Tonix Pharmaceuticals Announces IND Clearance for TNX-601 ER as a Potential Treatment for Major Depressive Disorder TNX-601 ER, Tianeptine Hemioxalate, is an Extended-Release Tablet for Once-a-Day Dosing Phase 2 Clinical

Tonix Pharmaceuticals Holding Corp. 8-K

Tonix Pharmaceuticals Announces IND Clearance for

TNX-601 ER as a Potential Treatment for Major Depressive Disorder

TNX-601 ER, Tianeptine Hemioxalate, is an Extended-Release

Tablet for Once-a-Day Dosing

Phase 2 Clinical Trial of TNX-601 ER Expected to

Start First Quarter 2023

CHATHAM, N.J., October 3, 2022 - Tonix Pharmaceuticals Holding Corp.

(Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company, today announced the U.S. Food and Drug Administration

(FDA) has cleared the Investigational New Drug (IND) application to support a Phase 2 clinical trial with TNX-601 ER (tianeptine hemioxalate

extended-release tablets), a once-daily formulation of tianeptine as a potential treatment for major depressive disorder (MDD)1.

Tianeptine is a new molecular entity in the U.S. that is being developed under the 505(b)(1) pathway. Tianeptine sodium (amorphous) immediate

release (IR) tablets have been available in Europe and many countries in Asia and Latin America for the treatment of depression over more

than three decades since it was first marketed in France in 1989. Tianeptine's activity is mechanistically distinct from traditional monoaminergic

treatments for depression available in the U.S. including the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine

reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs).

"This is an important milestone as we advance TNX-601 ER into clinical

development," said Seth Lederman, M.D., Chief Executive Officer of Tonix Pharmaceuticals. "TNX-601 ER is a novel, oral, extended-release

once-daily tablet. Studies from across the globe conducted over more than 30 years show that immediate-release (IR) tianeptine sodium

formulations have comparable efficacy to SSRIs and TCAs, fewer drug-drug interactions, and are associated with a lower incidence of sexual

dysfunction compared with SSRIs, SNRIs and TCAs. We expect that our new once-daily formulation will maintain these properties while also

providing convenience and adherence advantages over the three-times-a-day dosing of these IR tianeptine sodium products. We expect to

initiate the Phase 2 trial in MDD in the first quarter of 2023, with the potential for additional future indications in posttraumatic

stress disorder and neurocognitive dysfunction from corticosteroids."

TNX-601 ER is being developed as a monotherapy

and first-line treatment for MDD. No tianeptine-containing product has been approved by the FDA. The proposed mechanism of action of TNX-601

ER is distinct from traditional monoaminergic antidepressants, in that its principal mechanism in MDD is believed to be through indirect

modulation of glutamatergic neurotransmission. It is notable that in multiple placebo-controlled and comparative studies that tianeptine

demonstrates efficacy on par with both SSRIs and tricyclic antidepressants, while showing a more favorable tolerability profile, lacking

the sedative, autonomic, cardiovascular and side effects on memory and attention of TCAs and a low incidence of sexual side effects, nausea,

and sleep disruption as compared with SSRIs.2,3

In addition to its glutamatergic properties, tianeptine

has weak -opioid receptor agonist properties and has been linked to illicit misuse at much higher doses than those reported to

be effective in the treatment of MDD4. Previously, Tonix was developing a naloxone-containing tablet, TNX-601 CR (tianeptine

oxalate and naloxone controlled-release) for MDD, that was designed to mitigate the risk of parenteral abuse. TNX-601 ER is also designed

with abuse deterrent properties but without the -opioid receptor antagonist naloxone. The abuse-deterrent properties include gel

forming polymers which impede extraction for illicit misuse. In addition, the tablet's hardness makes it difficult to crush, cut

or grind to fine particle size, which hinders efforts to misuse by nasal insufflation or intravenous route.

1TNX-601 ER is an investigational new drug and is not approved for any

2McEwen, B.S., et al. Neurobiological

properties of the antidepressant tianeptine. Molecular Psychiatry 2010, 15, 237-249.

T.J., et al. Sleep and antidepressant medication. WPA Bulletin on Depression 2007, 11 (33), 7-11.

4Lauhan, R., et al. Tianeptine

abuse and dependence: case report and literature review. Psychosomatics 2018, 59 (6), 547-553.

About the Phase 2 Study

Tonix is proposing to conduct a registration-quality, potentially pivotal,

Phase 2, 6-week, randomized, double-blind, placebo-controlled, parallel-group study, to evaluate the efficacy, safety, and tolerability

of TNX-601 ER monotherapy in male and female subjects aged 18 to 65 years (inclusive), with current MDD as defined by DSM-5 criteria at

screening and a Montgomery- sberg Depression Rating Scale (MADRS) total score 25 at baseline. A total of 300 participants are

planned to be randomized to two treatment arms across approximately 30 clinical trial sites in the U.S. The study is expected to have

a single unblinded interim analysis for sample size re-estimation when the study has results of the first 50% of efficacy evaluable patients,

pending agreement on the comprehensive statistical analysis plan with the FDA.

