infected symptomatic people. Monkeypox is an acute contagious disease caused by the monkeypox virus or MPXV, which is also a member of
the orthopoxvirus family. Monkeypox symptoms are similar to those of smallpox, although less severe. Monkeypox is emerging as an important
zoonotic infection in humans in Central and West Africa. Some cases of monkeypox have been reported outside of Africa in patients who
had been infected while in Africa.
Smallpox was eradicated by a World
Health Organization program that vaccinated individuals with live replicating vaccinia vaccines wherever smallpox appeared. In the 1970s,
vaccination of civilians to protect against smallpox was discontinued in the U.S.; however, smallpox remains a material threat to national
security and a proportion of military personnel, including members of the Global Response Force continue to be vaccinated. We are developing
TNX-801 as a potential smallpox-preventing vaccine for the U.S. strategic national stockpile and for potential widespread immunization
in the event of malicious reintroduction of VARV.
Lead Product Candidates
We believe that our product candidates
offer innovative therapeutic approaches and may provide significant advantages relative to available therapies. We have worldwide commercialization
rights to all of our product candidates listed below. The following table summarizes our product candidates:
Product Candidate Indication Stage of Development
TNX-1500 Organ transplant rejection Pre-IND; Phase 1 Start Expected 2H22
TNX-1300 Cocaine Intoxication Phase 2 Ready
TNX-102 SL Fibromyalgia Mid-Phase 3
TNX-102 SL Posttraumatic stress disorder Phase 2 ready
TNX-102 SL Long COVID Pre-IND; Phase 2 Start Expected 1H22
TNX-1900 Binge eating disorder Non-IND; Phase 2 Start Expected 2H22
TNX-1900 Migraine Pre-IND; Phase 2 Start Expected 2H22
TNX-601 CR Depression Pre-IND; Phase 2 Start Expected 1Q23
TNX-801 Smallpox and monkeypox vaccine Preclinical
TNX-2100 COVID-19 Skin test Phase 1 ongoing
10
TNX-1500
TNX-1500 is a humanized mAb directed
against CD40-ligand, or CD40L, engineered to modulate binding to Fc receptors, that is being developed to prevent and treat organ transplant
rejection as well as to treat autoimmune conditions. TNX-1500 incorporates the antigen binding fragment (Fab) region of hu5c8, which has
been extensively characterized including at the atomic level in complex with CD40-ligand.
In experiments at the Massachusetts
General Hospital, a teaching hospital of Harvard Medical School, TNX-1500 is being studied as monotherapy or in combination with immunosuppressive
drugs in heart and kidney organ transplants in non-human primates. Preliminary results from an ongoing experiment in heart transplants
indicates that TNX-1500 appears to have comparable efficacy to historical experiments using the chimeric mouse/primate version of the
anti-CD40L mAb 5c8. In the non-human primate studies with TNX-1500 no evidence of thrombosis has been observed so far.
CD40-ligand
is a protein expressed on the surface of activated T lymphocytes that mediates T cell helper function. CD40-ligand is also known as CD154,
the T cell-B cell activating molecule (T-BAM), TRAP and gp39. CD154 is a member of the Tumor Necrosis Factor (TNF) Super Family. No mAb
against CD154 has been approved for commercial use anywhere in the world. Other TNF Super Family members have been successfully targeted
by antagonist mAbs. Approved mAbs against TNFα include: infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol
(Cimzia®), and golimumab (Simponi®) for the treatment of certain autoimmune conditions. Also, etanercept (Enbrel®) is a TNFα
antagonist receptor fusion protein. An approved mAb against RANKL (CD254) is denosumab (Prolia® or Xgeva®) for the treatment of
osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone.
