10-K
1
tnxp-10k_123120.htm
ANNUAL REPORT
UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
WASHINGTON,
D.C. 20549
FORM
10-K
ANNUAL
REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For
the Fiscal Year Ended December 31, 2020
Commission
File Number 001-36019
TONIX
PHARMACEUTICALS HOLDING CORP.
(Exact
name of registrant as specified in its charter)
26 Main Street, Suite 101 Chatham, New Jersey 07928
(Address of principal executive office) (Zip Code)
(862) 904-8182 (Registrant’s telephone number, including area code)
Securities
registered pursuant to Section 12(b) of the Act:
Title of each class Trading Symbol Name of each exchange on which registered
Common Stock, $0.001 par value TNXP The NASDAQ Stock Market LLC
Securities
registered pursuant to Section 12(g) of the Act: None
Indicate
by check mark if the registrant is a well-known seasoned issuer, as defined by Rule 405 of the Securities Act. Yes ☐
No ☒
Indicate
by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes ☐
No ☒
Indicate
by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange
Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports),
and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐
Indicate
by check mark whether the registrant has submitted electronically on its corporate Web site, if any, every Interactive Data File
required to be submitted pursuant to Rule 405 of Regulation S-T (§ 229.405 of this chapter) during the preceding 12 months
(or for such shorter period that the registrant was required to submit such files). Yes ☒ No ☐
Indicate
by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or a smaller
reporting company. See definitions of “large accelerated filer,” “accelerated filer” and “smaller
reporting company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☐
If
an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for
complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒
The
aggregate market value of the voting common equity held by non-affiliates as of June 30, 2020, based on the closing sales price
of the common stock as quoted on The NASDAQ Global Market was $63,913,845. For purposes of this computation, all officers, directors,
and 5 percent beneficial owners of the registrant are deemed to be affiliates. Such determination should not be deemed an admission
that such directors, officers, or 5 percent beneficial owners are, in fact, affiliates of the registrant.
As
of March 15, 2021, there were 323,917,731,
shares of registrant’s common stock outstanding.
DOCUMENTS
INCORPORATED BY REFERENCE
None.
TABLE OF CONTENTS
PAGE
PART I
Item 1. Business 3
Item 1A. Risk Factors 48
Item 1B. Unresolved Staff Comments 81
Item 2. Properties 81
Item 3. Legal Proceedings 82
Item 4. Mine Safety Disclosures 82
PART II
Item 6. Selected Financial Data 83
Item 7A. Quantitative and Qualitative Disclosures about Market Risk 96
Item 8. Financial Statements and Supplementary Data F-1 – F-32
Item 9A. Controls and Procedures 97
Item 9B. Other Information 97
PART III
Item 10. Directors, Executive Officers and Corporate Governance 98
Item 11. Executive Compensation 106
Item 14. Principal Accounting Fees and Services 117
PART IV
Item 15. Exhibits, Financial Statement Schedules 117
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.
*Tonmya has been conditionally accepted
by the U.S. Food and Drug Administration (FDA) as the proposed trade name for TNX-102 SL (cyclobenzaprine HCl sublingual tablets)
for posttraumatic stress disorder, or PTSD. TNX-102 SL is an investigational new drug and has not been approved for any indication.
Business Overview
We are a clinical-stage
biopharmaceutical company focused on discovering, licensing, acquiring and developing small molecules and biologics to treat and
prevent human disease and alleviate suffering. Tonix’s portfolio is primarily composed of central nervous system, or CNS,
and immunology product candidates. The CNS portfolio includes both small molecules and biologics to treat pain, neurologic, psychiatric
and addiction conditions. The immunology portfolio includes vaccines to prevent infectious diseases and biologics to address organ
rejection, cancer, and autoimmune diseases. Our lead programs are TNX-102 SL*, a sublingual tablet for the management of fibromyalgia,
or FM, and TNX-1800**, a live replicating virus vaccine to protect against COVID-19.
Our most advanced CNS product candidate is TNX-102 SL*, a proprietary
sublingual tablet formulation of cyclobenzaprine, or CBP, designed for bedtime administration. TNX-102 SL has active investigational
new drug applications, or INDs, for FM, 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 which is a pain disorder characterized
by chronic widespread pain, non-restorative sleep, fatigue and impaired cognition. We reported positive results from its
Phase 3 RELIEF study in December 2020 and expect interim analysis data from a second Phase 3 study, RALLY, in the third quarter
of 20211, followed by topline data in the fourth quarter of 2021. We completed enrollment of 50% of participants in
the RALLY study in March 2021. 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. As a next step, we intend to meet with
the U.S. Food and Drug Administration, or FDA, to discuss potential new endpoints for the indication of treatment of PTSD and also
to discuss potential endpoints for an indication of PTSD-related Sleep Disturbance. PTSD is a serious psychiatric condition that
develops in response to experiencing a traumatic event. 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. 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.
