Tonix Pharmaceuticals Initiates Enrollment in Phase 2 UPLIFT' Study of TNX-601 ER (Tianeptine Hemioxalate Extended-Release Tablets) for the Treatment of Major Depressive Disorder (MDD) Results from Planned Interim Analys

Tonix Pharmaceuticals 8-K

Tonix Pharmaceuticals

Initiates Enrollment in Phase 2 UPLIFT' Study of TNX-601 ER (Tianeptine Hemioxalate Extended-Release Tablets) for the Treatment

of Major Depressive Disorder (MDD)

Results from Planned Interim

Analysis Expected Fourth Quarter 2023

Approximately 21 Million

Adults in U.S. Suffer From a Major Depressive Episode Each Year

ER is a Once-Daily Tablet that is Bioequivalent to Three-Times-Daily Tianeptine Sodium Immediate Release (IR) that has been available

in Europe, Asia and Latin America for More than Three Decades

Tianeptine IR is Associated

with Low Incidences of Sexual Dysfunction, Sleep Disruption, Sedation, Weight Gain, and Cognitive Impairment Compared with Traditional

Monoaminergic Antidepressants

TNX-601 ER is a New Chemical

Entity in the U.S. and Represents a Potential Innovative Approach to Addressing Depression: Restoration of Neuroplasticity and Neurogenesis

Rather than Modulation of Neurotransmitter Levels and Activity

N.J., Mar. 16, 2023 (GLOBE NEWSWIRE) - Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage

biopharmaceutical company, today announced that the first participant was enrolled in the Phase 2 UPLIFT' study of TNX-601

ER1 (tianeptine hemioxalate extended-release

tablets) for the treatment of major depressive disorder (MDD). The double-blind, placebo-controlled registrational-quality study has a

target enrollment of 300 participants at approximately 30 sites across the U.S. Results from a planned interim analysis are expected to

be released in the fourth quarter of 2023.

proprietary once-daily formulation of TNX-601 ER was designed to be bioequivalent to the three-times-a-day formulation of tianeptine sodium

(amorphous) immediate release (IR) tablets. IR tianeptine sodium has been available in Europe and many countries in Asia and Latin America

for the treatment of MDD for more than three decades since being first marketed in France in 1989. No tianeptine-containing product has

been approved by the U.S. Food and Drug Administration (FDA).

availability of several classes of MDD treatments in the U.S. that directly modulate neurotransmitters and their synaptic receptors, there

remains an unmet need for novel approaches," said Seth Lederman, M.D., Chief Executive Officer of Tonix Pharmaceuticals. "In

animal studies, TNX-601 ER has a unique mechanism of action that restores brain neuroplasticity by exerting biological effects on neurons

and glial cells that increase arborization of dendrites in critical hippocampal circuits.2 In animal models, tianeptine also

reverses stress-induced impairments in synaptic glutamate neurotransmission, and it restores hippocampal neurogenesis.2"

M.D., Chief Medical Officer of Tonix Pharmaceuticals said, "After a decade of development of our proprietary once-daily tianeptine

formulation, it is very gratifying to enter the next stage of clinical testing required to make TNX-601 ER available to those suffering

from MDD in the U.S.

TNX-601 ER not only has the potential to relieve depressive symptoms, but also to improve the quality of life and

resiliency for the millions of MDD sufferers. The short and long-term safety of tianeptine sodium IR has been well-established based on

its clinical use outside the US."

Dr. Sullivan added, "The

efficacy of tianeptine sodium IR has repeatedly been shown to be comparable with that of either selective serotonin reuptake inhibitor

(SSRI) or tricyclic antidepressants3,4 while being associated with a lower incidence of sexual dysfunction, derangement

of sleep architecture, sedation, weight gain, or cognitive impairment.5-7 Given tianeptine's metabolic pathway, which

is independent of the hepatic cytochrome P450 system, we believe that TNX-601 ER has a reduced risk of drug-drug interactions compared

to antidepressants marketed in the U.S.7

disabling condition that is also often associated with suicidal behavior. Extensive animal studies have taught us that tianeptine restores

the stress-induced deficits in neuroplasticity and neurogenesis. The dramatic impact of tianeptine on a brain experiencing many types

of stress is best illustrated by the effects it has in restoring dendritic arborization and spine synapse remodeling of pyramidal neurons

in the CA3 region of hippocampus, as well as new neuron formation and their microglia-mediated integration into neuronal networks of the

hippocampal formation. With an estimated 21 million individuals suffering from a major depressive episode each year in the U.S., it's

exciting to move beyond neurotransmitter modulation and begin an era where MDD may be treated by enhancing a resilient biological phenotype

of neurons and glial cells under stress."

1TNX-601 ER is in the Phase 2 stage

of development and is not approved for any indication

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

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

3Jeon, H. J., et al. .J. Clin. Psychopharmacol. 2014, 34 (2), 218-225.

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

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

6Costa e Silva, J. A., et al. Neuropsychobiology 1997, 35 (1), 24-29.

7Wagstaff, A. J. et al. CNS Drugs 2001, 15 (3), 231-259.

About the Phase 2 UPLIFT

Phase 2 UPLIFT study, TNX-TI-M201, is a 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 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 300 participants will be randomized

in a 1:1 ratio into the two arms across approximately 30 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 (MDE) 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). An

interim analysis is expected to be completed after the first 50% of enrolled patients have completed the study for the purpose of potential

sample size re-estimation, currently anticipated in the fourth quarter of 2023. A 24-week open-label extension study, TNX-TI-M202, is

planned to receive patients completing the UPLIFT study.

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%. 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 behavior. 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.2 The current FDA approved drugs for long term monotherapy treatment of MDD include selective serotonin reuptake inhibitors

(SSRIs), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and Auvelity (dextromethorphan

HBr-bupropion HCl). Dextromethorphan is a direct antagonist of the NMDA-type glutamate receptor.

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

2Rush AJ, et al. (2007) Am J. Psychiatry 163:11, pp. 1905-1917 (STAR*D Study).

TNX-601 ER (tianeptine hemioxalate extended-release tablets) is a novel oral formulation

of tianeptine hemioxalate designed for once-daily daytime dosing in development as a candidate for the treatment

for 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 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 oxalate 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, restores hippocampal long-term potentiation and neurogenesis, and reverses the negative neuroplastic changes from

stress and corticosteroid exposure. In contrast with the modulation of neurotransmitter levels and activity at synaptic receptors like