Tonix Pharmaceuticals Announces Highly Statistically Significant and Clinically Meaningful Topline Results in Second Positive Phase 3 Clinical Trial of TNX-102 SL for the Management of Fibromyalgia Phase 3 RESILIENT stud

Tonix Pharmaceuticals Holding Corp. 8-K

Pharmaceuticals Announces Highly Statistically Significant and Clinically Meaningful Topline Results in Second Positive Phase 3 Clinical

Trial of TNX-102 SL for the Management of Fibromyalgia

3 RESILIENT study of TNX-102 SL successfully demonstrated daily pain reduction over placebo (primary endpoint, p = 0.00005)

six key secondary endpoints, including patient global impression, fibromyalgia-specific symptoms and dysfunction, fatigue and sleep measures

were significantly improved (all p 0.001)

results support planned New Drug Application (NDA) submission to the FDA in the second half of 2024

estimated 6 million to 12 million adults in the U.S. are living with fibromyalgia, the majority of whom are women

N.J., December 20, 2023 (GLOBE NEWSWIRE) - Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a biopharmaceutical

company with marketed products and a pipeline of development candidates, today announced that the Phase 3 RESILIENT study evaluating

TNX-102 SL (cyclobenzaprine HCl sublingual tablets) met its pre-specified primary endpoint in the second of two positive Phase 3 clinical

trials, significantly reducing daily pain compared to placebo (p=0.00005) in participants with fibromyalgia (Table 1). Statistically

significant and clinically meaningful results were also seen in all key secondary endpoints related to improving sleep quality, reducing

fatigue, and improving overall fibromyalgia symptoms and function. Additionally, as it relates to improving daily pain, treatment with

TNX-102 SL showed a robust and clinically meaningful analgesic effect size of 0.38, with rapid onset of action, separating from placebo

for each week of the study. TNX-102 SL was well tolerated with an adverse event profile comparable to prior studies, and no new safety

signals were observed. Tonix plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the second

half of 2024 for TNX-102 SL for the management of fibromyalgia. An estimated 6 million to 12 million U.S. adults are living with fibromyalgia,

the majority of whom are women.

SL is a tablet formulation containing 2.8 mg cyclobenzaprine HCl and is a novel, centrally-acting, non-opioid analgesic, designed

to be taken once daily at bedtime for the management of fibromyalgia. RESILIENT was a 14-week randomized, double-blind, placebo-controlled

trial of TNX-102 SL 5.6 mg, in which 457 participants with fibromyalgia were randomized in a 1:1 ratio to TNX-102 SL or placebo across

33 sites in the U.S. All participants received one 2.8 mg tablet of TNX-102 SL (2.8 mg) or placebo for the first 2 weeks, which was increased

to two 2.8 mg tablets of TNX-102 SL (5.6 mg) or placebo for the remaining 12 weeks.

December 2020, Tonix reported positive results from the first Phase 3 RELIEF study of TNX-102 SL 5.6 mg for the management of fibromyalgia.

The RELIEF study met its pre-specified primary endpoint, significantly reducing daily pain compared to placebo (p=0.010) in participants

with fibromyalgia, and showing activity in key secondary endpoints.

believe that the positive results of RESILIENT and RELIEF show that fibromyalgia can be successfully treated by TNX-102 SL 5.6 mg and

may provide the opportunity for Tonix to have the first FDA-approved drug for fibromyalgia in more than a decade," said Seth Lederman,

M.D., President and Chief Executive Officer of Tonix Pharmaceuticals. "We are now an important step closer to bringing a new, first-line

treatment to fibromyalgia patients that offers broad symptom relief and favorable tolerability for chronic use and adherence. We believe

that we are well positioned to submit an NDA to the FDA under the 505(b)(2) regulatory approval pathway in the second half of 2024, and

are on track to supply the U.S. market upon FDA approval."

1. Results of Primary and Secondary Endpoints for the Phase 3 RESILIENT Study of TNX-102 SL

FIQ-R = Fibromyalgia Impact Questionnaire - Revised; NRS = Numeric Rating Scale; PROMIS = Patient-Reported Outcomes Measurement Information

*Statistically significant; to control for overall

type 1 error, a pre-specified, serial gatekeeping procedure was utilized.

by mixed model repeated measures with multiple imputation unless otherwise indicated.

endpoint analysis for FDA approvals of Cymbalta and Lyrica in fibromyalgia.