Other CNS candidates in development include TNX-1900* (intranasal potentiated oxytocin), which is in development
as a candidate for prophylaxis of chronic migraine and for the treatment of craniofacial pain, insulin resistance and related conditions.
TNX-1900 was acquired from Trigemina, Inc. in 2020 and licensed from Stanford University in 2020. We intend to submit an IND to
the FDA in the second quarter of 2021 and initiate a Phase 2 study in migraine in the third quarter of 2021. Tonix also licensed
technology to use TNX-1900 for the treatment of insulin resistance from the University of Geneva. 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 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 later in life.
3
TNX-601 CR* (tianeptine
oxalate and naloxone controlled-release tablets) is another CNS product candidate,
in development as a daytime treatment for major depressive disorder, or depression, as well as for PTSD and neurocognitive dysfunction
associated with corticosteroid use. We completed a Phase 1 trial for formulation development outside of the U.S. and expect to
file an IND for TNX-601 for depression in the U.S. in 2021.
TNX-1300** (double-mutant cocaine esterase) is also in Tonix’s CNS portfolio and is in Phase 2 development
for the treatment of life-threatening cocaine intoxication. TNX-1300 has been granted Breakthrough Therapy designation, or BTD
by the FDA. TNX-1300 was licensed from Columbia University in 2019 after a Phase 2 study showed that it rapidly and efficiently
disintegrates cocaine in the blood of volunteers who had 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 second quarter of 2021.
Our immunology portfolio includes vaccines to prevent infectious diseases and biologics to address organ
rejection, cancer, and autoimmune diseases. Our lead vaccine candidate, TNX-1800**, is a live replicating vaccine based on the
horsepox viral vector platform to protect against COVID-19, primarily by eliciting a T cell immune response. We reported positive
immune response data in non-human primates in the fourth quarter of 2020 and expect to report efficacy data from animal challenge
studies using live SARS-CoV-2 in the first quarter of 2021. TNX-801**, a live horsepox virus vaccine for percutaneous administration,
is in the pre-IND stages of development to protect against smallpox and monkeypox. Both TNX-1800 and TNX-801 are based on the proprietary
horsepox viral vector platform.
TNX-2100** is a skin test we are developing to measure SARS-CoV-2
exposure and T cell immunity. It is an intradermal test to measure delayed-type hypersensitivity (DTH) response to SARS-CoV-2.
We have manufactured GMP peptides designed to stimulate SARS-CoV-2 specific T cells and expect to submit an IND to the FDA in the
second quarter of 2021 and initiate clinical trials in the second half of 2021.
TNX-1500** is monoclonal antibody, or 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 and autoimmune conditions.
Finally, our preclinical pipeline includes TNX-1600*, TNX-1700**, TNX-701* and TNX-2300**. TNX-1600 is
an inhibitor of the reuptake of neurotransmitters serotonin, norepinephrine and dopamine (a triple reuptake inhibitor). TNX-1600
was licensed from Wayne State University in 2019 and is being developed as a daytime treatment for PTSD, depression and attention-deficit/hyperactivity
disorder, or ADHD. TNX-1700 is a recombinant modified form of Trefoil Family Factor 2, or rTFF2, that was licensed from Columbia
University in 2019, and is a biologic being developed to treat gastric and pancreatic cancers. TNX-701 is an undisclosed small
molecule, which is being developed to prevent deleterious effects of radiation exposure which has the potential to be used as a
medical countermeasure to improve biodefense. Tonix is also developing TNX-2300** as a second COVID-19 vaccine under an option
agreement with Kansas State university. TNX-2300 is a live replicating viral vector based on the bovine parainfluenza virus.
1Pending submission and agreement
from FDA on statistical analysis plan.
*TNX-102 SL, TNX-601 CR, TNX-1600, TNX-1900,
TNX-2900 and TNX-701 are investigational new drugs and have not been approved for any indication.
**TNX-1800, TNX-801, TNX-2300, TNX-2100,
TNX-1300, TNX-1500 and TNX-1700 are investigational new biologics and have not been approved for any indication.
4
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 Global 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) 904-8182. Our website addresses are www.tonixpharma.com,
www.tonix.com, and www.krele.com.