In January 2021, the World Intellectual
Property Organization has published a patent application filed under the Patent Cooperation Treaty covering TNX-1500, a humanized mAb
directed against CD40-ligand, which is also known as CD154, T-BAM, 5c8 antigen, TRAP and gp39. The patent application is titled “Anti-CD154
Antibodies and Uses Thereof” and published under International Publication No. WO 2021/001458 A1. The application entered national phase in December 2021. The patent applications
include claims related to proprietary anti-human CD40-ligand mAbs that were engineered to have modified effector function, including TNX-1500,
which have reduced potential for Fc binding to FcγRII. The patent applications also claim uses of TNX-1500 for preventing and treating
conditions, such as organ transplant rejection and autoimmune disorders. If claims are granted, a patent
issuing from a national stage of this application could potentially provide U.S. patent coverage for the TNX-1500 composition of matter
through 2040 excluding possible patent term extensions or patent term adjustments. We also have filed a PCT patent application, PCT/US2022/011404, in January
2022, entitled “Methods of Inducing Immune Tolerance with Modified Anti-CD154 Antibodies.” It claims methods of inducing immune
tolerance in transplant recipients using anti-CD154 antibodies having modified effector functions. We expect to start a Phase 1 study of TNX-1500 in the second
half of 2022.
Remicade® and Simponi® are trademarks of Janssen;
Humira® is a trademark of AbbVie Inc.; Cimzia® is a trademark of UCB S. A.; Enbrel®, Prolia® and Xgeva® are trademarks
of Amgen Inc.
TNX-1300
TNX-1300 (T172R/G173Q double-mutant
cocaine esterase 200 mg, i.v. solution) is being developed for the treatment of cocaine intoxication. TNX-1300 is a recombinant protein
enzyme produced through rDNA technology in a non-disease-producing strain of E. coli bacteria. Cocaine Esterase (CocE) was identified
in bacteria (Rhodococcus) that use cocaine as the sole source of carbon and nitrogen and that grow in soil surrounding coca plants.1
The gene encoding CocE was identified and the protein was extensively characterized.1-4 CocE catalyzes the breakdown of cocaine
into metabolite ecgonine methyl ester and benzoic acid. Wild-type CocE is unstable at body temperature, so targeted mutations were introduced
in the CocE gene and resulted in the T172R/G173Q double-mutant CocE, which is active for approximately 6 hours at body temperature5.
Currently there is no specific
pharmacotherapy indicated for cocaine intoxication, a state characterized by acute agitation, hyperthermia, tachycardia, arrhythmias,
and hypertension, with the potential life-threatening sequalae of myocardial infarction, cerebrovascular accident, rhabdomyolysis, respiratory
failure, and seizures. Patients are currently managed only by supportive care for the adverse effects of cocaine overdose on the cardiovascular
and central nervous systems. By targeting the cause of cocaine intoxication, rather than the symptoms like other medicines in emergency
usage, we believe TNX-1300 may offer significant advantages to the current standard of care for cocaine overdose. TNX-1300 was developed
by Columbia University, University of Kentucky and University of Michigan, and in-licensed by Tonix from Columbia University in 2019.
TNX-1300 is designated as a breakthrough therapy by the FDA.
In a Phase 2 randomized, double-blind,
placebo-controlled clinical study, TNX-1300 at 100 mg or 200 mg i.v. doses was well tolerated and interrupted cocaine effects after cocaine
50 mg i.v. challenge.6 Tonix expects to initiate a Phase 2 open-label, safety study of TNX-1300 to take place in emergency
departments in the U.S. in the first half of 2022.
As
a biologic and new molecular entity, TNX-1300 is eligible for 12 years of U.S. market exclusivity upon approval by the FDA, in addition
to expected patent protection through 2029. Since in-licensing, Tonix has requalified existing inventory, developed a lyophilized drug
product to facilitate enhanced stability and handling conditions applicable for an ER treatment, updated the process and analytical methods
to current standards and are in the process of manufacturing Phase 2/3 drug product clinical supply.
1 Bresler MM, Rosser SJ, Basran A, Bruce
NC. Gene cloning and nucleotide sequencing and properties of a cocaine esterase from Rhodococcus sp. strain MB1. Appl Environ Microbiol.
2000. 66(3):904-8.
2 Larsen NA, Turner JM, Stevens J, Rosser
SJ, Basran A, Lerner RA, Bruce NC, Wilson IA. Crystal structure of a bacterial cocaine esterase. Nat Struct Biol. 2002. 9(1):17-21.
