Full Press Release Details
TONIX PHARMACEUTICALS HOLDING CORP. 8-K
Tonix Pharmaceuticals Announces Accelerating Completion
of Enrollment in Phase 2 UPLIFT Study of TNX-601 ER (Racemic Tianeptine) for Major Depressive Disorder: Topline Data Now Expected in Fourth
Reallocating Resources to Development of Single
Isomer TNX-4300 (Estianeptine)
Estianeptine in Preclinical Development Has Demonstrated
Key Activities Related to in vivo Novel Object Recognition and in vitro Neuroplasticity, Without the -Opioid Receptor Activity
of Racemic and (R)-Tianeptine
New Findings Support Development of TNX-4300 as
a First-in-Class Oral Therapy in Depression, Alzheimer's Disease and Other Psychiatric and Neurodegenerative Conditions with Memory
CHATHAM, N.J., July 26,
2023 - Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a biopharmaceutical company, today announced that
development of TNX-4300* (estianeptine), the single (S)-isomer of tianeptine will be prioritized over TNX-601 ER*, which is being
studied in the Phase 2 UPLIFT1 trial for the treatment of major depressive disorder (MDD). TNX-4300 is in preclinical development
for mood disorders, Alzheimer's disease and Parkinson's disease. Recent findings have shown estianeptine possesses the ability
to improve memory and cognition in vivo as measured in the rat Novel Object Recognition (NOR) test, and the ability to restore
neuroplasticity to neurons in cell culture. The finding that estianeptine is responsible for improving memory and cognition in vivo
suggests a role for peroxisome proliferator-activated receptor PPAR- / activation in memory. For these reasons, Tonix intends
to accelerate completion of enrollment for the Phase 2 UPLIFT1 trial to reallocate resources to the preclinical development
of TNX-4300 and now expects to report topline data from this study in the fourth quarter of 2023. Tonix is also accelerating completion
of enrollment in the RESILIENT study of TNX-102 SL for the management of fibromyalgia so that approximately 450 patients will be enrolled,
and topline results are expected in the fourth quarter of 2023.
Racemic tianeptine is an
antidepressant that has been marketed outside the U.S. for more than 30 years. Tianeptine is also a racemic drug composed of a 1:1 mixture
of two mirror-image isomers. Tonix recently reported that the (S)-isomer (estianeptine) is responsible for its positive effects
on neuroplasticity in cell culture, while the (R)-isomer is responsible for racemic tianeptine's off-target activity on the
-opioid receptor.2,3 Tonix also recently reported that estianeptine activates PPAR- / . These activities on
molecular targets in neurons and glia in the brain are believed to relate to tianeptine's ability to restore connectivity between
neurons that atrophy in conditions of stress or depression in animal models.4 Tianeptine's mechanism is distinct from
traditional antidepressants that alter the level or activity of serotonin, norepinephrine, and dopamine neurotransmitters, which are believed
to indirectly induce neurons to make new connections.5
"The memory- and cognition-enhancing
effects of racemic tianeptine and estianeptine seen in the NOR test are consistent with human clinical studies in which racemic tianeptine
treatment improved cognition and memory in patients with Alzheimer's disease and depression6 and in patients with bipolar
disorder,7" said Seth Lederman, M.D., Chief Executive Officer of Tonix Pharmaceuticals. "We also recently reported
that estianeptine induces neuroplasticity in cell culture.2 Together these findings support the development of estianeptine
in psychiatric and neurodegenerative diseases."
expense of developing new drugs, the scientific and clinical advantages of TNX-4300 lead us to focus our efforts on this preclinical program
as a potential treatment for mood disorders like depression and neurodegenerative conditions like Alzheimer's
disease," said Gregory Sullivan, M.D., Chief Medical Officer of Tonix Pharmaceuticals. "The finding that TNX-4300 possesses
the desirable attributes of racemic tianeptine and at the same time lacks a measurable opioid liability supports the focus of our resources
on this candidate. Multiple studies around the world have already shown that racemic tianeptine is effective
in treating depression. However, our in vivo animal studies and in vitro lab studies have indicated that TNX-4300 is potentially
a more active and safer drug."