TNX-102 SL – Fibromyalgia
TNX-102 SL is a small,
rapidly disintegrating tablet containing CBP for sublingual administration. TNX-102 SL employs a proprietary protective eutectic
formulation of CBP, ProtecticTM, which enables rapid systemic exposure and increased bioavailability through transmucosal
absorption. We are developing TNX-102 SL for the management of FM. TNX-102 SL for FM is a non-opioid, centrally-acting analgesic
that could potentially provide a new therapeutic option for FM patients. In September 2016, we interrupted the development of TNX-102
SL for the management of FM to focus on the treatment of PTSD. Our previous development efforts for TNX-102 SL in FM studied the
2.8 mg dose in a Phase 2 and a Phase 3 study. Based on our experience with higher doses of TNX-102 SL, 5.6 mg, in PTSD, we restarted
the clinical program in FM using TNX-102 SL 5.6 mg. We met with the FDA in March 2019 to discuss the clinical development plan
and the next Phase 3 study design to support the FM indication. We received guidance from the FDA to advance FM using TNX-102 SL
5.6 mg. We reported positive data for the RELIEF Phase 3 trial (F304) in December 2020. We are now in mid-Phase 3 development for
the management of fibromyalgia and are currently conducting a second Phase 3 study, the RALLY (F306) study, which started enrolling
patients in September 2020. Pending agreement with FDA, we plan to conduct an interim analysis, or IA, and we expect interim analysis
results from this study in the third quarter of 2021 and topline data in the fourth quarter of 2021. The program in FM is expected
to qualify for the 505(b)(2) regulatory pathway for FDA approval.
TNX-1800 – Potential COVID-19
Vaccine
TNX-1800 is a potential
vaccine for the novel coronavirus disease, COVID-19, based on a synthetic modified version of live horsepox virus grown in cell
culture. TNX-1800 is engineered to express the spike protein from SARS-CoV-2 virus, which causes COVID-19.
TNX-1800 is based on
our proprietary horsepox vector platform. Horsepox is closely related to vaccinia vaccines, which are a group of orthopoxviruses
that have been used as smallpox vaccines and as experimental vectors for certain other disease-related antigens. Orthopoxviruses,
like vaccinia, can be engineered to express foreign genes and have been explored as platforms for vaccine development because they
possess: (1) large packaging capacity for exogenous DNA inserts, (2) precise virus-specific control of exogenous gene insert expression,
(3) lack of persistence or genomic integration in the host, (4) strong immunogenicity as a vaccine, (5) ability to rapidly generate
vector/insert constructs, (6) potential to be manufactured at industrial scale, and (7) ability to provide direct antigen presentation
and T cell-mediated immune response. Although vaccinia vectors are available, different orthopoxvirus strains may behave differently
as vectors in part because of their different repertoire of genes that modulate immune responses and host range. Potential advantages
of horsepox-based vaccines include the strong immunogenicity we observed for TNX-801 in macaques and mice with good tolerability.
The protein synthesis connected with a replicating live virus vaccine provides direct antigen presentation, which can stimulate
cellular, or T Cell-mediated immunity in addition to humoral, or antibody-mediated, immunity.
In November 2020, we reported positive immune response results in
non-human primates following vaccination using TNX-1800. The research is part of an ongoing collaboration between us, Southern
Research Institute and the University of Alberta. At Day 14 after a single vaccination, all eight of the TNX-1800 vaccinated animals
made anti-SARS-CoV-2 neutralizing antibodies (≥1:40 titer) and, as expected, none of the eight TNX-801 vaccinated control animals,
or any of the four animals in the placebo group, made anti-SARS-CoV-2 neutralizing antibodies (≤1:10 titer). The level of neutralizing
anti-SARS-CoV-2 antibody production was similar between the low and high dose TNX-1800 groups (1 x 106 Plaque Forming Units [PFU]
and 3 x 106 PFU, respectively). TNX-1800 was well tolerated at both doses. In the second phase of the study, the TNX-1800 vaccinated
and control animals were challenged with SARS-CoV-2. Results are expected in the first quarter of 2021.
The further development
of TNX-1800 for human clinical trials will require manufacturing according to Good Manufacturing Practice, or GMP, standards and
sufficient animal testing. Tonix expects to initiate a Phase 1 safety study using TNX-1800 in humans in the second half of 2021.
We have filed a provisional
patent on TNX-1800’s technology. In addition, we expect TNX-1800 to be eligible for 12 years of non-patent-based exclusivity
under the Patient Protection and Affordable Care Act, or PPACA.
