TNXP: Deep Dive into Tianeptine and its Novel Mechanism of Action for MDD…
NASDAQ:TNXP
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New Insights into Mechanism of Action of Tianeptine
On June 5, 2023, Tonix Pharmaceuticals Holding Corp. (NASDAQ:TNXP) announced a presentation at the American Society of Clinical Psychopharmacology (ASCP) meeting that details the mechanism of action and pharmacokinetics of TNX-601 ER (tianeptine hemioxalate extended release) and TNX-4300 (estianeptine). TNX-601 ER is currently being investigated in a Phase 2 clinical trial for the treatment of major depressive disorder (MDD). We anticipate results from a preplanned interim analysis in the fourth quarter of 2023. TNX-4300 (the (S)-isomer of tianeptine) is in preclinical development for neurodegenerative disorders (MDD, Alzheimer’s, Parkinson’s, etc.).
Tianeptine is a unique antidepressant that has been used in Europe, Asia, and Latin American since first being approved in France in 1989. A multitude of studies have shown that tianeptine’s efficacy in treating MDD is comparable to therapies targeting monoaminergic (MA) neurotransmitters, such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). In contrast to SSRIs and TCAs, treatment with tianeptine is not accompanied by significant sexual side effects, adverse effects on sleep, or weight gain.
Traditionally, the “monoamine hypothesis” of depression stipulated that imbalances in serotonergic, noradrenergic, and dopaminergic functions led to the development of MDD. This was supported by the antidepressant properties of monoamine oxidase inhibitors (MAOIs) and TCAs. However, more recent insights into mechanisms of MDD development show that not only is there an imbalance of neurotransmitters and neuromodulators but also an impairment of neuroplasticity and cellular resilience. Neuroplasticity refers to the ability of the adult brain to adapt functionally and structurally to internal and external stimuli, which is altered in those suffering from MDD and other psychiatric or neurodegenerative diseases. Tianeptine’s effect on neuroplasticity has been extensively studied (McEwen et al., 2005), including its ability to trigger the development of new connections in stress-atrophied neurons of the hippocampus. This mechanism is not unique to tianeptine, but is also caused indirectly by traditional antidepressants through altering the level and activity of synaptic neurotransmitters (Price et al., 2019).
While tianeptine’s effect on neuroplasticity is known, the knowledge of how it exerts these effects has thus far been incomplete. On May 17, 2023, Tonix announced that its scientists had established that tianeptine is an agonist for the nuclear peroxisome proliferator-activated receptor (PPAR) isoforms PPAR-β/δ and PPAR-γ, and that this binding to PPAR isoforms is responsible for its ability to induce neuroplasticity in cultured neurons. This mechanism of action helps to explain why tianeptine does not cause the common side effects seen with traditional antidepressants, such as sexual dysfunction, weight gain, and other treatment-limiting toxicities, which are derived from alterations in levels of MA neurotransmitters. The following image shows how tianeptine works in the nucleus to more directly affect neuroplasticity, as opposed to MA antidepressants that work at the synapse.
One of the drawbacks of tianeptine and its main metabolite MC5 is they are both weak µ-opioid receptor agonists, and thus could be susceptible to abuse (8-80x therapeutic daily dosing) (Lauhan et al., 2018). To counteract this possibility, TNX-601 ER was formulated with multiple abuse deterrent properties, including lower solubility of the hemioxalate salt, microcrystalline cellulose as a compression aid and compressed to >100 Newtons (decreases ability to crush to fine powder), and inclusion of high molecular weight gel-forming polymers (poorly injectable).
To further characterize tianeptine’s mechanism of action, Tonix scientists recently isolated and characterized the two mirror image isomers of racemic tianeptine. The results of those studies showed that the (S)-isomer of tianeptine binds to and activates PPAR-β/δ, restores neuroplasticity in vitro, and does not possess any µ-opioid receptor activity. In contrast, the (R)-isomer activates the µ-opioid receptor and does not activate PPAR-β/δ. Tonix has initiated development of the (S)-isomer (TNX-4300) as a treatment for a range of psychiatric and neurodegenerative disorders (MDD, Alzheimer’s, Parkinson’s, etc.).
