Tonix Pharmaceuticals Announces the Isolation and Characterization of the (S) -Isomer of Tianeptine, TNX-4300 (Estianeptine), Now Under Development for Psychiatric and Neurodegenerative Diseases TNX-4300 is a Dual PPAR-

TONIX PHARMACEUTICALS HOLDING CORP. 8-K

Tonix Pharmaceuticals

Announces the Isolation and Characterization of the (S)-Isomer of Tianeptine, TNX-4300 (Estianeptine), Now Under Development for

Psychiatric and Neurodegenerative Diseases

TNX-4300 is a Dual PPAR- / and PPAR-

Agonist, Free from -Opioid Receptor Activity

TNX-4300's Mechanism of Restoring Neuroplasticity

Supports Development as a First-in-Class Oral Therapy for Depression, Bipolar Disorder, Alzheimer's Disease and Parkinson's

Restoring Atrophied Neuronal Connections in Psychiatric

and Neurological Diseases Seen as Paramount to Achieving Better and More Durable Outcomes

CHATHAM, N.J., May 23, 2023

- Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company, today announced

the isolation and functional characterization of the two mirror image isomers of racemic tianeptine, which is marketed outside the U.S.

as a treatment for major depressive disorder (MDD). Tonix scientists discovered that the (S)-isomer of tianeptine activates PPAR- / ,

restores neuroplasticity in neuronal tissue culture and is free of -opioid receptor activity. In contrast, (R)-tianeptine

activates the -opioid receptor and lacks PPAR- / activity. Based on these discoveries, Tonix has begun preclinical development

of the (S)-isomer, TNX-4300 (estianeptine)*, as a treatment for MDD, bipolar disorder, Alzheimer's disease, and Parkinson's

disease. Tonix is planning to submit data supporting tianeptine's mechanism of action for presentation at upcoming scientific conferences

and for publication in peer reviewed journals.

Tonix recently announced that tianeptine, a drug

marketed outside the U.S. for more than 30 years, is a plastogen1 that acts on nuclear PPAR- / and PPAR- in

neurons and glia to restore neuronal connectivity in depression and has direct applicability in a number of neurodegenerative diseases

in which neuronal connections are atrophying.2 The newly reported mechanism also provided clarity on why tianeptine does not

cause sexual dysfunction, weight gain or several other treatment-limiting toxicities frequently associated with antidepressants.

"The tianeptine marketed outside the U.S. for

treating depression is a 1:1 racemic mixture of two mirror image isomers," said Seth Lederman, M.D., Chief Executive Officer of

Tonix Pharmaceuticals. "The discovery reported today is that the (S)-isomer is responsible for tianeptine's activity

on PPAR- / and restoring neuroplasticity, and the (R)-isomer for its off-target activity on the -opioid receptor.

Our team of scientists isolated and characterized the (S)-isomer, that is now TNX-4300 and under development for psychiatric and

neurological diseases."

Dr. Lederman continued, "Our ongoing work on

racemic tianeptine in depression is expected to inform and potentially accelerate the development of TNX-4300. Although the dose of tianeptine

for treating depression is well-established from racemic studies, the dose range for treating neurological diseases is not yet determined.

Because TNX-4300 lacks the -opioid receptor activity, we believe such effects will not limit the dosing of the (S)-tianeptine

for these other indications."

Gregory Sullivan, M.D., Chief Medical Officer of

Tonix Pharmaceuticals, said, "(S)-tianeptine mimics naturally occurring polyunsaturated fatty acid ligands in binding PPAR- /

and PPAR- . (S)-tianeptine's activation of nuclear PPAR- / and PPAR- receptors appears to be a more

direct mechanism to achieve the goal of restoring neuronal connectivity than current therapies. Its proposed mechanism as a plastogen

is consistent with its clinical effects in promoting cognition in Alzheimer's disease and bipolar disorder2,3 in addition

to posttraumatic stress disorder (PTSD) and corticosteroid-induced cognitive dysfunction. The PPAR- / target is validated

by prior work on agonists treating animal models of neurodegenerative and autoimmune diseases of the central nervous system4

and the concept that Alzheimer's can be considered a form of diabetes that affects the CNS, or type-III diabetes."5

Key experiments were performed by scientists at Tonix's

Research and Development Center (RDC) in Frederick, Maryland.

TNX-4300 is an investigational new drug and is not approved for any indication

press release, May 17, 2023 https://ir.tonixpharma.com/news-events/press-

releases/detail/1389/tonix-pharmaceuticals-announces-pharmacology-and-medicinal

2 Garc a-Alberca JM,

et al. J Alzheimer's Dis 2022, 88 (2), 707-720.

3 Kauer-Sant'Anna M, et al.

J Psychopharmacol 2019, 33 (4), 502-510.

4 Kahremany S et al. Br

J Pharmacol 2015, 172(3):754-70

5 Nguyen et al., Int J

Mol Sci. 2010, 21(9):3165

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. 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 its 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 basis).2 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. 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.

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

Psychiatry 2010, 15 (3), 237-249.

2 Lauhan, R., et al. Psychosomatics 2018, 59 (6),

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 5, 2012.

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

5 Bonierbale M, et al. Curr Med Res Opin 2003, 19(2):114-124.

6 Guelfi, J. D., et al. Neuropsychobiology 1989, 22 (1),

7 Invernizzi, G. et al., Neuropsychobiology 1994, 30 (2-3),

8 Lepine, J. P., et al. Hum. Psychopharmacol. 2001, 16 (3),

9 Guelfi, J. D. et al., Neuropsychobiology 1992, 25 (3),

10 L o, H. et al., Br. J. Psychiatry. Suppl. 1992,

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 topline data expected in the fourth quarter of 2023. TNX-102 SL is also being developed to treat

Long COVID, a chronic post-acute COVID-19 condition. Enrollment in a Phase 2 study has been completed, and topline results are expected

in the third quarter of 2023. TNX-1900 (intranasal potentiated oxytocin), in development for chronic migraine, is currently enrolling

with topline data expected in the fourth quarter of 2023. TNX-601 ER (tianeptine hemioxalate extended-release tablets), a once-daily formulation

being developed as a treatment for major depressive disorder (MDD), is also currently enrolling with interim data expected in the fourth

quarter of 2023. TNX-1300 (cocaine esterase) is a biologic designed to treat cocaine intoxication and has been granted Breakthrough Therapy

designation by the FDA. A Phase 2 study of TNX-1300 is expected to be initiated in the third quarter of 2023. Tonix's rare disease

portfolio includes TNX-2900 (intranasal potentiated oxytocin) for the treatment of Prader-Willi syndrome. TNX-2900 has been granted Orphan

Drug designation by the FDA. Tonix's immunology portfolio includes biologics to address organ transplant rejection, autoimmunity