5
TNX-801 – Potential Smallpox
and Monkeypox Vaccine
TNX-801 is a novel
potential smallpox-preventing vaccine based on a synthetic version of live horsepox virus, grown in cell culture. Though it shares
structural characteristics with vaccinia-based vaccines, TNX-801 has unique properties that we believe indicate potential safety
advantages over existing live replicating vaccinia virus vaccines, which have been associated with adverse side effects such as
myopericarditis in some individuals. Emergent BioSolutions’ ACAM2000® is the only replicating vaccinia
virus vaccine currently approved by the FDA to protect against smallpox. We believe replicating virus vaccines have potential efficacy
advantages over non-replicating vaccines, relating to the stimulation of cell mediated immunity. Bavarian Nordic’s Jynneos®
is the only non-replicating virus vaccine currently approved by the FDA to protect against smallpox and monkeypox. We believe TNX-801
has the potential to have improved tolerability relative to replicating vaccinia vaccines and the potential to have improved efficacy
relative to non-replicating vaccinia vaccines.
Smallpox was eradicated
by a World Health Organization program that vaccinated individuals with live replicating vaccinia vaccines wherever smallpox appeared.
In the 1970s, vaccination of civilians to protect against smallpox was discontinued in the U.S.; however, smallpox remains a material
threat to national security and a proportion of military personnel, including members of the Global Response Force, continue to
be vaccinated. We are developing TNX-801 as a potential smallpox-preventing vaccine for the U.S. strategic national stockpile and
for potential widespread immunization in the event of malicious reintroduction of variola, the virus that causes smallpox.
Monkeypox
is a growing problem in certain regions of Africa. Some cases of monkeypox have been reported outside of Africa in patients who
had been infected while in Africa.
In January 2020 at
the American Society of Microbiology Biothreats conference, we reported the results of experiments on TNX-801 that were performed
in collaboration with Southern Research, that showed TNX-801 vaccinated macaques were protected against monkeypox challenge. The
TNX-801 vaccinated macaques showed no overt clinical signs after monkeypox challenge. Furthermore, eight of eight animals vaccinated
with two different doses of TNX-801 showed no lesions after monkeypox challenge.
We have filed a patent to protect the TNX-801 vaccine candidate. In addition, we expect that TNX-801 will
be eligible for 12 years of non-patent-based exclusivity under the PPACA. Following the passage of the 21st Century Cures Act,
a law designed to help accelerate medical product development, we believe TNX-801 will qualify as a medical countermeasure and
would therefore be eligible for a Priority Review Voucher upon receiving FDA approval. However, the Priority Review Voucher program
provision of the 21st Century Cures Act is set to expire in 2023. If TNX-801 does not receive FDA approval by 2023, we may not
be able to capitalize on the incentives contained in the 21st Century Cures Act unless the provision allowing for the Priority
Review Voucher Program is extended until such time as TNX-801 is licensed by the FDA.
We intend to meet with
the FDA to discuss the most efficient and appropriate investigational plan, to establish the safety and effectiveness evidence
to support the licensure TNX-801.We are currently working to develop a vaccine that meets cGMP quality to support an IND study.
TNX-102 SL – Posttraumatic
Stress Disorder
We are developing TNX-102
SL for the treatment of PTSD. TNX-102 SL 5.6 mg was studied in the first Phase 3 study for military-related PTSD, HONOR (P301),
which was discontinued after the results of an interim analysis indicated the study met a pre-defined threshold p-value for futility.
Retrospective analysis of this Phase 3 study revealed a treatment effect in participants who experienced trauma less than or equal
to nine years prior to screening. This analysis defined an optimal treatment window for TNX-102 SL in PTSD within nine years after
the index trauma that resulted in PTSD. This retrospective analysis guided the design of the Phase 3 RECOVERY (P302) study, which
was initiated in March 2019. Based on interim analysis results of the first 50% of enrolled participants of the RECOVERY trial,
an Independent Data Monitoring Committee recommended stopping the study for futility as TNX-102 SL was unlikely to demonstrate
a statistically significant improvement over placebo on the primary endpoint after 12 weeks. We stopped enrollment of new participants
but continued to study those participants enrolled until completion. We reported topline data in December 2020, which revealed
that the RECOVERY study did not achieve statistical significance in the prespecified primary efficacy endpoint of change from baseline
to Week 12 in the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) between TNX-102 SL and placebo (p=0.343) (TNX-102 SL separated
from placebo in the first key secondary endpoint, Clinical Global Impression – Severity (CGI-S) scale (p=0.024) and in the
Patient Global Impression of Change (PGIC), (p=0.007). TNX-102 SL also trended for improvement on the PROMIS Sleep Disturbance
scale (p=0.055), consistent with the proposed mechanism of targeting the PTSD sleep disturbance. TNX-102 SL is generally well tolerated,
and no new safety signals were observed. We plan to meet with the FDA to discuss potential new endpoints for the indication of
treatment of PTSD and also to discuss potential endpoints for an indication of PTSD-related Sleep Disturbance. Sleep disturbance
is a core symptom of PTSD and believed to play roles in vulnerability, onset, progression and chronicity. Treating sleep disturbance
is recognized as a clinically valid approach for addressing global improvement in PTSD. We plan to begin enrolling a Phase 3 study
of police in Kenya in 2021. The program in PTSD is expected to qualify for the 505(b)(2) regulatory pathway for FDA approval.