The following images show the results of a murine forced swim test (FST), which is a behavioral test to evaluate antidepressant drugs (Can et al., 2012), to test racemic tianeptine along with its isolated isoforms. The image on the left shows the results of the FST using racemic tianeptine, in which increasing amounts of racemic tianeptine results in a decrease in total time immobile and is on par with the positive control sertraline. The image on the right shows that (S)-tianeptine is not active in the FST, however (R)-tianeptine is active. Since the (R)-isomer maintains µ-opioid activity, these results suggest that it is the µ-opioid receptor activity that is responsible for modulating animal behavior in the FST. These results are consistent with previous studies that showed the effect of tianeptine on the FST was a µ-opioid receptor-dependent phenomenon (Samuels et al., 2017).
Large Market Opportunity in MDD
MDD is a debilitating condition that affects over 20 million adults and 4 million adolescents each year in the U.S. (SAMHSA.gov). It dramatically decreases overall health scores more than other chronic conditions (asthma, diabetes, arthritis, etc.) and also worsens mean health scores when comorbid with those diseases than those diseases do on their own (Moussavi et al., 2007). Antidepressants are commonly used to treat depression, however the STAR*D study reported that approximately 30% of depressed patients fail to achieve remission (Rush et al., 2006). In addition, the side effects (sexual side effects, adverse effects on sleep, weight gain, etc.) for MA antidepressants are intolerable for a large percentage of patients. Thus, what is needed is a novel class of antidepressants that are efficacious but without the intolerable side effects. A drug that fit those characteristics would enter an MDD market that is currently valued at $4.8 billion and is expected to increase to $8.3 billion in 2028 (EvaluatePharma).
Phase 2 UPLIFT Trial Underway
In March 2023, Tonix announced the initiation of the Phase 2 UPLIFT trial of TNX-601 ER for the treatment of MDD. The double blind, placebo controlled trial is expected to enroll approximately 300 participants at approximately 30 trial sites across the U.S. (NCT05686408). All participants will have a DSM-5 diagnosis of major depression and a duration for the current major depressive episode of at least 12 weeks. The primary efficacy endpoint is the mean change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at Week 6. An interim analysis is expected after 50% of enrolled patients have completed the study for the purpose of potential sample size re-estimation. We expect results from the interim analysis in the fourth quarter of 2023. An overview of the trial is given below.
Phase 3 RESILIENT Topline Results Expected in 4Q23
Tonix is currently conducting the Phase 3 RESILIENT trial, which is a randomized, double blind, placebo controlled potentially pivotal study of TNX-102 SL 5.6 mg for the treatment of fibromyalgia. In December 2022, the company announced that the first 50% of participants had been enrolled. Recently, Tonix announced that it is eliminating the interim analysis of the RESILIENT trial to ensure that topline data will be available in the fourth quarter of 2023. The target enrollment remains at approximately 470 participants.
In December 2020, Tonix announced positive topline results for the Phase 3 RELIEF study of TNX-102 SL 5.6 mg (primary endpoint, P=0.010). Thus, since Tonix has already conducted one positive trial in fibromyalgia, positive results from the RESILIENT study could put the company in position to file a new drug application (NDA) for TNX-102 SL 5.6 mg for the treatment of fibromyalgia.
Topline Results for Phase 2 PREVENTION Study of TNX-1900 in 4Q23
In February 2023, Tonix announced the initiation of the Phase 2 PREVENTION study of potentiated intranasal oxytocin (TNX-1900) for the prevention of migraine headaches in chronic migraineurs. It is a double blind, randomized, multicenter, placebo controlled study with three arms: two treatment regimens of TNX-1900 and one of placebo in a 1:1:1 ratio in approximately 300 patients. After a four-week run-in phase to confirm chronic migraine criteria are met, the participants will be treated for 12 weeks followed by a two-week safety follow up. The primary efficacy endpoint is the mean change in the number of migraine headache days between the 28-day run-in phase and the last 28-days of the treatment phase. We anticipate approximately 150 participants being enrolled in the trial and topline results will be available in the fourth quarter of 2023.
