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TONIX PHARMACEUTICALS 8-K
Tonix Pharmaceuticals Announces Pharmacology and
Medicinal Chemistry Results that Reveal the Molecular Mechanism of Action of Tianeptine, the Active Ingredient of TNX-601 ER, in Treating
Research Supports Direct Role for Restoring Neuroplasticity
and Upsets Previously Held Beliefs About the Significance of Neurotransmitters in Treating Depression
Findings Explain Why Tianeptine Is Not Associated
with Sexual Dysfunction and Weight Gain
Mechanism Supports Development of TNX-601 ER for
Neurodegenerative Diseases and Psychiatric Disorders
CHATHAM, N.J., May 17, 2023 - Tonix Pharmaceuticals
Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company, today announced the molecular mechanism
of action of tianeptine, the active ingredient of TNX-601 ER (tianeptine hemioxalate extended-release tablets), currently in Phase 2 clinical
development for the treatment of major depressive disorder (MDD)*. Based on pharmacology and medicinal chemistry experiments,
scientists at Tonix have established that tianeptine is an agonist for the nuclear peroxisome proliferator-activated receptor (PPAR) isoforms
PPAR- / and PPAR- , and tianeptine's effects on these PPAR isoforms account for its ability to induce neuroplasticity
in cultured neurons.
The findings upset a long-held belief that the only
way to restore the connectivity of neurons damaged in the state of depression was to increase the synaptic levels or activity of neurotransmitters
such as the monoamines serotonin, norepinephrine, and dopamine. The new findings show that selective activation of nuclear PPAR- /
and PPAR- in neurons and supporting glia appears to be a more direct mechanism to achieve the goal of restoring neuronal connectivity,
which is called neuroplasticity. Drugs that restore neuroplasticity are called plastogens.1-3 Consequently, tianeptine is a
plastogen that acts directly on nuclear receptors that regulate gene expression in neurons and microglia.
tianeptine stimulates neuroplasticity by activating certain PPAR isoforms could lead to a paradigm shift in designing new antidepressants,
and change the relative reliance developers place on targeting synaptic neurotransmitter levels and activity," said Stephen Stahl,
M.D., Ph.D., Adjunct Professor of Psychiatry at the University of California San Diego, Chairman
of Neuroscience Education Institute, author of the
bestselling clinical manual, Essential Psychopharmacology Prescriber's
Guide, and consultant to Tonix. "This may lead to better pharmacological treatments for depression and for a range
of neurodegenerative diseases in which neuronal connections are atrophying and the need to restore the connectivity is paramount to achieving
more positive and more sustainable outcomes. Tianeptine avoids some of the more intolerable side effects of the traditional antidepressants
because it cuts in line and intervenes downstream from the monoamine transporters and receptors."
The new research provides clarity on why tianeptine
does not cause sexual dysfunction, weight gain, or several other treatment-limiting toxicities associated with traditional antidepressants.
Tianeptine treats depression by activating select nuclear PPAR isoforms, and has little to do with monoaminergic neurotransmitters, which
are known to be implicated in the most frequently cited side effects of most marketed antidepressants. Key experiments were performed
by scientists at Tonix's Research and Development Center (RDC) in Frederick, Maryland.
mechanism of action of a molecule generally speeds its development and often points the way to broader clinical application," said
Seth Lederman, M.D., Chief Executive Officer of Tonix Pharmaceuticals. "Despite its success in treating depression outside of the
U.S. for more than 30 years, tianeptine's mechanism has remained obscure. Pioneering studies by Prof. Bruce McEwen, Ph.D. at Rockefeller
University revealed that tianeptine stimulates stress-atrophied neurons to form new connections.1 Subsequently, Prof. Ronald
Duman, Ph.D. at Yale University discovered that enhancing these connections is a common principle underlying the therapeutic effects of
traditional antidepressants, which only act indirectly on neuroplasticity by changing the level and activity of synaptic neurotransmitters."4
"In animal models, tianeptine restores neuroplasticity
and reverses stress-induced impairments through activation of select nuclear PPAR isoforms without modulating synaptic monoamine neurotransmitters,"1
said Gregory Sullivan, M.D., Chief Medical Officer of Tonix Pharmaceuticals. "Tianeptine mimics naturally occurring polyunsaturated
fatty acid in binding to PPARs.5 When compared to the traditional classes of antidepressants (SSRIs, tricyclics, etc.), the
tianeptine sodium immediate release products available outside of the U.S. demonstrate comparable efficacy6 and decreased side
effects including sexual dysfunction7-9, derangement of sleep architecture10, sedating effects11 despite
anxiolysis, weight gain even with long term treatment12, and cognitive impairment."11, 13-15
Dr. Sullivan continued,
"Regarding potential future indications beyond our current program in MDD, the proposed mechanism is consistent with the clinical
effects of tianeptine in promoting cognition in Alzheimer's disease, Parkinson's disease and bipolar disorder14,15
and motivates us to develop TNX-601 ER as a treatment for these and other conditions, in addition to our previously stated objectives
to study it in 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 disease of the central nervous system.16
The PPAR- target is validated by prior work treating peripheral diabetes in animals and as FDA-approved drugs, and the concept that
Alzheimer's can be considered a form of diabetes that affects the CNS, or type-III diabetes."17
Dr. Sullivan noted that
the new Tonix findings about tianeptine's mechanism dispel the notion that tianeptine's weak -opioid receptor activity
was central to its mechanism of treating depression.18 This hypothesis was proposed based on results in the forced swim test
(FST) using high-dose tianeptine in mice.19 "Our work found no connection between tianeptine's neuroplastic effects
on cultured neurons and its weak -opioid receptor agonism," Dr. Sullivan said. "In fact, we have identified a new chemical
entity related to tianeptine, TNX-4300, that restores neuroplasticity in cultured neurons and is free from -opioid receptor activity."
Tonix is planning to submit
data supporting tianeptine's mechanism of action for presentation at upcoming scientific conferences and for publication in peer
is an investigational new drug and is not approved for any indication
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15 Kauer-Sant'Anna M, et al. J Psychopharmacol
2019, 33 (4), 502-510.
16 Kahremany S et al. Br J Pharmacol
17 Nguyen et al., Int J Mol Sci. 2010,
18 Samuels BA, et al. Neuropsychopharmacol
2017, 42 (10), 2052-2063.
19 Reardon S. Nature 2019, 571
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