TNX-102 SL – Agitation in Alzheimer’s
Disease (AAD)
We are developing TNX-102
SL for the treatment of AAD, which has been designated as a Fast Track development program by the FDA. The program is ready for
a Phase 2 study which could potentially serve as a pivotal efficacy study to support NDA approval. The program in AAD is expected
to qualify for the 505(b)(2) regulatory pathway for FDA approval.
TNX-102 SL – Alcohol Use Disorder
(AUD)
We are developing
TNX-102 SL for the treatment of alcohol use disorder (AUD). We announced clearance of the IND for AUD in August of 2020. The FDA
cleared the IND for the initiation of a Phase 2 proof-of-concept study. The program in AUD is expected to qualify for the 505(b)(2)
regulatory pathway for FDA approval.
6
TNX-1900 – Migraine and craniofacial pain
We are developing TNX-1900 (intranasal potentiated oxytocin) as
a candidate for prophylaxis of chronic migraine and for the treatment of insulin resistance and related conditions. TNX-1900 was
acquired from Trigemina in 2020 and licensed from Stanford University in 2020. Oxytocin is a naturally occurring human peptide
hormone that acts as a neurotransmitter in the brain. It was originally approved by the FDA as Pitocin®, an intravenous infusion
or intramuscular injection drug, for use in pregnant women to induce labor. An intranasal form of oxytocin was marketed in the
U.S. by Novartis to assist in the production of breast milk as Syntocinon® (oxytocin nasal 40 units/ml), but the product was
withdrawn, and the New Drug Application (NDA) has been discontinued. TNX-1900 is in the pre-Investigational New Drug (IND) stage
and have not been approved for any indication. We intend to submit an IND in the second quarter of 2021 and initiate a Phase 2
study in the third quarter of 2021.
TNX-2900 – Prader-Willi Syndrome
TNX-2900 (intranasal potentiated oxytocin)
is also based on our patented intranasal potentiated oxytocin formulation, like TNX-1900. TNX 2900 is being developed for the
treatment of Prader-Willi syndrome. We licensed technology using oxytocin-based therapeutics for the treatment of Prader-Willi
syndrome and non-organic failure to thrive disease from the French National Institute of Health and Medical Research (Inserm).
The licensing agreement has been negotiated and signed by Inserm Transfert, the private subsidiary of Inserm, on behalf of Inserm
(the French National Institute of Health and Medical Research), Aix-Marseille Université and Centre Hospitalier Universitaire
of Toulouse. Prader-Willi syndrome is recognized as the most common genetic cause of life-threatening childhood obesity and affects
males and females with equal frequency and all races and ethnicities. There is currently no approved treatment for either the
suckling deficit in infants or the obesity and hyperphagia in older children associated with Prader-Willi syndrome. Since Prader-Willi
syndrome is an orphan disease that occurs in approximately one in 15,000 births, we plan at the appropriate time to submit an
application to the FDA for Orphan Drug designation for TNX-2900.
TNX-601 CR – Major Depressive
Disorder, PTSD and Neurocognitive Dysfunction from Corticosteroids
We are developing TNX-601 CR (tianeptine oxalate and naloxone controlled release tablets) for the treatment
of major depressive disorder, or depression, PTSD, and neurocognitive dysfunction from corticosteroid therapies. TNX-601 CR is
a new, controlled release formulation of a novel salt of tianeptine. An immediate release form of tianeptine, with three times
a day dosing, has been marketed outside of the U.S. for the treatment of depression for several decades. Tianeptine is believed
to work in depression as a modulator of the glutamatergic system. Tianeptine and its major metabolite MC5 are also weak agonists
of the mu-opioid receptor. Neither tianeptine nor MC5 have been shown to bind other neurotransmitter receptors. No tianeptine
product is FDA approved in the U.S., but some products containing tianeptine are marketed as nutritional supplements in some states.
Other states have restricted the use of tianeptine as a controlled substance. In animals, tianeptine has been shown to reverse
the adverse neuroplastic changes that are observed during periods of extreme stress and elevated corticosteroid exposure. Tianeptine’s
reported pro-cognitive and anxiolytic effects as well as its ability to attenuate the neuropathological effects of excessive stress
responses suggest that it may be used to treat PTSD by a different mechanism of action than TNX-102 SL. Several preliminary clinical
studies conducted by others have suggested that tianeptine immediate release tablets have activity in combat and military-related
PTSD. We reported the results of a Phase 1 pharmacokinetic study in the fourth quarter of 2019, performed outside of the U.S.,
that was the basis for selecting the TNX-601 CR formulation with controlled release characteristics suitable for once-daily dosing.
