Tonix Pharmaceuticals Completes Clinical Stage of Phase 2 UPLIFT Study of TNX-601 ER for the Treatment of Major Depressive Disorder Topline Results Expected Early November 2023 Tianeptine, the Active Ingredient in TNX-60

Tonix Pharmaceuticals Holding Corp - 8-K

Tonix Pharmaceuticals Completes Clinical Stage

of Phase 2 UPLIFT Study of TNX-601 ER for the Treatment of Major Depressive Disorder

Topline Results Expected Early November 2023

Tianeptine, the Active Ingredient in TNX-601

ER, is Not Associated with Sexual Dysfunction or Weight Gain Which are Treatment-Limiting Side Effects of Many Traditional Antidepressants

Tianeptine Acts by Directly Restoring Neuroplasticity

and Neurogenesis and Limiting the Effects of Oxidative Stress in the Brain

CHATHAM, N.J., October 16, 2023 - Tonix

Pharmaceuticals Holding Corp. (Nasdaq: TNXP), a clinical-stage biopharmaceutical company, today announced the completion of the clinical

phase of the Phase 2 potential registration-quality, double-blind, randomized, multicenter, placebo-controlled UPLIFT1 study

of TNX-601 ER2 (tianeptine hemioxalate extended-release tablets) as a potential treatment for major depressive disorder (MDD).

Topline results from the intention-to-treat (ITT) sample (N=132) are expected in early November 2023.

developed as a monotherapy and first-line treatment for MDD and works by a distinct mechanism of action as compared to traditional monoaminergic

antidepressants. Tonix recently reported that tianeptine activates peroxisome proliferator-activated receptors PPAR- / and

PPAR- . These activities on intracellular molecular targets in neurons and glia in the brain are believed to relate to tianeptine's

ability to restore connectivity between neurons that atrophy under conditions of stress, in animal models.3,4 Tianeptine is

the active ingredient of an antidepressant that has been marketed as a three-times-a-day medicine outside the U.S. for more than 30 years.

Tonix has developed a novel, patented once-daily oral formulation.

"Because of its unique mechanism, tianeptine

avoids some of the treatment-limiting side effects of traditional antidepressants, including sexual dysfunction and weight gain,"

said Seth Lederman, M.D., Chief Executive Officer of Tonix Pharmaceuticals. "Tianeptine restores connectivity between neurons, or

neuroplasticity, and limits the effects of oxidative stress in the brain in animal models of depression. In contrast to traditional antidepressants

which alter the levels of neurotransmitters in the synapse, tianeptine directly induces mature neurons to sprout new connections and also

induces formation of new neurons."

"With the last patient now treated, we

look forward to analysis of the results of this registration-quality study, which will help to inform our plans as we discuss next steps

with the U.S. Food and Drug Administration (FDA)," said Gregory Sullivan, M.D., Chief Medical Officer of Tonix Pharmaceuticals.

"We would like to thank the participants, their families, and all the investigators and researchers who have been an important part

of this journey so far."

About the Phase 2 UPLIFT Study

The Phase 2 UPLIFT study, TNX-TI-M201, is a

potential registration-quality, double-blind, randomized, multicenter, placebo-controlled study to evaluate the efficacy and safety of

TNX-601 ER taken by mouth once-daily for 6 weeks for the treatment of moderate-to-severe MDD. It is a parallel design study with two arms,

a TNX-601 ER 39.4 mg arm and a placebo arm. A total of 132 participants were randomized in a 1:1 ratio into the two arms across approximately

27 U.S. sites, enrolling adult patients 18-65 years old with a DSM-5 diagnosis of depression and a duration for the current major depressive

episode of at least 12 weeks. The primary efficacy endpoint is mean change from baseline in the Montgomery- sberg Depression Rating

Scale (MADRS) total score at Week 6. Key secondary efficacy endpoints include the Clinical Global Impression of Severity Scale (CGI-S)

and the Sheehan Disability Scale (SDS).

For more information, see ClinicalTrials.gov

Identifier: NCT05686408.

About Major Depressive Disorder (Depression)

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 therapy.4

1 Data 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

2 IMS NSP, NPA, NDTI MAT-24-month

data through Aug 2017.

3 Kubitz N, et al. PLoS One 2013,

4 Rush AJ, et al. Am J. Psychiatry

2007, 163 (11), 1905-1917.

TNX-601 ER (tianeptine hemioxalate extended-release

tablets) is a novel oral formulation of tianeptine designed for once-daily daytime dosing in development as a candidate for the treatment

of MDD, posttraumatic stress disorder, and neurocognitive dysfunction associated with corticosteroid use. Tianeptine sodium (amorphous)

immediate release (dosed 3 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 no tianeptine-containing product is approved in the U.S. and no extended-release tianeptine product

is approved in any jurisdiction. Tonix discovered a novel oxalate salt of tianeptine that may provide improved stability, consistency,

and manufacturability compared to known salt forms of tianeptine. In animal models, tianeptine restores dendritic arborization of pyramidal

neurons in the CA3 region of hippocampus and in the dentate gyrus region promotes new neuron formation and integration into hippocampal

networks.1 Tianeptine's enhancement of neuroplasticity in animal models of stress is believed to be mediated by activation

of PPAR isoforms PPAR- / and PPAR- , which makes TNX-601 ER's properties distinct from traditional monoaminergic

antidepressants in the U.S. and contributes to its potential for clinical indications beyond MDD and stress disorders. Tianeptine and

its MC5 metabolite are also weak mu-opioid receptor (MOR) agonists that present a potential abuse liability if illicitly misused in large

quantities (typically abused at 8-80 times the therapeutic dose on a daily basis2). 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 treated3

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 does not appear to result in dependence or withdrawal symptoms following

6-weeks4-8, 3-months9, or 12-months10 of treatment. The ER formulation of TNX-601 includes several potentially

abuse deterrent ingredients, such as gel forming polymers which impede extraction. In addition, the tablet's hardness makes it difficult

to crush, cut or grind to fine particle size, which potentially hinders efforts to misuse by insufflation or intravenous routes. 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 (PTSD), and neurocognitive dysfunction associated with corticosteroid

use. TNX-601 ER is expected to have patent protection through 2037.

1 McEwen, B. S., et al. Mol. Psychiatry

2010, 15 (3), 237-249.

2 Lauhan, R., et al. Psychosomatics

2018, 59 (6), 547-53.

3 Haute Authorite de Sante; Transparency

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

4 Emsley, R., et al. J. Clin. Psychiatry

5 Bonierbale M, et al. Curr Med Res

Opin 2003, 19(2):114-124.

6 Guelfi, J. D., et al. Neuropsychobiology

1989, 22 (1), 41-48.

7 Invernizzi, G. et al., Neuropsychobiology

1994, 30 (2-3), 85-93.

8 Lepine, J. P., et al. Hum. Psychopharmacol.

2001, 16 (3), 219-227.

9 Guelfi, J. D. et al., Neuropsychobiology

1992, 25 (3), 140-148.

10 L o, H. et al., Br. J. Psychiatry.

Suppl. 1992, 15, 61-65.

Tonix Pharmaceuticals Holding Corp.*