Full Press Release Details
Tonix Pharmaceuticals Holding Corp. 8-K
Tonix Pharmaceuticals Announces Development
of TNX-601 ER, a Potential Abuse Deterrent, Extended-Release Formulation of Tianeptine Oxalate for the Treatment of Major Depressive
Formulation of Tianeptine is an Extended-Release Tablet that Includes Inactive Ingredients and Compression Properties Designed to Confer
Once-Daily Tablet Formulation of Tianeptine
is Bioequivalent to the Three Times a Day Antidepressant Marketed in Europe for Over 30 years
Tianeptine's Enhancement of Neuroplasticity
in Animal Models of Stress Implies a Distinct Indirect Glutamatergic Mechanism of Action Relative to Antidepressants Marketed in the U.S.
Planning to Initiate Enrollment in U.S. Phase
2 Study in First Quarter 2023, Pending FDA Clearance of IND
CHATHAM, N.J., July 11, 2022 - Tonix Pharmaceuticals
Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company, today announced development of TNX-601
ER (tianeptine oxalate extended-release tablets), a naloxone-free formulation of TNX-601 designed to confer abuse-deterrence, for the
treatment of major depressive disorder (MDD)1. Tonix expects to initiate a Phase 2 study of TNX-601 ER for the treatment of
MDD in the first quarter of 2023, pending U.S. Food and Drug Administration (FDA) clearance of its Investigational New Drug (IND) application.
Tonix's TNX-601 ER is being developed as
a treatment for MDD, posttraumatic stress disorder, and neurocognitive dysfunction associated with corticosteroid use. Tianeptine sodium
(amorphous) immediate release (IR) tablets have been available in Europe and many countries in Asia and Latin America for the treatment
of MDD over the more than three decades since it was first marketed in France in 1989. No tianeptine-containing product has been approved
by the FDA. The proposed mechanism of action of TNX-601 ER is distinct from traditional monoaminergic antidepressants in the U.S. In addition
to its glutamatergic properties central to its antidepressant effect, tianeptine has weak -opioid receptor agonist properties and
has been linked to illicit misuse at much higher doses than those reported to be effective in the treatment of MDD2. Previously,
Tonix was developing a naloxone-containing tablet, TNX-601 CR (tianeptine oxalate and naloxone controlled-release) for MDD, that was designed
to mitigate the risk of parenteral abuse.
a naloxone-free tablet formulated with inactive ingredients
that we believe will make the tablet more difficult to adulterate for misuse and abuse, while maintaining extended-release characteristics,
even if the tablet is subjected to physical manipulation, and/or chemical extraction," said Seth Lederman, M.D., President
and Chief Executive Officer of Tonix Pharmaceuticals. "The potentially abuse deterrent ingredients include gel forming polymers
which impede extraction, and excipients which cause nasal irritation. In addition, the tablet's hardness makes it difficult to crush,
cut or grind to fine particle size, which hinders efforts to misuse by insufflation or intravenous routes."
tianeptine sodium IR is comparable to both selective serotonin inhibitor (SSRI) and tricyclic antidepressants3,4 while
being associated with a low incidence of sexual dysfunction than either of those classes5,6, and no associated derangement
of sleep architecture, sedation effects, weight gain, or cognitive impairment,7" said Gregory Sullivan, M.D., Chief Medical
Officer of Tonix Pharmaceuticals. "Given tianeptine's unique metabolic pathway, which is independent of the hepatic P450 system,
we believe that TNX-601 ER has a reduced risk of drug-drug interactions compared to most antidepressants7. Tianeptine's
antidepressant activity is believed to relate to indirect modulation of the glutamatergic system. While it does not have measurable interactions
with the NMDA, AMPA or kainate receptors, tianeptine is known to modulate AMPA receptor trafficking and to promote synaptic plasticity
in hippocampus under conditions of stress or corticosteroid use. In animal models, tianeptine restores neuroplasticity and reverses stress-induced
impairments in synaptic glutamate neurotransmission, which are perturbed in depression.8 Additionally, TNX-601
ER is designed for once daily dosing, which is believed to provide an adherence advantage relative to the three times per day dosing
of the immediate-release sodium salt products available in Europe and other jurisdictions around the world."
1TNX-601 ER is in the
pre-IND (Investigational New Drug) stage of development and is not approved for any indication
2Lauhan, R., et al. Psychosomatics 2018, 59 (6),
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.
8McEwen, B. S., et al. Mol. Psychiatry 2010, 15 (3), 237-249.
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
important areas of functioning. The majority of people who suffer from depression do not respond adequately to initial antidepressant
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
2IMS NSP, NPA, NDTI MAT-24-month data through Aug 2017.
3Kubitz N, et al. (2013) PLOS One,.
8(10):e76882. doi: 10.1371/journal.pone.0076882. PMID: 24204694;
4Rush AJ, et al. (2007) Am J. Psychiatry 163:11, pp. 1905-1917 (STAR*D Study).
TNX-601 ER is a novel
oral formulation of tianeptine oxalate designed for once-daily daytime dosing that is in the pre-IND (Investigational New Drug) stage
of development for the treatment of MDD. Tonix reported the official minutes of an FDA Pre-IND meeting on March 22, 2021. Tianeptine sodium
(amorphous) immediate release (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, restoring hippocampal long-term potentiation and reversing the neuroplastic changes from stress and corticosteroid
exposure. 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 (8-80 times the therapeutic dose). 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 treated1 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-weeks2,3,4-6,
3-months7, or 12-months8 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. TNX-601 ER is expected to have patent protection through 2037.
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.
2Emsley, R., et al. J. Clin. Psychiatry 2018, 79 (4)
3Bonierbale M, et al. Curr Med Res Opin 2003, 19(2):114-124.4Guelfi, J. D.,
et al. Neuropsychobiology 1989, 22 (1), 41-48.
5Invernizzi, G. et al., Neuropsychobiology 1994, 30 (2-3), 85-93.
6Lepine, J. P., et al. Hum. Psychopharmacol. 2001, 16 (3), 219-227.
7Guelfi, J. D. et al., Neuropsychobiology 1992, 25 (3), 140-148.
8L o, H. et al., Br. J. Psychiatry. Suppl. 1992, No. 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 a new Phase 3 study launched in the second quarter of 2022 and interim data expected in the first
quarter of 2023. TNX-102 SL is also being developed to treat Long COVID, a chronic post-acute COVID-19 condition. Tonix expects to initiate