PTSD is a prevalent global disorder in which individuals experience a prolonged maladaptive response following exposure to life-threatening or severely injurious trauma (sexual or physical assault, natural disasters, combat, and accidents).
Tonix is developing Tonmya®* as a potential treatment for the symptoms of PTSD. It is currently in Phase 3 clinical development. Tonmya targets mechanisms which are associated with disturbed sleep and nightmares. It is believed that increasing sleep quality in PTSD may facilitate the body's adaptive ability to recover from severe trauma, resulting in the improvement of daytime symptoms.
TNX-102 SL is a small, rapidly-disintegrating, under the tongue (sublingual) product candidate containing 2.8 mg of cyclobenzaprine HCl. The unique formulation has been designed to optimize the delivery and absorption of cyclobenzaprine for the therapeutic benefit of improving sleep quality, while minimizing the potential residual effects of oral formulations of cyclobenzaprine. The dose of TNX-102 SL being studied in PTSD is two tablets, or 5.6 mg of cyclobenzaprine each night at bedtime.
Low drug exposure favors the recruitment of high affinity target receptors over lower affinity off-target receptors. Cyclobenzaprine has been shown to have high affinity for three relevant receptor sites (target sites) and is a functional antagonist at all three sites.1
As such, TNX-102 SL is believed to possess a trimodal mechanism of action which may be beneficial in addressing disorders in which sleep disturbances play a central role. In addition, TNX-102 SL is being developed for long-term use, in contrast to oral formulations of cyclobenzaprine which are only approved for 2-3 weeks of daily use. The proposed registration plan for TNX-102 SL for PTSD, agreed to by the FDA, does not require further assessment of abuse and drug dependency potential in clinical or nonclinical study.
Pharmacokinetic studies have shown that TNX-102 SL, after sublingual administration, is distinguished from oral formulations of cyclobenzaprine:
Sleep disturbances (nightmares, insomnia and restless sleep) are core symptoms of PTSD, and evidence suggests that these disturbances may have a role in the onset and development of PTSD, as well as sustaining PTSD in individuals experiencing prolonged symptoms.8 Therapies designed to treat sleep disturbances may therefore offer a unique approach to the overall treatment of PTSD symptoms.
Results from earlier clinical trials have provided evidence that TNX-102 SL improves sleep quality in fibromyalgia, another disorder characterized by poor sleep quality.9
Phase 2 clinical trial in PTSD
A randomized, placebo-controlled Phase 2 P201 study ("AtEase") evaluated the potential clinical benefit of using Tonmya 2.8 mg (one 2.8 mg tablet) and 5.6 mg (two 2.8 mg tablets) given at bedtime to treat military-related PTSD. The entrance criteria included total Clinical-Administered PTSD Scale for DSM-5 (CAPS-5) score ≥ 29. In AtEase 245 participants were enrolled at 24 U.S. clinical sites. The primary endpoint was mean change from baseline in total CAPS-5 at Week 12 between Tonmya 2.8 mg and placebo. https://clinicaltrials.gov/ct2/show/NCT02277704
The Tonmya 2.8 mg group did not achieve statistical significance on CAPS-5 compared with placebo at Week 12. Yet, secondary and retrospective analyses from AtEase provided evidence that Tonmya, at a dose of 5.6 mg nightly for 12 weeks of treatment, was active in reducing symptoms of PTSD, as well as improving the sustained remission rate (at weeks 8 and 12), relative to the placebo treated group. There was also an early and continued reduction in sleep disturbances, supporting the mechanistic hypothesis that Tonmya exerts its overall effect on PTSD symptoms by reducing the impact of sleep disturbances on natural recovery from severe trauma. Tonmya was well tolerated, with the most common adverse event being local administration site reactions, i.e., tongue numbness (hypoaesthesia), which was generally transient and never rated as severe (see Scientific Presentations).
The results from this Phase 2 study formed the basis of the Breakthrough Therapy designation granted by the FDA and informed the design of the Phase 3 HONOR study.