According to the National

Institute of Mental Health, an estimated 21 million adults in the U.S. in 2020 experienced at least one major depressive episode1,

with highest prevalence among individuals aged 18-25 at a rate of 17.0%. For approximately 2.5 million adults in the U.S., adjunctive

therapies are necessary for depression treatment.2,3 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

1Data Courtesy of SAMHSA

on Past Year Prevalence of Major Depressive Episode Among U.S. Adults (2020). Retrieved from http://www.nimh.nih.gov/health/statistics/major-depression.shtml

2IMS NSP, NPA, NDTI MAT-24-month data through Aug 2017.

3Kubitz N, et al. (2013) PLOS One,.

8(10):e76882. doi: 10.1371/journal.pone.0076882. PMID: 24204694.

4Rush AJ, et al. (2007) Am J. Psychiatry 163:11, pp. 1905-1917 (STAR*D Study).

TNX-601 ER is a novel oral formulation of tianeptine hemioxalate designed

for once-daily daytime dosing that is now in the IND (Investigational New Drug) stage of development for the treatment of MDD. Tianeptine

sodium (amorphous) immediate release (dosed three times daily) was first marketed for depression in France in 1989 and has been available

for decades in Europe, Russia, Asia, and Latin America for the treatment of depression. Tianeptine sodium has an established safety profile

from decades of use in these jurisdictions. Currently there is no tianeptine-containing product approved in the U.S. and no extended-release

tianeptine product approved in any jurisdiction. Tonix discovered a novel hemioxalate salt of tianeptine that may provide improved stability,

consistency, and manufacturability compared to known salt forms of tianeptine. Tianeptine is believed to work in depression as an indirect

modulator of the glutamatergic system, without direct binding NMDA, AMPA or kainate receptors. Tianeptine reverses stress induced increases

in AMPA receptor trafficking, restoring hippocampal long-term potentiation and reversing the neuroplastic changes from stress and corticosteroid

exposure. Tianeptine and its MC5 metabolite are also weak -opioid receptor agonists, that present a potential abuse liability if

illicitly misused in large quantities (8-80 times the therapeutic dose for depression). In patients who were prescribed tianeptine for

depression, the French Transparency Committee found an incidence of misuse of approximately 1 case per 1,000 patients treated1 suggesting

low abuse liability when used at the antidepressant dose in patients prescribed tianeptine for depression. Clinical trials have shown

that cessation of a therapeutic course of tianeptine did not appear to result in dependence or withdrawal symptoms following 6-weeks2,3,4-6,

3-months7, or 12-months8 of treatment. 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 also be used to treat

posttraumatic stress disorder. TNX-601 ER is expected to have patent protection through 2037.

1Haute Authorite de Sante;

Transparency Committee Opinion. Stablon 12.5 Mg, Coated Tablet, Re- Assessment of Actual Benefit at the Request of the Transparency Committee.

2Emsley, R., et al. J. Clin. Psychiatry 2018, 79 (4)

3Bonierbale M, et al. Curr Med Res Opin 2003, 19(2):114-124.4Guelfi, J. D.,

et al. Neuropsychobiology 1989, 22 (1), 41-48.

5Invernizzi, G. et al., Neuropsychobiology 1994, 30 (2-3), 85-93.

6Lepine, J. P., et al. Hum. Psychopharmacol. 2001, 16 (3), 219-227.

7Guelfi, J. D. et al., Neuropsychobiology 1992, 25 (3), 140-148.

8L o, H. et al., Br. J. Psychiatry. Suppl. 1992, No. 15, 61-65.

Tonix Pharmaceuticals Holding Corp .*

Tonix is a clinical-stage

biopharmaceutical company focused on discovering, licensing, acquiring and developing therapeutics to treat and prevent human disease

and alleviate suffering. Tonix's portfolio is composed of central nervous system (CNS), rare disease, immunology and infectious

disease product candidates. Tonix's CNS portfolio includes both small molecules and biologics to treat pain, neurologic, psychiatric

and addiction conditions. Tonix's lead CNS candidate, TNX-102 SL (cyclobenzaprine HCl sublingual tablet), is in mid-Phase 3 development

for the management of fibromyalgia with a new Phase 3 study launched in the second quarter of 2022 and interim data expected in the second

quarter of 2023. TNX-102 SL is also being developed to treat Long COVID, a chronic post-acute COVID-19 condition. Tonix initiated a Phase