Tonix Pharmaceuticals Reports Topline Results from Phase 3 RECOVERY Study of TNX-102 SL in PTSD and Outlines Future Development Plans

Primary Endpoint For Full Cohort of Enrolled Participants Did Not Achieve Statistical Significance (P=0.343), Consistent with Previously Reported Interim Analysis 

Encouraging Activity of TNX-102 SL Observed in Secondary Endpoints: Clinical Global Impression – Severity (P=0.024), Patient Global Impression of Change (P=0.007) and PROMIS Sleep Disturbance (P=0.055)

Participants were 94% Civilian PTSD and 79% Female: Global Impression and Sleep Results Similar to Prior Studies of TNX-102 SL in Predominantly Male, Military-Related PTSD Studies

TNX-102 SL Generally Well Tolerated; No New Safety Signals Observed: No Change in Weight or Blood Pressure

Total CAPS-5 Decreased by 58% in Treatment Group and 49% in Placebo Group

Planning Development of TNX-102 SL for Treatment of PTSD Sleep Disturbance Indication, Pending FDA Discussion

CHATHAM, N.J., Dec. 21, 2020 (GLOBE NEWSWIRE) -- Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company, today announced topline results from its Phase 3 RECOVERY study1 of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) 5.6 mg for the treatment of civilian and military-related posttraumatic stress disorder (PTSD). The RECOVERY study did not achieve statistical significance in the prespecified primary efficacy endpoint of change from baseline to Week 12 in the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) between TNX-102 SL and placebo (p=0.343) (Table 1). In the primary analysis, TNX-102 SL subjects achieved a 20.7 unit reduction in CAPS-5 versus 18.5 units for placebo. TNX-102 SL separated from placebo in the first key secondary endpoint, Clinical Global Impression – Severity (CGI-S) scale (p=0.024) (Table 1) and in the Patient Global Impression of Change (PGIC), (p=0.007). TNX-102 SL also trended for improvement on the PROMIS Sleep Disturbance scale (p=0.055), consistent with the proposed mechanism of targeting the PTSD sleep disturbance (Table 1). Among completers, there was a 58% observed mean reduction in symptoms in the active group compared to 49% in the placebo group, as measured by CAPS-5 total. TNX-102 SL is generally well tolerated and no new safety signals were observed.

“As expected from the futility result at the interim analysis in the first quarter of 2020, TNX-102 SL did not separate on the primary endpoint of CAPS-5 at Week 12,” said Seth Lederman, M.D., President and Chief Executive Officer. “Given the complexity of PTSD as a syndrome and the demonstrated potential of TNX-102 SL to improve sleep quality in PTSD, we plan to meet with the U.S. Food and Drug Administration (FDA) to discuss a proposed new indication: TNX-102 SL for the treatment of sleep disturbance associated with PTSD. Sleep disturbance is a core symptom of PTSD and believed to play roles in onset, consolidation and chronicity. Treating sleep disturbance is recognized as a clinically valid approach for addressing global improvement in PTSD2-5. This new direction is supported by consistent results observed from all three registration-quality studies of TNX-102 SL in PTSD (nearly 800 participants randomized across three placebo-controlled trials) showing trends or nominal benefits in treating sleep disturbance, global improvement by patient self-rating or by clinician-rating. These results included female-predominant, civilian PTSD in RECOVERY and male-predominant, military-related PTSD in the Phase 2 AtEase6 and Phase 3 HONOR7 studies. The FDA-approved insomnia drugs of the benzodiazepine or non-benzodiazepine classes are DEA-Schedule IV, have not been shown useful in PTSD and have the potential to impair sleep-dependent memory processing at high doses or when combined with alcohol.”

Greg Sullivan, M.D., Chief Medical Officer, said, “We are encouraged by TNX-102 SL’s activity on the sleep disturbance in PTSD and on the clinician-rated and patient self-rated global measures of clinical improvement, CGI-S and PGIC, in this predominantly female and civilian PTSD sample. Pending discussion with the FDA, we intend to pursue TNX-102 SL as a treatment for the sleep disturbance that is integral to the development and maintenance of PTSD. PTSD is a memory processing disorder, and adequate quality and quantity of deep slow wave sleep and rapid eye-movement sleep are known to be important for emotional memory processing necessary for recovery from trauma. Although treatment of the PTSD sleep disturbance would be a new indication, instruments like sleep quality assessments can be validated by patient- and clinician-perception of global improvement. Therefore, the discriminatory power of CGI-S and PGIC on TNX-102 SL’s activity in PTSD support such a development. TNX-102 SL is mechanistically distinct from the two FDA approved PTSD drugs; both are SSRIs, and neither target the sleep disturbance.

Dr. Sullivan continued, “We are also encouraged by the tolerability profile that has been expanded by the RECOVERY study. TNX-102 SL treatment was not associated with weight gain or sexual side effects, and TNX-102 SL treatment notably trended towards improvement of female sexual function in RECOVERY (Table 3). This tolerability profile has the potential to differentiate TNX-102 SL from the reported tolerability of the two SSRIs that are FDA-approved for PTSD.”

“Tonix has worked diligently to develop a treatment for PTSD, a serious and disabling condition affecting nearly 12 million civilian and veteran adults in the U.S.,” said Dr. Lederman. “The demographics of the RECOVERY study participants, 94% civilians and 79% female, largely reflect the real-world metrics of those living with PTSD in which the vast majority are civilians and, among diagnosed civilians, approximately two-thirds are female. We are grateful for the contributions from all our study participants and their families in helping advance this program.”