Phase 3 clinical trial in PTSD
The Phase 3 P301 ("HONOR") study was a randomized, placebo-controlled study that was planned to enroll 550 participants with military-related PTSD at 44 U.S. clinical sites. The primary efficacy endpoint was the 12-week mean change from baseline in the severity of PTSD symptoms as measured by CAPS-5 between those treated with Tonmya and those receiving placebo. The CAPS-5 is a structured clinical interview and serves as the standard in research for measuring the symptom severity of PTSD. A planned, unblinded interim analysis was completed in July 2018 when approximately 50 percent (n=274) of planned participants were randomized and completed 12 weeks of treatment with either bedtime sublingual Tonmya 5.6 mg (2 x 2.8 mg tablets) or placebo sublingual tablets. https://clinicaltrials.gov/ct2/show/NCT03062540
Based on a pre-specified study continuation threshold at Week 12, the study was discontinued due to inadequate separation from placebo in the primary efficacy endpoint. Meaningful improvement in overall PTSD symptoms was observed at Week 4, at which time the Tonmya treated group separated from placebo in CAPS-5 (-3.6 improvement in CAPS-5 at Week 12 and p = 0.019). The Clinical Global Impression - Improvement (CGI-I) scale, a key secondary endpoint, also showed separation at Week 4 (p = 0.015). Finally, at Week 4, sleep quality improved as measured by both the PROMIS Sleep Disturbance scale and the CAPS-5 sleep disturbance item, supporting the proposed mechanism of action of Tonmya.
Retrospective analysis of the HONOR study revealed a clinically meaningful response to Tonmya in PTSD participants with trauma experienced within nine years prior to screening but not in participants with trauma experienced greater than nine years prior to screening. For this subgroup, using mixed model repeated measures with multiple imputation (MMRM with MI), the CAPS-5 improvement at Week 12 was -5.9 points (p=0.039). In contrast, there was no benefit in the participants who experienced trauma more than nine years prior to screening. The treatment response seen in HONOR participants with trauma experienced within nine years replicated the results of the Tonmya 5.6 mg group in the Phase 2 AtEase Study.
There were no serious and unexpected adverse events (AEs) in the HONOR study. The AEs observed were comparable and also consistent with the experience in prior studies in fibromyalgia. Observed systemic AEs were consistent with those described in approved oral cyclobenzaprine product labels. Similar severity and incidence of oral hypoesthesia (tongue/mouth numbness) has been observed across studies (37% in HONOR) for Tonmya 5.6 mg.
The findings from HONOR will inform and improve the next Phase 3 study design and increase the chances of success. The new Phase 3 trial will be a double-blind, randomized, placebo-controlled study of Tonmya 5.6 mg over 12 weeks of treatment for civilian and military-related PTSD. The primary efficacy endpoint will be the Week 4 mean change from baseline in the severity of PTSD symptoms as measured by CAPS-5 between those treated with Tonmya and those receiving placebo. A key secondary endpoint will be the Week 12 mean change from baseline in CAPS-5.The new study will restrict enrollment to study participants with PTSD who experienced an index trauma ≤ 9 years from the date of screening, based on the findings from the retrospective analysis of the Phase 3 HONOR study. The study will also include civilian as well as military-related traumas. The Company plans to start a new Phase 3 trial of Tonmya for the treatment of PTSD in the first quarter of 2019, based on guidance from its meeting with the U.S. Food and Drug Administration (FDA).
Tonmya or TNX-102 SL is covered by a number of issued and pending worldwide patents which cover the eutectic composition of matter, method of use, and pharmacokinetic profile. These patents are owned outright by Tonix Pharmaceuticals, and no obligations are owed to another party.
*Tonmya has been conditionally accepted by the FDA as the proposed trade name for TNX-102 SL (cyclobenzaprine HCl sublingual tablets) for PTSD. TNX-102 SL is an investigational new drug and has not been approved for any indication.