3 Turner JM, Larsen NA, Basran A, Barbas
CF 3rd, Bruce NC, Wilson IA, Lerner RA. Biochemical characterization and structural analysis of a highly proficient cocaine esterase.
Biochemistry. 2002. 41(41):12297-307.
4 Gao D, Narasimhan DL, Macdonald J, Brim
R, Ko MC, Landry DW, Woods JH, Sunahara RK, Zhan CG. Thermostable variants of cocaine esterase for long-time protection against cocaine
toxicity. Mol Pharmacol. 2009. 75(2):318-23.
5 Overdose Death Rates - National Institute
on Drug Abuse - https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates; accessed May 11, 2019
6 Nasser AF, Fudala PJ, Zheng B, Liu Y,
Heidbreder C. A randomized, double-blind, placebo-controlled trial of RBP-8000 in cocaine abusers: pharmacokinetic profile of rbp-8000
and cocaine and effects of RBP-8000 on cocaine-induced physiological effects. J Addict Dis. 2014;33(4):289-302.
11
TNX-102
SL
Overview
TNX-102
SL, in clinical development for registration in five indications. TNX-102 SL is a proprietary sublingual tablet formulation of
CBP that efficiently delivers CBP across the oral mucosal membrane into the systemic circulation. We are developing TNX-102 SL
as a bedtime treatment for FM, PTSD, PASC or Long Covid and AAD and AUD. We own all rights to TNX-102 SL in all geographies, and
we bear no obligations to third-parties for any future development or commercialization. Excipients used in TNX-102 SL are approved
for pharmaceutical use. Some of the excipients were specially selected to promote a local oral environment that facilitates mucosal
absorption of cyclobenzaprine or CBP.
The
current TNX-102 SL sublingual tablets contain 2.8 mg of CBP. For the treatment of FM, TNX-102 SL 5.6 mg (two 2.8 mg tablets) at
bedtime is in Phase 3 development. We selected this dose with the goal of providing a balance of efficacy, safety, and tolerability
that would be acceptable as a first-line therapy and for long-term use, and in-patient populations characterized by burdensome
symptoms and sensitivity to medications.
The
active ingredient in TNX-102 SL, is CBP, a serotonin-2A and alpha-1 adrenergic receptor antagonist as well as an inhibitor of
serotonin and norepinephrine reuptake. In addition, TNX-102 SL acts upon other receptors in the central nervous system including
muscarinic M1 and histaminergic H1 receptors.
CBP
is the active ingredient of two products that are approved in the U.S. for the treatment of muscle spasm: Flexeril® (5
mg and 10 mg oral immediate-release, or IR, tablet) and Amrix® (15 mg and 30 mg oral extended-release capsule).
The Flexeril brand of CBP IR tablet has been discontinued since May 2013. There are numerous generic versions of CBP IR tablets
on the market. CBP-containing products are approved for short term use (two to three weeks) only as an adjunct to rest and physical
therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. CBP IR tablets are recommended for
three times per day dosing, which results in relatively stable blood levels of CBP after several days of treatment. Extended-release
CBP capsules taken once a day mimic, and flatten, the pharmacokinetic profile of three times per day CBP IR tablets.
We
designed TNX-102 SL to be administered once-daily at bedtime and with the intention for long-term use. We believe the selected
dose of TNX-102 SL and its unique pharmacokinetic profile will enable it to achieve a desirable balance of efficacy, safety, and
tolerability. Our Phase 1 comparative trials showed that, on a dose-adjusted basis, TNX-102 SL results in faster systemic absorption
and significantly higher plasma levels of CBP in the first hour following sublingual administration relative to oral IR CBP tablets.
It also showed that the sublingual route of administration, which largely bypasses the “first pass” hepatic metabolism
that swallowed medications undergo, results in a higher plasma ratio of CBP to its main active metabolite, norcyclobenzaprine.
