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By David Bautz, PhD
NASDAQ: TNXP
READ TNXP’S FULL RESEARCH REPORT
Company Update
Phase 2 trial of TNX-102 SL begins in prolonged COVID
On August 22, 2022, Tonix (NASDAQ:TNXP) announced the initiation of the Phase 2 PREVAIL clinical trial of TNX-102 SL in patients with prolonged COVID (NCT05472090), a heterogeneous condition that reaches nociplastic pain following infection and recovery from SARS-CoV-2, the virus that causes COVID-19 (Bierle et al. , 2021). Interestingly, several symptoms of prolonged COVID (multi-site pain, fatigue, sleep disturbances, and cognitive dysfunction) overlap with the main symptoms of fibromyalgia. , and it is those patients that society will follow.
Research continues to advance in the study of musculoskeletal pain and, recently, a new descriptor has been proposed to describe pain that is neither nociceptive (due to the activation of nociceptors by actual or imminent lesions of non-nervous tissue) nor neuropathic (caused by injury or disease of the somatosensory nervous system) (Trouvin et al. , 2019). Nociplastic pain is used to describe pain that occurs from an altered pain sensation despite the absence of clear evidence of actual or potential tissue damage, or from a disease or injury to the somatosensory system. Patients suffering from FIBROMYALGIA type COVID Long have compatibility in the description of those suffering from nociplastic pain.
Central sensitization (neuronal signaling amplified in the central nervous system formula that causes the hypersensitivity reaction to pain) is a complementary explanation for why patients suffer from chronic nonspecific pain, especially in fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome (Woolf et al. al. , 2011). The Central Sensitization Inventory (CSI) is a screening tool for identifying patients with central sensitization (Neblett et al. , 2013). A survey of 491 patients with prolonged COVID showed that 70% had central sensitization symptoms (ICS ≥40/100) and 65% had severe symptoms of central sensitization (Goudman et al. , 2021).
About 50% of patients who contract SARS-CoV-2 experience prolonged COVID symptoms up to a month after infection. Even after six months, 30% of patients continue to have long-lasting symptoms of COVID. Hospitalized patients with severe symptoms after SARS-CoV-2 infection are likely to suffer from prolonged COVID (Hirschtick et al. , 2021). A recent report from the Brookings Institution reported that between two and 4 million Americans were not running due to the effects of prolonged COVID. , which translates to about $170 billion a year in lost wages.
To better perceive the prospective duration of the Long COVID market, a retrospective and observational database examination was conducted to identify the number of Long COVID patients among approximately 75 million patients of a network of inpatient and outpatient electronic medical records of 48 US healthcare organizations. The effects showed that of 1 million patients diagnosed with COVID, about 52,000 had prolonged COVID symptoms lasting 3-6 months. Additionally, among patients with prolonged COVID, 41% had pain at multiple sites. These patients were taking a variety of medications, including benzodiazepines, opioids, and antidepressants. The rate of opioid use was 50% for patients with multisite pain and insomnia, with or without fatigue. long-term opioids will suffer from opioid addiction (US Department of Labor). The effects of this study obviously show that there is a giant population of patients with prolonged COVID who want more remedy options.
The Phase 2 PREVAIL review is a 14-week, double-blind, randomized, multicenter, placebo-controlled trial to compare the efficacy and protection of TNX-102 SL in patients with multisite pain related to post-acute SARS-CoV-2 infection (PASC). We expect approximately 470 patients to be enrolled in the trial, with the number one efficacy endpoint being the replacement from the start of the weekly average of the worst self-reported daily pain intensity scores at week 14. Primary secondary outcomes come with a replacement from the outset in self-reported scores for sleep disorders, fatigue and cognitive function. We expect interim research to be conducted after the first 50% of enrolled patients have completed the study, and the effects of this research will guide a possible reestimation of pattern length or early termination of the study for efficacy reasons. The outcome of the interim investigation is expected in the first half of 2023.
Launch of TNX-801 Phase 1 Test in 1S23
In July 2022, Tonix Pharmaceuticals Holding Corp. announced a collaboration with the Kenya Medical Research Institute (KEMRI) to plan, seek regulatory approval and conduct a Phase 1 clinical trial in Kenya to expand TNX-801, a living form of the smallpox virus. as a vaccine to save you from monkeypox and smallpox. We expect the study to be published in early 2023.