TNX-601 CR is formulated with naloxone to prevent illicit parenteral abuse. Tonix is planning to start a Phase 2 study, pending
IND clearance from the FDA, in depression in the fourth quarter of 2021.
TNX-1300 – Cocaine Intoxication
We licensed TNX-1300 from Columbia University in May 2019. We are developing TNX-1300 for the treatment
of cocaine intoxication. TNX-1300 (T172R/G173Q double-mutant cocaine esterase 200 mg) 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 a bacterium (Rhodococcus) that uses cocaine as its sole source of carbon and nitrogen and that grows in soil surrounding
coca plants. The gene encoding CocE was identified and the protein was extensively characterized. CocE catalyzes the breakdown
of cocaine into metabolites 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 shows activity for approximately
6 hours at human body temperature. In a Phase 2 study of volunteer cocaine abusers conducted prior to Tonix licensing the program,
TNX-1300 was well tolerated at 100 mg or 200 mg i.v. doses and rapidly, within a few minutes, interrupted cocaine effects
after cocaine 50 mg i.v. challenge. TNX-1300 has been granted BTD by the FDA for the treatment of cocaine intoxication.
In August 2019, we met with the FDA to seek guidance on the nonclinical study plans to support the clinical development of TNX-1300.
We intend to initiate a Phase 2 open-label safety study in an emergency department (ED) setting in the second quarter of 2021.
7
TNX-2100 – COVID-19 Skin Test
TNX-2100 (SARS-CoV-2 epitope
peptide mixtures for intradermal administration) is designed to measure T cell immunity to SARS-CoV-2 as a diagnostic skin test.
TNX-2100 measures the delayed-type hypersensitivity (DTH) reaction to SARS-CoV-2 (CoV-2), the virus that causes COVID-19. There
currently is no FDA approved laboratory test available to measure T cell immune responses to CoV-2. The research test currently
performed by specialized laboratories is called intracytoplasmic cytokine staining, or ICS, and is not standardized. FDA recently
granted Emergency Use Authorization to T-DetectTM COVID from Adaptive Biotechnologies Corporation, which is based on a novel
technology that identifies rearranged TCRβ sequences from patient genomic DNA and uses a proprietary algorithm to compare
patient sequences to a database of sequences from patients known to have been infected with SARS-CoV-2. From the available information,
it appears T-Detect COVID can assess past infection with SARS-CoV-2 by traces of SARS-CoV-2 specific T cells, but it does not appear
to be a measure of functional T cell immunity. T cell immunity to CoV-2 persists longer than antibody immunity, is sometimes present
in the absence of a measurable antibody response and is believed to provide an important element of protection against serious
COVID-19 illness after infection with CoV-2. Tonix’s proposed skin test has the potential to serve as: 1) a biomarker for
cellular immunity and protective immunity; 2) a method to stratify participants in COVID-19 vaccine trials by immune status; 3)
an endpoint in COVID-19 vaccine trials, and 4) a biomarker of durability of vaccine protection. Discovered in 1882 by Robert Koch,
the DTH reaction has been used for more than a century as a clinical test for T cell-mediated immune reactions. In the 1940s, Landsteiner
and Chase demonstrated that the reaction was mediated by the cellular and not the antibody arm of the immune system. When small
quantities of antigen are injected intradermally, a hallmark response is elicited which includes induration, swelling and monocytic
infiltration into the site of the lesion within 24 to 48 hours. This reaction has been shown to be dependent on the presence of
memory T cells. Both the CD4+ and CD8+ T cells have been shown to participate in this response. DTH skin tests have been commonly
used to detect T cell responses to tuberculosis, fungal pathogens, and mumps virus. Tonix expects to initiate clinical trials in
the second half of 2021, upon receiving IND clearance by the FDA.
TNX-1500 – anti-CD40L mAb
TNX-1500 (monoclonal antibody anti-CD40-L or anti-CD154) is a third-generation monoclonal antibody, or
mAb, currently in preclinical development as a potential first line monotherapy for preventing or treating organ transplant rejection
autoimmunity. Several studies have shown mAbs that react with the same molecular target as TNX-1500 to be active in the treatment
of human systemic lupus erythematosus and in transplant rejection. TNX-1500 is specifically designed to retain the efficacy
of anti-CD40L mAbs while mitigating potential side effects. In August 2019, we announced a research collaboration with the Massachusetts
General Hospital (MGH) in Boston for the testing of TNX-1500 for the prevention of heart transplant rejection. In January 2021,
we announced a second research collaboration with MGH for the testing of TNX-1500 for the prevention of kidney transplant rejection.