In clinical studies, TNX-102 SL 2.8 mg and TNX-102 SL 5.6 mg were generally well-tolerated, with no drug-related serious and unexpected
adverse reactions reported in these studies. Some subjects experienced transient numbness of the tongue after TNX-102 SL administration.
We
have successfully completed the pivotal exposure bridging study with TNX-102 SL compared to Amrix. Results from this study
support the approval of TNX-102 SL under Section 505(b)(2) of the Federal Food, Drug and Cosmetic Act, or FDCA, with Amrix as
the reference listed drug, or RLD. In general, the development timeline for a 505(b)(2) NDA is shorter and less expensive than
an NDA developed under Section 505(b)(1), which is for new chemical entities, or NCEs, that have never been approved in the U.S.
We believe that TNX-102 SL has the potential to provide clinical benefit to FM, PTSD and Long COVID patients and possibly other
CNS (central nervous system) indications that are underserved by currently marketed products or have no approved treatment.
TNX-102
SL – FM program
We
are developing TNX-102 SL as a bedtime treatment for FM under an active IND application. The potential approval of TNX-102 SL
for FM is expected to be under Section 505(b)(2) of the FDCA.
12
Clinical
Development Plan
Phase
3 RALLY Study (F306)
The
Phase 3 RALLY study is clinically complete. We enrolled the first patient in September 2020. The RALLY study is a double-blind,
randomized, placebo-controlled adaptive design trial designed to evaluate the efficacy and safety of TNX-102 SL in FM. The trial
was expected to enroll approximately 670 patients across approximately 40 U.S. sites. For the first two weeks of treatment, there
was a run-in period in which patients started on TNX-102 SL 2.8 mg (1 tablet) or placebo. After the first two weeks, all patients
had the dose increased to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets for 12 weeks. The primary endpoint was
daily diary pain severity score change from baseline to Week 14 (using the weekly averages of the daily numerical rating scale
scores), analyzed by mixed model repeated measures with multiple imputation.
The
RALLY study had one pre-specified unblinded interim analysis by an Independent Data Monitoring Committee, or IDMC, to be conducted
when the study has results from approximately the first 50% of efficacy-evaluable patients. In July 2021, we reported interim
analysis and, based on the recommendation from the IDMC that the RALLY trial was unlikely to demonstrate a statistically significant
improvement in the primary endpoint, we stopped enrollment of new participants but allowed those participants who were already
enrolled to complete the study. We expect to report topline data from the completed study in the first quarter of 2022. We expect
to analyze the RALLY results to improve the design of subsequent Phase 3 studies. In addition, we plan to employ pharmacogenomic
techniques to compare the RALLY and RELIEF study populations, which may provide a path to precision medicine-based companion diagnostics
for TNX-102 SL in FM.
Tonix
intends to initiate a new Phase 3 study in FM, F307, in the first half of 2022. Following analysis of F306 results, including
pharmacogenomic comparison of RELIEF and RALLY, Tonix may modify the protocol for this next Phase 3 study.
Completed
Phase 3 RELIEF Study (F304)
In
the fourth quarter of 2020, we announced the results of a randomized, double-blind, placebo-controlled, 12-week Phase 3 study
of TNX-102 SL in 503 participants with FM, which we refer to as the RELIEF study. The primary objective of this study was to evaluate
the potential clinical benefit of using TNX-102 SL to treat FM at a dose of 5.6 mg, administered sublingually once daily at bedtime
for 12 weeks. The primary endpoint of the RELIEF trial was the daily diary pain severity score change from baseline to Week 14
(using the weekly averages of the daily numerical rating scale scores), analyzed by mixed model repeated measures with multiple
imputation. The RELIEF study achieved statistical significance on the primary efficacy endpoint: change from baseline in the weekly
average of daily diary pain severity numerical rating scale (NRS) scores for TNX-102 SL 5.6 mg (LS mean [SE]: -1.9 [0.12] units)
versus placebo (-1.5 [0.12] units), analyzed by mixed model repeated measures with multiple imputation (LS mean [SE] difference:
-0.4 [0.16] units, p=0.010). The statistically significant improvement in pain is further substantiated when diary pain was analyzed
by another standard statistical approach, a 30 percent responder analysis, with 46.8% on active and 34.9% on placebo having a
30 percent or greater reduction in pain (logistic regression; odds ratio [95% CI]: 1.67 [1.16, 2.40]; p=0.006). Consistent with
the proposed mechanism that TNX-102 SL acts in fibromyalgia through improving sleep quality, TNX-102 SL showed nominal improvement
of sleep by several measures. For daily diary sleep quality ratings, TNX-102 SL (-2.0 [0.12] units) compared to placebo (-1.5
[0.12] units) was nominally significant (LS mean difference: -0.6 [0.17] units; p<0.001). For the PROMIS Sleep Disturbance
instrument, TNX-102 SL was also nominally significant over placebo on T-scores (LS mean difference: -2.9 [0.82] units; p<0.001).
