Full Press Release Details
TONIX PHARMACEUTICALS HOLDING CORP. 8-K
Tonix Pharmaceuticals Announces
Data Supporting the Memory- and Cognition-Enhancing Effects of Racemic Tianeptine and (S)-Tianeptine, but not (R)-Tianeptine,
in the In Vivo Rat Novel Object Recognition (NOR) Test
New Findings Support Development of Racemic Tianeptine
and (S)-Tianeptine (Estianeptine) as First-in-Class Oral Therapies in Alzheimer's Disease and Other Psychiatric and Neurodegenerative
Conditions with Memory Deficits
(S)-Tianeptine Effects on Novel Object Recognition
are Consistent with a Role for PPAR- / Activation in Improving Memory and Cognition
Topline Results Expected First Quarter 2024 from
the Currently Enrolling Potentially Pivotal Phase 2 UPLIFT Study of TNX-601 ER (Racemic Tianeptine) in Major Depressive Disorder
CHATHAM, N.J., July 24, 2023
- Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a biopharmaceutical company, today announced data supporting
the memory- and cognition-enhancing effects of two Tonix drug candidates, TNX-601 ER (tianeptine hemioxalate extended release) and TNX-4300
(estianeptine), the single (S)-isomer of tianeptine. TNX-601 ER is being tested in the potentially pivotal Phase 2 UPLIFT1
trial for the treatment of major depressive disorder (MDD), with topline results expected in the first quarter of 2024. TNX-4300 is in
preclinical development for mood disorders, Alzheimer's disease and Parkinson's disease.* The findings reported
today show that tianeptine and estianeptine improve memory and cognition as measured in the rat Novel Object Recognition (NOR) test. The
finding that estianeptine is responsible for improving memory and cognition suggests a role for PPAR- / activation in memory.
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 peroxisome proliferator-activated receptors PPAR- / and 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 recently reported that
estianeptine induces neuroplasticity in cell culture.2 The new findings indicate that estianeptine also improves memory and
cognition in the in vivo rat NOR test. We believe that together these findings support the development of tianeptine and estianeptine
in psychiatric and neurodegenerative diseases. Tianeptine's ability to restore atrophied neuronal connections in animals2
suggests the potential to achieve durable outcomes."
rat NOR test is an experimental tool to assess drug effects on memory and evaluate their potential as treatments for neurodegenerative
conditions like Alzheimer's disease," said Gregory Sullivan, M.D., Chief Medical Officer of Tonix Pharmaceuticals.
"Since the main initial clinical feature in Alzheimer's disease is impairment in newly learned
facts or memories, improving learning and memory are important properties of potential new therapeutics. The specific type of learning
and recognition memory measured by the NOR is believed to be relevant to the neurocircuitry impaired in Alzheimer's disease."
Dr. Sullivan continued, "Our
ongoing clinical studies in major depression on TNX-601 ER, which contains racemic tianeptine, are expected to inform and potentially
accelerate the 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 the PPAR- / gene."8
In depression, estianeptine
is believed to act on PPAR- / and PPAR- targets in the nucleus to enhance genetic transactivation involved in restoring
hippocampal neuroplasticity and neurogenesis. These findings also have applicability to neurodegenerative diseases in which neuronal connections
are atrophied.2 The reported PPAR mechanism has potential relevance to why tianeptine is not associated with sexual dysfunction,
weight gain or several other treatment-limiting toxicities associated with the antidepressants currently marketed in the U.S. for long-term
use. However, tianeptine has other potential side effects that are described in its labeling outside the U.S. where it is marketed as
a prescription drug.
Tonix owns worldwide rights
to the novel salt, racemic tianeptine hemioxalate and to the proprietary extended-release formulation employed in TNX-601 ER that allows
once daily dosing. TNX-601 ER is currently being studied in the Phase 2 UPLIFT trial, which is targeting enrollment of approximately 300
patients at about 30 U.S. clinical sites. Tonix has also filed patents claiming single (S)-isomer estianeptine, the active ingredient
in TNX-4300, which is devoid of activity on the -opioid receptor. 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 treated9 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
About the Novel Object Recognition Test (NOR)
of several cognitive tests that engage working memory and is considered a model for testing therapeutics or co-factors for Alzheimer's
disease.20 The NOR task depends on the accurate comparison of novel information with recently
stored memories. Among animal behavioral models for assessing cognitive functioning, the NOR test measures
a specific form of recognition memory without assumptions about drug mechanism. The NOR is based on the spontaneous behavior of rodents
without the need for external motivation, reward, or punishment. Impairments of NOR are seen in many animal models, including mice
that overexpress the amyloid protein associated with Alzheimer's disease.21 The NOR tests on tianeptine and estianeptine
were performed by a third-party contract research organization. In the NOR test, rats were assessed for cognitive ability in a test apparatus
comprising an open-field arena and were scored by an observer blind to treatments. The positive control for a drug effect was the acetylcholinesterase
inhibitor medication galantamine, which is the active ingredient of Razadyne , approved by the U.S. Food and Drug administration as