We expect to have GMP material available in the third quarter of 2021.
TNX-2300 – Potential COVID-19 Vaccine
We are party to a preclinical research and option agreement with Kansas State University to develop a
vaccine candidate for the prevention of COVID-19 that utilizes a novel live virus vaccine vector platform and the CD40-L, to stimulate
T cell immunity. Under the research agreement, Kansas State will advance preclinical development of a live replicating virus vaccine
to protect against COVID-19 based on bovine parainfluenza virus. Attenuated bovine parainfluenza virus has previously been shown
to be an effective antigen delivery vector in humans. Reports of testing in non-human primates, indicate the attenuated BPI3V was
well tolerated, infectious, and immunogenic. The vector is well suited for mucosal immunization using a nasal atomizer, but it
can also be delivered parenterally. The technology also includes CD40-ligand, as a molecular stimulant to trigger strong immunity
including T cell responses. The vaccine is designed to potentially stimulate immunity against the SARS-CoV-2 spike protein. We
expect data from small animals to measure efficacy in challenge studies using SARS-CoV-2 in the second quarter of 2021.
Other Preclinical Product Candidates
TNX-1600 was licensed from Wayne
State in August 2019 in a transaction that included an asset acquisition agreement with TRImaran, a biopharmaceutical company that
had previously licensed the technology from Wayne State. TNX-1600 is a triple reuptake inhibitor, which inhibits the reuptake
of dopamine, norepinephrine, and serotonin. TNX-1600 is in development to treat PTSD, depression and ADHD and potentially other
central nervous system disorders. TNX-1600 is a new chemical entity and is being developed as first line monotherapy, as an oral
daytime treatment.
● TNX-1700 – Gastric and Pancreatic Cancers
TNX-1700 (rTFF2) was licensed
from Columbia University in September 2019. TNX-1700 is a biologic molecule currently in preclinical development as a treatment
for gastric and pancreatic cancers. TFF2 is a small, secreted protein, encoded by the TFF2 gene in humans, that is expressed in
gastrointestinal mucosa where it functions to protect and repair mucosal tissue. TFF2 is also expressed at low levels in splenic
immune cells and is now appreciated to have intravascular roles in spleen and in the microenvironment of tumors. In gastric cancer,
TFF2 is epigenetically silenced, and TFF2 is suggested to be protective against cancer development through several mechanisms.
The mechanism of action of rTFF2 is different from anti-PD-1 or anti-PD-L1 monoclonal antibodies and Tonix is studying rTFF2 to
determine whether there are additive or synergistic effects of combining rTFF2 with other anti-neoplastic treatments in gastric
and pancreatic cancers.
We own rights to intellectual
property on a biodefense technology relating to the development of protective agents against radiation exposure, which we refer
to as TNX-701. We have begun preclinical research and development on TNX-701. We plan to develop TNX-701 under the Animal Rule,
which is applicable when human efficacy studies are not ethical or feasible.
8
Our Strategy
Our objective is to develop and commercialize
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 clinical-stage product candidates and lead COVID-19 vaccine candidate is set forth below.
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Fibromyalgia
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.
COVID-19
On December 31, 2019
the Wuhan Health Commission reported a cluster of atypical pneumonia cases in the city of Wuhan, China. The first patients began
experiencing symptoms of illness in mid-December 2019. Clinical isolates were found to contain a novel coronavirus. The novel coronavirus
is currently referred to as SARS-CoV-2 and is related to SARS coronavirus (SARS-CoV), although with only approximately 80% similarity
at the nucleotide level. The SARS-CoV-2 virus is reportedly highly contagious.
COVID-19
is a respiratory disease. Symptoms may appear 2-14 days after exposure and include fever, cough and shortness of breath. The World
Health Organization, or WHO, declared COVID-19 a global pandemic.
Coronaviruses are a
large family of viruses that are common in people and many different species of animals, including camels, cattle, cats, and bats.
Rarely, animal coronaviruses can infect people and then spread between people such as with MERS-CoV, SARS-CoV, and now with SARS-CoV-2.
New strains of SARS-CoV-2 have emerged and some appear to have the potential to evade vaccine-induced immunity.
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.
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 variola, which is the virus that causes smallpox.
Monkeypox is a growing problem in certain regions of Africa. Some cases of monkeypox have been reported outside of Africa in patients
who had been infected while in Africa.