The effect sizes on the diary sleep ratings and PROMIS Sleep Disturbance instrument were 0.31 and 0.32, respectively.
In
the RELIEF study, TNX-102 SL was similarly well tolerated as in the Phase 2 BESTFIT and Phase 3 AFFIRM studies, which both studied
TNX-102 SL at a lower dose of 2.8 mg daily. There were no new safety signals observed in the RELIEF study at the 5.6 mg daily
dose. Among participants randomized to the TNX-102 SL and placebo arms, 82.3% and 83.5%, respectively, completed the 14-week dosing
period. As expected based on prior TNX-102 SL studies, administration site reactions are the most commonly reported adverse events
and were higher in the TNX-102 SL treatment group, including rates of oral numbness (17.3% vs. 0.8%), oral pain/discomfort (11.7%
v. 2.0%), taste impairment (6.5% vs. 0.4%), and oral tingling (5.6% v. 0.4%). Oral numbness or tingling and taste impairment were
local administration site effects nearly always temporally related to dose administration and transiently expressed (<60 minutes)
in almost all occurrences. The only systemic treatment-emergent adverse events that occurred at a rate of 5.0% or greater in either
arm was somnolence/sedation at 5.6 percent in the TNX-102 SL arm vs. 1.2% in placebo, which was consistent with known side effects
of marketed oral cyclobenzaprine. Adverse events resulted in premature study discontinuation in 8.9% of those who received TNX-102
SL compared with 3.9% of placebo recipients. There were a total of seven serious adverse events reported during the study, none
of which were deemed related to investigational product; five in placebo arm, and two in TNX-102 SL arm. Of the two in the TNX-102
SL arm, one was a motor vehicle accident with multiple bone fractures, and the other was a pneumonia secondary to an infection.
Completed
Phase 3 AFFIRM Study (F301)
In
the third quarter of 2016, we announced the results of a randomized, double-blind, placebo-controlled, 12-week Phase 3 study of
TNX-102 SL in 519 participants with FM, which we refer to as the AFFIRM study. The primary objective of this study was to evaluate
the potential clinical benefit of using TNX-102 SL to treat FM at a dose of 2.8 mg, administered sublingually once daily at bedtime
for 12 weeks. The primary endpoint of the AFFIRM trial was the 30% pain responder analysis in which a responder is defined as
a subject for whom pain intensity was reduced by at least 30% at Week 12 as compared to baseline. AFFIRM did not achieve statistical
significance at the primary endpoint (p=0.095). Yet, statistical significance was achieved when pain was analyzed instead
as a continuous variable, either by MMRM (p<0.001) or by MMRM with multiple imputation for missing data (p=0.005), a generally
accepted approach to pain data. TNX-102 SL also showed statistically significant improvements in the declared secondary analyses
of the Patient Global Impression of Change, or PGIC (p=0.038) and the Fibromyalgia Impact Questionnaire-Revised, or FIQ-R (p<0.001).
The study also showed statistically significant improvement with TNX-102 SL on measures of sleep quality, including the Patient-Reported
Outcomes Measurement Information System, or PROMIS, Sleep Disturbance instrument (p<0.001).
13
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