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-β/δ, restores neuroplasticity in neuronal
tissue culture and is free of µ-opioid receptor activity. In
contrast, (R)-tianeptine activates the µ-opioid receptor and lacks
PPAR-β/δ 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-β/δ and PPAR-γ 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-β/δ and
restoring neuroplasticity, and the (R)-isomer for its off-target
activity on the µ-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 µ-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-β/δ
and PPAR-γ. (S)-tianeptine’s activation of nuclear PPAR-β/δ and
PPAR-γ 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-β/δ 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 indication1Tonix press release,
May 17, 2023
https://ir.tonixpharma.com/news-events/press-releases/detail/1389/tonix-pharmaceuticals-announces-pharmacology-and-medicinal2
García-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):754-705
Nguyen et al., Int J Mol Sci. 2010, 21(9):3165
About Tianeptine
Racemic 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. 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-β/δ and PPAR-γ, 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), 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 Lôo, H. et al., Br.
J. Psychiatry. Suppl. 1992, 15, 61–65.
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 and cancer, including
TNX-1500, which is a humanized monoclonal antibody targeting
CD40-ligand (CD40L or CD154) being developed for the prevention of
allograft rejection and for the treatment of autoimmune diseases. A
Phase 1 study of TNX-1500 is expected to be initiated in the third
quarter of 2023. Tonix’s infectious disease pipeline includes
TNX-801, a vaccine in development to prevent smallpox and mpox, for
which a Phase 1 study is expected to be initiated in the second
half of 2023. TNX-801 also serves as the live virus vaccine
platform or recombinant pox vaccine platform for other infectious
diseases. The infectious disease portfolio also includes TNX-3900
and TNX-4000, classes of broad-spectrum small molecule oral
antivirals.
*All of Tonix’s product candidates are
investigational new drugs or biologics and have not been approved
for any indication.
This press release and further information about
Tonix can be found at www.tonixpharma.com.
Forward Looking Statements
Certain statements in this press release are
forward-looking within the meaning of the Private Securities
Litigation Reform Act of 1995. These statements may be identified
by the use of forward-looking words such as “anticipate,”
“believe,” “forecast,” “estimate,” “expect,” and “intend,” among
others. These forward-looking statements are based on Tonix's
current expectations and actual results could differ materially.
There are a number of factors that could cause actual events to
differ materially from those indicated by such forward-looking
statements. These factors include, but are not limited to, risks
related to the failure to obtain FDA clearances or approvals and
noncompliance with FDA regulations; delays and uncertainties caused
by the global COVID-19 pandemic; risks related to the timing and
progress of clinical development of our product candidates; our
need for additional financing; uncertainties of patent protection
and litigation; uncertainties of government or third party payor
reimbursement; limited research and development efforts and
dependence upon third parties; and substantial competition. As with
any pharmaceutical under development, there are significant risks
in the development, regulatory approval and commercialization of
new products. Tonix does not undertake an obligation to update or
revise any forward-looking statement. Investors should read the
risk factors set forth in the Annual Report on Form 10-K for the
year ended December 31, 2022, as filed with the Securities and
Exchange Commission (the “SEC”) on March 13, 2023, and periodic
reports filed with the SEC on or after the date thereof. All of
Tonix's forward-looking statements are expressly qualified by all
such risk factors and other cautionary statements. The information
set forth herein speaks only as of the date thereof.
Contacts
Jessica Morris (corporate)Tonix
Pharmaceuticalsinvestor.relations@tonixpharma.com(862) 904-8182
Maddie Stabinski (media)Russo
PartnersMadeline.Stabinski@russopartnersllc.com(212) 845-4273
Peter Vozzo
(investors)Westwicke/ICRpeter.vozzo@westwicke.com(443) 213-0505
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