Currently, there are
two FDA approved smallpox vaccines, one of which is also indicated for monkeypox. ACAM2000® (Smallpox [Vaccinia]
Vaccine, Live) was approved in 2007 and is indicated for active immunization against smallpox disease in persons determined to
be at high risk for smallpox infection. Jynneos® (Smallpox and Monkeypox Vaccine, Live, Non-replicating) or MVA-BN
is indicated for the prevention of smallpox and monkeypox disease in adults 18 years of age and older determined to be at high
risk for smallpox or monkeypox infection.
These two smallpox
vaccines are FDA approved and purchased by the U.S. Strategic National Stockpile. The U.S. Strategic National Stockpile currently
stores more than 300 million doses of smallpox vaccine to protect the U.S. population in the event of reintroduction of variola.
We believe that the Strategic National Stockpile will continue to be stocked primarily with a live replicating virus vaccine and
secondarily with a non-replicating virus. ACAM2000® is the only replicating vaccinia virus vaccine currently approved
by the FDA to protect against smallpox. Jynneos® is the only non-replicating virus vaccine currently approved by
the FDA to protect against smallpox. In the post-eradication world, the risk of variola infection is low, so non-replicating vaccines
like Jynneos have an appropriate ratio of risk and benefit. However, in a potential post-reintroduction world, we believe live
replicating virus vaccines like TNX-801 would be administered to healthy, immunocompetent, non-pregnant adults without risk factors
such as eczema or heart disease. The assessment of efficacy of modern smallpox vaccines and the expected benefit of vaccination
policy are based on the historical success of predicate live replicating vaccinia vaccines to control smallpox during the time
the disease was endemic. We believe TNX-801 has the potential to have improved safety and tolerability relative to replicating
vaccinia vaccines and the potential to have improved efficacy relative to non-replicating vaccinia vaccines.
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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.
Agitation in Alzheimer’s Disease
Alzheimer’s disease is a chronic neurodegenerative disease in which behavioral symptoms are a major
clinical complication. Sleep disturbances and agitation are common and co-morbid features of Alzheimer’s disease. Agitation,
which includes emotional lability, restlessness, irritability, and aggression, is one of the most distressing and debilitating
of these behavioral complications of Alzheimer’s disease. AAD is likely to affect more than half of the 6.2 million Americans
who currently suffer from Alzheimer’s disease, and this number is expected to nearly double by 2050. The presence of agitation
nearly doubles the cost of caring for patients with Alzheimer’s disease, and agitation is estimated to account for more than
12 percent of the $355 billion in healthcare and societal cost of associated with Alzheimer’s disease for the year 2021 in
the U.S.
Agitation in Alzheimer’s
disease is associated with significant negative consequences for both patients as well as their caregivers. Development of agitation,
or its worsening, is one of the most common reasons for patients having to transition to nursing homes and other long-term care
settings.
Currently, there is
no treatment approved by the FDA for behavioral symptoms such as agitation and aggression in Alzheimer’s which affect the
quality of life of both the patients and caregivers. Off-label use of atypical anti-psychotic medications for behavioral symptoms
in Alzheimer’s disease is a common practice, despite the lack of evidence for their effectiveness and significant morbidity
and mortality risks associated with their use in this population.
Alcohol Use Disorder
An estimated 36 million
adults in the U.S. have AUD. 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. Sleep disturbance is extremely common in alcohol recovery and
it significantly impacts daytime cognition, mood, and ability to participate in alcohol treatment, and, importantly, is associated
with increased risk of relapse. Three drugs have been approved by the FDA, but AUD remains an unmet need due to compliance and
safety issues.
Major Depressive Disorder
According to the National
Institute of Mental Health, depression affects approximately 16 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.
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Cocaine Intoxication
Cocaine is an illegal recreational drug which is 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.
Attention Deficit Hyperactivity Disorder
Previously called hyperkinetic
syndrome, ADHD is defined by a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning
or development. Symptoms of ADHD must have been present prior to 12 years of age and must have been present in two or more settings,
e.g. at home, school, work; with friends or relatives; in other activities. And there must be clear evidence that the symptoms
interfere with, or reduce the quality of, social, academic, or occupational functioning. ADHD is a
chronic condition that begins in childhood and is one of the most common mental disorders among children. While high activity levels
and short attention spans are generally observed in young children, children with ADHD have greater hyperactivity and inattention
relative to children their same age. The consequences of ADHD can cause distress for the individual and result in behavioral problems
in structured environments such as school, as well as in less structured environments which occur in social settings or in the
home. For a majority of these individuals, the diagnosis will carry into adulthood, and symptoms may only partially remit. The
American Psychiatric Association estimates that 8.4 percent of children and 2.5 percent of adults have ADHD.
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
is recognized as the most common genetic cause of life-threatening childhood obesity and affects males and females with equal frequency