Table 1. RECOVERY study: Primary and Secondary Efficacy Endpoints

Abbreviations: CAPS-5 = Clinician-Administered PTSD Scale; CFB = change from baseline; CGI-S = Clinical Global Impression – Severity; CI = confidence interval; ES = effect size; LS = least squares; LSMD = least squares mean difference; N = number; PGIC = Patient Global Impression of Change; PROMIS = Patient-Reported Outcomes Measurement Information System; SD = sleep disturbance; SE = standard error; Wk = week.# Primary efficacy endpoint *All secondary p-values are descriptive

Table 2. RECOVERY study: Changes in Weight, Blood Pressure and Heart Rate Between Baseline and Last Assessment

Abbreviations: CI = confidence interval;N = number

Table 3. RECOVERY study: Changes in Sexual Functioning Questionnaire Short Form

*higher score on CSFQ-14 indicates better sexual functioning** p-value is descriptiveAbbreviations: CSFQ-14 = Changes in Sexual Functioning Questionnaire short form: CI = confidence interval; ES = effect size; LS = least squares; LSMD = least squares mean difference; N = number; SE = standard error; Wk = week.

RECOVERY STUDYThe RECOVERY study was a double-blind, randomized, placebo-controlled, adaptive design study evaluating the efficacy and safety of TNX-102 SL 5.6 mg over 12 weeks of treatment for civilian and military-related PTSD. The study enrolled 192 participants across 29 clinical sites in the U.S. Enrollment was restricted to individuals with PTSD who experienced an index trauma within nine years of screening. The primary efficacy endpoint was the mean change from baseline in the severity of PTSD symptoms as measured by the CAPS-5 between those treated with TNX-102 SL 5.6 mg and those receiving placebo.

Interim AnalysisA pre-specified interim analysis (IA) was conducted by an unblinded Independent Data Monitoring Committee (IDMC) after half the target population was enrolled and evaluable in Q1 2020. The Company announced it stopped enrollment in RECOVERY following a non-binding recommendation to stop the trial for futility by the IDMC (N=112; IA modified Intent-to-Treat (mITT) population). The Company chose to discontinue new enrollment but continue all currently enrolled participants at that time to completion. The IDMC decision to discontinue enrollment in the study was not related to safety of TNX-102 SL; the blinded safety data from the IA did not reveal any serious and unexpected adverse events.

Full cohort topline analysis:In the full cohort topline analysis, 163 of the 192 participants enrolled were included in the modified mITT population. TNX-102 SL did not achieve statistical significance in the prespecified primary efficacy endpoint of change from baseline in CAPS-5 (p=0.343; Table 1). The CAPS-5 is a standardized structured clinical interview and serves as the standard in research for measuring the symptom severity of PTSD, although it was developed as a diagnostic instrument. The CAPS-5 assesses 20 items by rating severity (a function of intensity and frequency of each symptom) on a 5 point Likert scale (0-4), so the total scores range from 0 to 80. Earlier versions of the CAPS, which assessed 17 items from the DSM-IV or earlier by recording intensity and frequency as separate 5 point Likert scales (total score range 0 to 136), were used to support the approval of the two currently marketed PTSD treatments.

TNX-102 SL separated from placebo in the first key secondary endpoint, CGI-S scale, by LS mean (SE) of -0.5 units (p=0.024) (Table 1). The CGI-S measures how clinicians rate the severity of PTSD in study participants over the preceding week and is not tied to any theoretical construct of disease recovery such as the assumptions inherent in the CAPS-5 items. Previous studies of TNX-102 SL, AtEase and HONOR, used the Clinical global impression of improvement (CGI-I), which is similar to CGI-S, but is based on a “lookback” to patient baseline, rather than 7 days.

TNX-102 SL also separated from placebo in the PGIC analyzed as a continuous measure with a least squares mean difference (standard error) -0.5 (0.19), p=0.007 by Mixed Models Repeated Measures (MMRM). Similarly to previous TNX-102 SL studies (AtEase and HONOR), in RECOVERY TNX-102 SL separated in the PGIC by responder analysis, with TNX-102 SL treatment resulting in 51.3% responders relative to 34.9% on placebo, odds ratio 1.88 [1.00, 3.54], p=0.049 by Cochran-Mantel-Haenszel test. The PGIC measures how study participants themselves rate how they feel; it is not tied to any theoretical construct of disease recovery such as the assumptions inherent in the CAPS-5 items.

Dr. Sullivan said, “In RECOVERY, the placebo response elicited on CAPS-5 was more pronounced than that reported by CGI-S and PGIC. Similar results were observed in our two previous studies. The high levels of PTSD symptom improvement of placebo-treated trial participants detected by CAPS, was not reported by the patients themselves as measured by PGIC, nor by the clinicians by CGI-S in the RECOVERY study or by CGI-I in the AtEase or HONOR studies. We believe that the high levels of CAPS-5 improvement in the placebo groups of these trials do not correspond to the clinical challenges of treating moderate-to severe PTSD patients in practice, which suggests a measurement problem. Although we devoted significant efforts to CAPS-5 rater-training, certification and monitoring, the CAPS-5 data from these studies have not tracked the patient and clinician perceptions of global improvement, which are typically anchors for observable units of improvement on disease symptom-specific scales.”

Effects of TNX-102 SL on Sleep QualitySimilar to prior studies, TNX-102 SL at 5.6 mg in RECOVERY demonstrated trends on measures of sleep quality including the PROMIS Sleep Disturbance inventory, which at Week 12 showed a least squares (LS) mean difference (SE) from placebo of -3.5 (1.82), p=0.055 (Table 1). Although the early stop of enrollment due to the interim analysis outcome resulted in an underpowered sample size for detecting effects on sleep at p