The World Health Organization (WHO) has declared apepox a global fitness emergency. More than 40,000 cases of the disease have been reported in 94 countries around the world. Although the precise cause of the existing outbreak is unknown, it has highlighted the possible need for a vaccine opposed to monkeypox.
In June 2022, Tonix announced the presentation of a poster at the 4th Symposium of the Canadian Society of Virology describing the effects of animals vaccinated with TNX-801 to protect themselves from monkeypox. You can get a copy of the presentation poster here. All animals (n = 8) vaccinated with TNX-801 were completely immune to sterilization (p. e. g. , without evolved lesions) as opposed to intratracheal provocation with monkeypox. Vaccines with TNX-801 were well tolerated, as shown through solid weights and frame temperature for all treated animals.
Tonix recently announced that the U. S. Patent and Trademark Office has been able to do so. The U. S. Department of Homeland Security (USPTO) granted the U. S. Patent. U. S. 11,345,896, titled “Synthetic Chimeric Poxviruses,” which includes claims covering the artificial smallpox virus and for the company’s recombinant smallpox virus platform to protect against other pathogens, adding SARS-CoV-2. The patent is expected to provide market exclusivity in the United States through 2037, any extension of the patent term, or any adjustment of the patent term.
Update on the Phase RESILIENT trial for TNX-102 SL in fibromyalgia
In April 2022, Tonix presented the RESILIENT study, a randomized, double-blind, placebo-controlled, potentially pivotal Phase 3 trial of TNX-102 SL for the fibromyalgia remedy. It is expected to recruit about 470 participants in the United States. The effects of a planned interim investigation are expected in the current quarter of 2023.
In March 2022, Tonix announced that, as expected based on a pre-specified interim analysis reported in the past, TNX-102 SL did not meet the number one endpoint of reducing daily fibromyalgia (FM) pain at week 14 in the Rally Phase 3 trial (P = 0. 115).
In December 2020, Tonix announced the first positive effects of the Phase 3 RELIEF test of TNX-102 SL 5. 6 mg (primary endpoint, P = 0. 010). Therefore, since Tonix has already conducted a positive trial in fibromyalgia, the positive effects of RESILIENT’s examination may put the company in a position to register a New Drug Application (NDA) for TNX-102 SL for the treatment of fibromyalgia.
Phase 2 of TNX-1900 for chronic migraine to be launched in 4Q22
In June 2022, Tonix announced the publication of an article in Pharmaceutics describing the stimulating effect of magnesium on intranasal oxytocin activity in an animal style of craniofacial pain (Bharadwaj et al. , 2022). TNX-1900 is based on magnesium-enriched formulas of intranasal oxytocin to prevent migraines in chronic migraineArrayThe generation is also used in TNX-2900, which is being developed to treat overfeeding in adolescents and young adults with Prader-Willi syndrome. We expect the company to initiate a clinical trial of TNX-1900 for saving migraines in chronic migraine in the fourth quarter of 2022.
Migraine
A migraine is a headache that can cause severe pain, can last up to 72 hours, has a pulsating quality and can be related to nausea, vomiting, phonophobia or photophobia. Around one billion people worldwide suffer from migraines (GBD 2016 Headache Collaborators). In the United States, migraines affect approximately 72 million more people (Gooch et al. , 2017). Chronic migraines, which are explained as headaches at least 15 times a month for 3 months, are less common (1-5% of migraine sufferers). Although not fatal, migraines contribute to a significant reduction in quality of life and the overall estimated rate of all migraines is approximately $78 billion per year (Gooch et al. , 2017).
Migraine remedies are classified as abortifacient (intended to prevent a migraine once it has started) or prophylactic (decrease the frequency and/or severity of migraines). Abortion remedies come with triptans and ditanes (which in particular target serotonin receptors), without a prescription. medications (which come with a mixture of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen and/or caffeine), ergots, and calcitonin-related genes. peptide antagonists (CGRP). By 2026, the migraine remedies market is estimated at around $12 billion (EvaluatePharma).
Antibodies that target the interaction of CGRP with its receptor constitute the new class of prophylactic remedies and come with Aimovig (erenumab), which targets the CGRP receptor, and Ajovy (fremanezumab), Emgality (galcanezumab), and Vyepti (eptinezumab), which target CGRP. These drugs generated more than a billion dollars in sales in 2021 and are expected to generate sales of 2. 2 billion dollars in 2026 (EvaluatePharma). The following table presents a summary of its effects in phase 3 clinical trials.