Phase 2 Trial of TNX-1300 to Initiate in 3Q23
We anticipate that Tonix will initiate a Phase 2 clinical trial of TNX-1300, a double mutant cocaine esterase, for the treatment of cocaine intoxication in the third quarter of 2023. Tonix licensed the asset in May 2019 from Columbia University, which has Breakthrough Therapy Designation from the U.S. FDA.
TNX-1300 is a recombinant enzyme derived from the cocE gene of a Rhodococcus species that utilizes cocaine as a sole source of carbon and nitrogen (Bresler et al., 2000). The CocE enzyme was tested in a rat model of cocaine toxicity to determine if it could protect the animals from cocaine-induced lethality (Cooper et al., 2006). Results showed that it required a 1000 mg/kg dose of cocaine to overcome the protective effects of 1 mg CocE (LD50 for IP dose is 70 mg/kg cocaine).
One of the issues with the native CocE enzyme is that its half-life is only a few minutes at physiological temperature (37ºC) (Cooper et al., 2006). Thus, a study was performed to develop thermostable variants of CocE using a computational approach along with in vitro and in vivo studies (Gao et al., 2009). A variant was identified with two amino acid substitutions (T172R/G173Q) that resulted in increased stability at 37ºC.
The double mutant CocE enzyme (then called RBP-8000, now TNX-1300) was evaluated in a Phase 2 clinical trial conducted by Reckitt Benckiser Pharmaceuticals, the previous licensee to the product (NCT01846481). It was a double blind, placebo controlled, randomized, four-sequence, two-period cross-over study. Subjects were non-treatment seekers with a DSM-IV diagnosis of cocaine abuse. During the study period, subjects were given an IV infusion of 50 mg of cocaine over 10 minutes followed by TNX-1300 (100 mg or 200 mg) or matching placebo one minute after completion of the cocaine infusion. Outcomes included pharmacokinetics of both cocaine and TNX-1300 along with any effect by TNX-1300 on cocaine-induced physiological changes (Nasser et al., 2014).
A total of 29 subjects were randomized in the trial. Safety results showed that no anti-TNX-1300 antibodies were detected in any of the subjects at any time point. In addition, there were no clinically significant abnormalities in vital signs, clinical laboratory markers, or physical examinations. A total of seven subjects reported treatment-emergent adverse events that were considered related to treatment with any study drug, with most being assessed as mild in severity. Of note, vital signs of subjects treated with TNX-1300 returned to or below baseline earlier than subjects that received placebo.
Plasma cocaine rapidly decreased following administration of TNX-1300, with a 90% drop of peak plasma cocaine concentrations within two minutes and a 95% decline in plasma cocaine exposure. The 200 mg dose of TNX-1300 produced a longer-lasting effect on cocaine pharmacokinetics compared to the 100 mg dose. These preliminary results fully support the continued development of TNX-1300 as a treatment for cocaine intoxication.
Phase 2 PREVAIL Trial Results in 3Q23
In August 2022, Tonix announced the initiation of the PREVAIL Phase 2 clinical trial of TNX-102 SL in patients with Long COVID (NCT05472090), a heterogeneous condition that involves nociplastic pain following infection with and recovery from SARS-CoV-2, the virus that causes COVID-19 (Bierle et al., 2021). It is a 14-week, double blind, randomized, multicenter, placebo controlled trial to evaluate the efficacy and safety of TNX-102 SL in patients with multi-site pain associated with post-acute SARS-CoV-2 infection (PASC). The company has discontinued enrollment and the approximately 60 patients enrolled to date will be followed to completion, with topline data expected in the third quarter of 2023. The data from this study will be used to guide future development and support grant applications.
In February 2023, Tonix participated in a virtual event titled, “Long COVID: What Will it Take to Accelerate Therapeutic Progress?”. The company presented emerging research describing the role of infections in triggering fibromyalgia or chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and other fibromyalgia-like illnesses. Symptoms of Long COVID, such as multi-site pain, fatigue, and insomnia, are the hallmarks of chronic pain syndromes like CFS/ME.
