Full Press Release Details
TONIX PHARMACEUTICALS HOLDING CORP. 8-K
Tonix Pharmaceuticals Announces
Presentation of Data Supporting Development of Racemic and Single (S)-Isomer Tianeptine, Plastogen Anti-Depressants, at the American
Society of Clinical Psychopharmacology Meeting
Tianeptine's Mechanism of Restoring Neuroplasticity
and Neurogenesis by Dual PPAR- / and PPAR- Agonism Supports Development as a First-in-Class Oral Therapy for Psychiatric
and Neurodegenerative Diseases
Racemic Tianeptine, or TNX-601 ER, is Enrolling
in a Potentially Pivotal Phase 2 Study for the Treatment of Major Depressive Disorder; Results from Interim Analysis Expected Fourth Quarter
Single (S)-Isomer of Tianeptine, or TNX-4300, is
Free from -Opioid Receptor Activity Associated with the (R)-Isomer
TNX-4300 is in Preclinical Development for Depression,
Bipolar Disorder, Alzheimer's Disease and Parkinson's Disease
CHATHAM, N.J., June 5, 2023
- Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company, today announced
the presentation of data detailing the mechanism of action and pharmacokinetics of TNX-601 ER (tianeptine hemioxalate extended release)
and TNX-4300 (estianeptine) at the American Society of Clinical Psychopharmacology (ASCP) meeting in Miami, Fla. TNX-601 ER is being tested
in a potentially pivotal Phase 2 trial for the treatment of major depressive disorder (MDD) for which results of a preplanned interim
analysis are expected in the fourth quarter of 2023. TNX-4300 is in preclinical development for mood disorders, Alzheimer's disease
and Parkinson's disease. The active ingredient of both products is the (S)-isomer of tianeptine.1 The (S)-isomer
of tianeptine activates PPAR- / , restores neuroplasticity in neuronal tissue culture and lacks -opioid liability. In
contrast, the (R)-isomer of tianeptine lacks PPAR- / activity and is an agonist at the -opioid receptor. The
poster presentation is available on Tonix's website: www.tonixpharma.com.
Tonix recently announced that the plastogen anti-depressant
tianeptine, a drug marketed outside the U.S. for more than 30 years, acts on nuclear PPAR- / and PPAR- in neurons and
glia to restore neuronal connectivity in depression.2 The understanding that tianeptine bypasses the synapse and acts on the
nucleus to exert its effects on restoring neuroplasticity and neurogenesis has direct applicability in a number of neurodegenerative diseases
in which neuronal connections are atrophying.2 The newly reported mechanism also provides clarity on why tianeptine is not
associated with sexual dysfunction, weight gain or several other treatment-limiting toxicities, which are associated with the antidepressants
currently marketed in the U.S. for long-term use.
"Restoring atrophied neuronal connections in
psychiatric and neurodegenerative diseases has the potential to achieve better and more durable outcomes," said Seth Lederman, M.D.,
Chief Executive Officer of Tonix Pharmaceuticals. "The tianeptine marketed outside the U.S. for treating depression is a 1:1 racemic
mixture of two mirror image isomers. Our team of scientists isolated and characterized the (S)-isomer of tianeptine, which is free
from -opioid receptor activity and is now under development as TNX-4300 for treating psychiatric and neurodegenerative diseases.
The (S)-isomer of tianeptine is responsible for tianeptine's activity on PPAR- / and restoring neuroplasticity
and neurogenesis, while the (R)-isomer is responsible for any off-target activity on the -opioid receptor."
The findings reported at the meeting show how the
pharmacokinetics of oral TNX-601 ER in humans differ from intraperitoneal (i.p.) tianeptine in mice. In humans, after an oral dose
of TNX-601 ER the half-life of tianeptine in the blood is approximately 5-7 hours. In contrast, in mice after an i.p. dose of tianeptine
the half-life of tianeptine in the blood has been reported to be less than approximately 30 minutes and the behavioral effects appear
dominated by the longer-lasting MC5 metabolite, which maintains -opioid receptor activity.3 The data Tonix presented
also show that the (R)-isomer of tianeptine is responsible for the decrease in immobility in the mouse forced swim test after i.p.
administration, which is consistent with previous reports that the effect of tianeptine on the forced swim test is a -opioid receptor-dependent
Gregory Sullivan, M.D., Chief Medical Officer of Tonix
Pharmaceuticals, said, "From our clinical studies on volunteers, after oral dosing with TNX-601 ER, the extended pharmacokinetics
of parent tianeptine is consistent with tianeptine exerting activity on PPAR- / and resulting in neurorestorative effects.
In contrast, after i.p. dosing of tianeptine in mice, the exposure of tianeptine is brief and the behavioral effects appear dominated
by the MC5 metabolite.3 While tianeptine's MC5 metabolite has been reported to maintain -opioid receptor activity3,
we found that MC5 metabolite lacks activity on either PPAR- / or PPAR- in culture. Together, we believe these findings
support the interpretation that the parent tianeptine and specifically, the (S)-isomer of tianeptine exert antidepressant effects
in humans by interacting with PPAR- / and PPAR- ."
Dr. Sullivan continued, "Our ongoing work on
racemic tianeptine in depression is expected to inform and potentially accelerate the development of TNX-4300. The dose of tianeptine
for treating depression is well-established from racemic studies, so we plan to test single isomer TNX-4300 at a dose equivalent to 50%
of the racemic dose, which is expected to provide equivalent exposure of (S)-tianeptine as racemic tianeptine. Subsequently, we
plan to test higher doses of (S)-tianeptine, because TNX-4300 lacks -opioid receptor activity, but such studies will require
additional non-clinical studies."
Key experiments were performed by scientists at Tonix's
Research and Development Center (RDC) in Frederick, Maryland.
TNX-601 and TNX-4300 are investigational new drugs and are not approved for any indication
press release, May 23, 2023 https:// ir.tonixpharma.com/news-events/press-releases/detail/1392/tonix-pharmaceuticals-announces-the-isolation-and
3 Samuels et al., Neuropsychopharmacology.
2017, 42(10):2052-2063
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. (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 disorder11,12
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 system13
and the concept that Alzheimer's can be considered a form of diabetes that affects the CNS, or type-III diabetes."14Tianeptine'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
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 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), 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.
11 Garc a-Alberca JM,