Dr. Sullivan continued,
"TNX-601 ER, which contains racemic tianeptine, has informed the future development of TNX-4300 which contains the single isomer,
estianeptine. We believe that estianeptine bypasses the synapse and activates intracellular PPAR- / and PPAR- targets.
The finding that estianeptine is responsible for tianeptine's ability to improve memory and cognition in the NOR test implicates
PPAR- / activation specifically as a molecular target. This finding is consistent with the impaired memory of mice lacking
Tonix has filed patents
claiming single (S)-isomer estianeptine, the active ingredient in TNX-4300, which is devoid of activity on the -opioid receptor
in tissue culture. Tonix has filed patent claims that describe crystalline salt forms of estianeptine that appear well suited to formulation.
TNX-4300 is currently in preclinical development for depression, bipolar disorder, Alzheimer's disease, and Parkinson's disease.
Key experiments were performed by scientists at Tonix's Research and Development Center (RDC) in Frederick, Maryland.
*TNX-601 ER and TNX-4300 are investigational
new drugs and are not approved for any indication. TNX-601 ER is being developed under an IND. TNX-4300 is at the pre-IND stage of development.
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
tolerability profile from decades of use in these jurisdictions. Currently no tianeptine-containing product is approved in the U.S. and
no extended-release once-daily 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.4 Tianeptine's enhancement of neuroplasticity in animal models of stress is believed to be
mediated by activation of PPAR isoforms PPAR- / and PPAR- , which is mechanistically distinct from traditional monoaminergic
antidepressants marketed in the U.S. and contributes to its potential for clinical indications beyond depression and stress disorders.
Tianeptine and its MC5 metabolite are also weak -opioid
receptor (MOR) agonists that present a potential abuse liability if illicitly misused in large quantities.3,9 In cases where
tianeptine has been abused, the dose has been approximately 8-80 times the therapeutic dose in depression on a daily basis.9
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 treated10 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-weeks11-15, 3-months,16 or 12-months17 of treatment.
Estianeptine is believed to mimic naturally occurring
polyunsaturated fatty
acid ligands in low affinity interactions with PPAR- /
and PPAR- . Estianeptine's activation of nuclear PPAR- / and PPAR- receptors appears to be a more direct mechanism
to achieve the goal of restoring neuronal connectivity than the active ingredients of current pharmacologic therapies for depression.
Tianeptine's proposed mechanism as a plastogen is consistent with its clinical effects in promoting cognition in depressed patients
with Alzheimer's disease5 and in patients with bipolar disorder.6 The PPAR- / target is validated
by prior work on agonists treating animal models of neurodegenerative and autoimmune diseases of the central nervous system.18
Alzheimer's disease has been proposed to be a form of diabetes that affects the CNS, sometimes termed type-III diabetes."19
The PPAR superfamily plays key roles in metabolic processes, and activation of PPAR- / in brain by tianeptine shows promise
to prevent the cognitive dysfunction associated with CNS insulin resistance. Tianeptine's reported pro-cognitive and anxiolytic
effects as well as its ability to attenuate the neuropathological effects of excessive stress responses suggest other potential uses including
as a treatment for posttraumatic stress disorder (PTSD), as well as for preventing neurocognitive dysfunction associated with corticosteroid
Tonix Pharmaceuticals Holding Corp.*
Tonix is a biopharmaceutical
company focused on commercializing, developing, discovering and licensing therapeutics to treat and prevent human disease and alleviate
suffering. Tonix markets Zembrace SymTouch (sumatriptan injection) 3 mg and Tosymra (sumatriptan nasal spray) 10 mg. Zembrace
SymTouch and Tosymra are each indicated for the treatment of acute migraine with or without aura in adults. Tonix's development
portfolio is composed of central nervous system (CNS), rare disease, immunology and infectious disease product candidates. Tonix's
CNS development 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, nearing complete enrollment in a potentially registration-enabling study 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 proof-of-concept
study has been completed, and topline results are expected in the third 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 nearing complete enrollment
with topline results of a proof-of-concept study expected in the fourth quarter of 2023. TNX-4300 (estianeptine) is a small molecule oral
therapeutic in preclinical development to treat MDD, Alzheimer's disease and Parkinson's disease. TNX-1900 (intranasal potentiated
oxytocin), in development for chronic migraine, has completed enrollment with topline 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.