Each of the antibody remedies directed through CGRP is administered as injections or subcutaneous infusions in a monthly program or once every 3 months. Side effects related to CGRP antibodies are sometimes mild or moderate, with redness and/or pain at the injection site. being the most common, due to a number of fundamental systems in which CGRP is involved, there are a number of theoretical long-term adverse effects that can occur once knowledge is available (≥ 10 years), adding the role of CGRP in hypertension, wound healing and insulin levels (Robbins, 2020).
Oxytocin in migraine
Although the precise cause of migraines remains to be elucidated, it appears to be related to the hypothalamus and its connections to the trigeminal spinal nuclei and the sensory trigenovascular system, so neuromodulators that target the trigeminal pathway would possibly prove effective in migraines.
Oxytocin is a nine-amino acid peptide hormone involved in a wide variety of biological processes, including learning and memory, anxiety, addiction, eating behavior, maternal behavior, and social data processing (Cilz et al. , 2019). A review of the available literature showed that in 29/33 animal studies, oxytocin increases tolerance to “pain” (Rash et al. , 2014), suggesting that it would possibly act as an analgesic. Circumstantial evidence shows that oxytocin could be an effective migraine remedy based on the fact that higher levels of oxytocin in pregnancy and lactation correlate with a lower migraine frequency (Hoshiyama et al. , 2012) and some women who suffer from migraines report that sex (resulting in higher levels of oxytocin) provides in transient minimal relief from the condition. (Hambach et al. , 2013).
While the prospect of oxytocin as a remedy for migraines looks promising, the delivery of oxytocin to the trigeminal formula is complicated due to the fact that: 1) oxytocin is a small peptide that breaks down to the maximum without delay in the gastrointestinal formula; and 2) its half-life in the bloodstream is very short (3-5 min) with only a limited ability to cross the blood-brain barrier, thus eliminating the advantage of oral or parenteral management. But administered intranasally, oxytocin penetrates the nasal mucosa and is transported along the trigeminal nerve pathway to the trigeminal ganglion, where it can inhibit the release along trigeminal neurons that synapse with the dura mater mucosa and inhibit the release of CGRP. The barrier and access to the CNS would possibly be nasal management along the olfactory and trigeminal pathways to the brain (Dhuria et al. , 2010).
Several preclinical studies have proven the possibility that oxytocin is a migraine remedy. Oxytocin receptors are provided in rat trigeminal neurons, and the vast majority of neurons containing oxytocin receptors also contain CGRP (Tzabazis et al. , 2016). Intranasal management of radiolabeled oxytocin in rats has effects on a very high concentration of oxytocin in the 3 branches of the trigeminal nerve and trigeminal ganglion (Tzabazis et al. , 2017). Administration of nitroglycerin triggers migraines in patients (Sances et al. , 2004), so intraperitoneal injection of nitroglycerin is used in a type of migraine in rats (Ma et al. , 2008). This trend affects C-fos expression in several trigeminal neurons (a marker of trigeminal nerve activation), but prior treatment with intranasal oxytocin particularly reduces C-fos expression, indicating a prospective role of oxytocin in preventing pain transmission.
In the past, a Phase 2 clinical trial of intranasal oxytocin was conducted through Trigemina, Inc. , from which Tonix acquired TNX-1900 in June 2020. This was a double-blind, placebo-controlled trial in 218 migraine patients, most commonly women (143 with oxytocin; 75 with placebo) and was conducted in Chile, Australia, and New Zealand (NCT01839149). The trial consisted of a 28-day ‘discontinuation’ era to identify a baseline of migraine days, followed by 56 days of ‘as needed’ dosing with intranasal oxytocin or placebo. The effects showed that intranasal oxytocin was well tolerated, the study did not meet the number one endpoint of a relief on migraine days compared to baseline. This was basically due to an incredibly high placebo reaction rate at clinical sites in Chile, which was 74%, while subjects from New Zealand and Australia experienced an overall reaction to placebo and showed a statistically significant difference between active teams and placebo (Tzabazis et al. , 2017).