In September 2022, Tonix announced the presentation of a retrospective observational study from approximately 75 million patients from a network of inpatient and outpatient electronic medical records from 48 U.S. healthcare organizations at the 2022 World Congress on Pain. The results showed that of 1 million patients diagnosed with COVID, approximately 52,000 had Long COVID symptoms that lasted between 3 and 6 months. In addition, of the patients with Long COVID, 41% had multi-site pain. These patients took a variety of medications, including benzodiazepines, opioids, and antidepressants. The rate of opioid use was 50% for patients that had multi-site pain and insomnia, with or without fatigue. This is especially concerning since approximately 25% of patients prescribed opioids long term will struggle with opioid addiction (U.S. Department of Labor). The results of this study clearly show that there is a large patient population suffering from Long COVID that need additional treatment options.
Phase 1 Trial of TNX-1500 to Initiate in 3Q23
TNX-1500 is a third-generation anti-CD40 ligand (CD40L) monoclonal antibody (mAb) that is being developed for the prevention of allograft rejection, xenotransplantation, and the treatment of autoimmune disease. The CD40/CD40L signaling pathway is involved in the activation of both the innate and adaptive immune response. CD40 is predominantly expressed on antigen presenting cells (APCs) and delivers intracellular activating signals. CD40L, which does not contain any signaling capacity, is found on multiple cell types, including T cells, B cells, natural killer (NK) cells, macrophages, and platelets (Schönbeck et al., 2001). The CD40/CD40L pathway is essential for humoral immune responses to T cell-dependent antigens (Lederman et al., 1992), the production of proinflammatory cytokines (Cella et al., 1996), and generating effective cytotoxic T cell responses (Liu et al., 2013).
Tonix has an ongoing collaboration for the development of TNX-1500 with Massachusetts General Hospital (MGH), which recently published two manuscripts on it:
• TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate renal allograft survival (Lassiter et al., 2023).
• TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate cardiac allograft survival (Miura et al., 2023).
Now that the IND has cleared, Tonix will be initiating a Phase 1 clinical trial of TNX-1500 in healthy volunteers evaluating single ascending doses of TNX-1500 and the assessment of pharmacokinetics and pharmacodynamics with a target indication of the prophylaxis of organ rejection in adult patients receiving a kidney transplant. We anticipate the trial initiating in the third quarter of 2023.
Financial Update
On May 8, 2023, Tonix announced financial results for the first quarter of 2023. As expected, the company did not report any revenues for the first quarter of 2023. Net loss available to common shareholders for the first quarter of 2023 was $33.0 million, or $0.52 per share (or $3.26 per share post-split), compared to a net loss available to common shareholders of $26.4 million, or $1.61 per share (or $10.12 per share post-split), for the first quarter of 2022. The weighted average common shares outstanding for the first quarter of 2023 were approximately 63.4 million compared to approximately 16.4 million in the first quarter of 2022.
R&D expenses for the first quarter of 2023 were $26.5 million, compared to $18.4 million for the first quarter of 2022. The increase was primarily due to increased clinical development expenses and investment in the development pipeline. G&A expenses for the first quarter of 2023 were $7.4 million, compared to $8.0 million for the first quarter of 2022. The decrease was primarily due to decreased employee-related and financial reporting expenses.
As of March 31, 2023, Tonix had approximately $72.0 million in cash and cash equivalents. We estimate the company has sufficient capital to fund operations into the fourth quarter of 2023. As of May 8, 2023, Tonix had approximately 64.6 million shares outstanding. On May 9, 2023, the company announced a 6.25-to-1 reverse stock split. Thus, we estimate that the company currently has approximately 10.3 million common shares outstanding and, when factoring in stock options and warrants, a fully diluted share count of approximately 11.7 million.
Conclusion
The novel mechanism of action for TNX-601 ER could represent an exciting paradigm shift in the treatment of MDD and we look forward to the publication the company is planning later this year detailing the studies that support its conclusions. This will be another important milestone in 2023, which includes data readouts in the third quarter for the Phase 2 PREVAIL study of TNX-102 SL for the treatment of Long COVID and in the fourth quarter for the Phase 2 PREVENTION study of TNX-1900 for chronic migraine, the Phase 3 RESILIENT study of TNX-102 SL for the treatment of fibromyalgia, and interim results from the Phase 2 UPLIFT trial of TNX-601 ER for MDD. Our model has been modified to account for the reverse split and our valuation now stands at $14 per share.
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