Based on the effects of preclinical studies demonstrating increased analgesic activity of oxytocin-mediated oxytocin in the presence of magnesium, Trigemina has developed patented and potentiated formulas of oxytocin containing magnesium. Tonix has acquired the intellectual assets of these formulas and plans to improve them first in that of chronic migraine.
Based on the effects of the latest Phase 2 trial, we expect Tonix to conduct a designed Phase 2 trial of TNX-1900, which are magnesium-enhanced intranasal oxytocin formulas, for the prophylactic remedy of chronic migraine. We expect the trial to be designed in the same way as the previous Phase 2 trial with a reference era of 28 days followed by 84 dosing days. We expect the trial to begin in the fourth quarter of 2022.
Development of TNX-601 ER as a deterrent to abuse, prolonged release of tianeptin oxalate
In July 2022, Tonix announced the progression of TNX-601 ER (tianeptin oxalate extended-release tablets) as naloxone-free formulas of TNX-601, which is designed to be a deterrent to abuse of primary depressive disorder (MDD), post-traumatic stress disorder, and corticosteroid-related neurocognitive disorder. In the past, Tonix had developed a tablet containing naloxone, TNX-601 CR, for CT, designed to mitigate the threat of parenteral abuse. Households and has been linked to misuse at much higher doses than would be effective in the treatment of CT (Lauhan et al. , 2018).
Tianeptin sodium immediate-release tablets have been approved in Europe and many countries in Asia and Latin America for the treatment of CT for more than 3 decades, but the FDA has not approved any products containing tianeptin. The efficacy of tianeptin sodium is comparable to either selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, while the occurrence of sexual disorders (which is very high for SSRIs and tricyclic antidepressants) is lower.
• In a study comparing tianeptin and escitalopram (an SSRI) in patients with MDD, treatment with tianeptine resulted in more innovations in the neurocognitive service compared to escitalopram (Jin Jeon et al. , 2014).
• An eight-week study of tianeptin in elderly patients with MDD used escitalopram as an active comparator (Emsley et al. , 2018). The effects showed that tianeptin advanced in depressive symptoms and was tolerated well, with only minimal differences in tolerance compared to placebo.
• A study examining the prevalence of sexual disorders in patients with MDD found that tianeptin treatment was associated with a lower point of sexual disorders compared to SSRIs or tricyclic antidepressants (Bonierbale et al. , 2003).
• Tianeptin is not subject to first-pass hepatic metabolism, so there is a reduced likelihood of drug interactions that are not unusual with other CT remedies (Wagstaff et al. , 2001). In addition, its aspect effect profile is similar to that of SSRIs. and minimal compared to tricyclic antidepressants, adding anticholinergic effects.
TNX-601 ER is designed for once-daily dosing, which contrasts with the three-fold dose required for tianeptin sodium in Europe and other jurisdictions, which helps increase patient adherence. We expect Tonix to initiate a Phase 2 trial of TNX-601 ER in the first quarter of 2023, pending approval of the investigational new drug application (IND) through the U. S. FDA. USA
Financial update
On August 8, 2022, Tonix announced its monetary effects for the current quarter of 2022. As expected, the company reported no profit for the current quarter of 2022. Net loss to non-unusual shareholders for the current quarter of 2022 $27. 4 million, or $1. 22 in stock, compared to a net loss to common shareholders of $23. 6 million, or $2. 25 in stock, for the current quarter of 2021. The weighted average number of common shares currently stands out quarter 2022 approximately 22. 4 million, compared to approximately 10. 5 million in the current quarter of 2021.
expenditure R
As of June 30, 2022, Tonix had approximately $145. 5 million in money and money equivalents. As of August 8, 2022, the Company had approximately 43. 1 million notable non-unusual inventories and, adding inventory features and warranties, a fully diluted amount of inventories of approximately 45. 5 million.
concluding observations
The monkeypox outbreak has sparked renewed interest in the TNX-801 and we await updates from the company on its development. The COVID program is prolonged, as the company will focus on patients whose symptoms overlap with fibromyalgia. The next major turning point that investors should be aware of is likely the interim research from the Resilient Phase 3 study of fibromyalgia, the effects of which are expected at this time. Quarter 2023. After taking into account the company’s recent capital increases through the ATM and acquisition agreement, our valuation has decreased to $8 in line with the stock.
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