3Pearson's chi-squared test responder analysis, with missing data considered non-responders

data are terrific news for patients with fibromyalgia," said Daniel J. Clauw, M.D., Professor

of Anesthesiology, Medicine and Psychiatry at the University of Michigan. "Despite

approved medications, there remains a need for new treatment options to better address the quality of life impacts many fibromyalgia

patients experience on a chronic basis. TNX-102 SL is a non-opioid, centrally-acting analgesic, the active ingredient of which

has a known, favorable safety profile from decades of use. The fact that cyclobenzaprine was also beneficial in many other key

symptom domains, including sleep quality, sleep disturbance and fatigue, will be appreciated by fibromyalgia patients that struggle with

not just pain but multiple other symptoms."

positive data from RESILIENT and previously with RELIEF, with remarkable separation from placebo on pain, sleep, and fatigue, add support

to TNX-102 SL's proposed mechanism of improving sleep quality to improve the syndromal effects

of fibromyalgia," commented Gregory Sullivan, M.D., Chief Medical Officer of Tonix Pharmaceuticals. "The

sublingual formulation of TNX-102 SL, which uses our proprietary Protectic and Angstro technologies, is integral to

our treatment paradigm. These technologies enable transmucosal delivery of cyclobenzaprine with distinctive pharmacokinetic properties

that include rapid absorption after dosing and bypass of first-pass hepatic metabolism. I would like to thank the RESILIENT study participants

and their families and caregivers, as well as the investigators and their hard-working staff who all made this a highly successful trial."

of Topline Results of the RESILIENT Study

RESILIENT study achieved statistical significance on the pre-specified primary efficacy endpoint: change from baseline in the weekly

average of daily diary pain severity numerical rating scale (NRS) scores for TNX-102 SL 5.6 mg (LS mean [SE]: -1.8 [0.12] units) versus

placebo (-1.2 [0.12] units), analyzed by mixed model repeated measures with multiple imputation (LS mean [SE] difference: -0.7 [0.16]

units, p=0.00005, Table 1). In addition, all pre-specified sensitivity analyses of the primary endpoint were statistically significant

(p<0.001). Figure 1 shows reduction in pain across all weeks of the 14-week study, with nominal p<0.01 for every week. Note the

rapid onset of action with separation from placebo at Week 1 was sustained throughout all weeks of dosing.

LS = least squares; NRS = numerical rating scale; SE = standard error

statistically significant improvement in pain is further substantiated when diary pain was analyzed by another standard statistical approach,

a 30 percent responder analysis, with 45.9% on active and 27.1% on placebo having a 30 percent or greater reduction in pain (Pearson

Chi-Squared Test; difference in proportions [95% CI]: 18.8% [10.1%, 27.4%]; nominal p<0.001).

SL showed statistical significance (p 0.001) on all six pre-specified key secondary efficacy outcome measures (Table 1).

with the proposed mechanism that TNX-102 SL acts in fibromyalgia through improving sleep quality, TNX-102 SL showed statistically significant

improvement of sleep by two main measures. For the daily diary sleep quality ratings, improvement in sleep quality for TNX-102 SL (-1.8

[0.12] units) was significantly greater than that of placebo (-1.2 [0.12] units; LS mean [SE] difference from placebo: -0.6 [0.17] units;

p<0.001). For the PROMIS Sleep Disturbance instrument, TNX-102 SL also demonstrated significantly greater improvement over placebo

on T-scores (LS mean [SE] difference from placebo: -4.2 [0.79] units; p<0.001). Fatigue is another cardinal symptom of fibromyalgia

and has a major impact on quality of life. TNX-102 SL showed significant improvement over placebo on the PROMIS Fatigue instrument T-scores

(-3.0 [0.77] units; p<0.001).

Fibromyalgia Impact Questionnaire - Revised (FIQ-R) is a 21-item self-rated instrument that assesses level of function, overall

impact, and symptoms due to fibromyalgia, and the sympoms and function domains were key secondary endpoints in RESILENT. At Week 14 on

the FIQ-R Symptoms domain, there was significantly greater improvement with TNX-102 SL than with placebo (LS mean [SE] difference from

placebo: -7.7 [1.62], p<0.001). Similarly, TNX-102 SL resulted in greater improvement on FIQ-R Function (LS mean [SE] difference from

placebo: -5.4 [1.66], p=0.001). Although not a key secondary efficacy endpoint, TNX-102 SL also separated from placebo on the FIQ-R Impact

domain (nominal p=0.001). These results, along with the robust effects on improving sleep and fatigue, suggests broad symptomatic coverage

of the syndrome of fibromyalgia.

Results of the Phase 3 RESILIENT Study

the RESILIENT study, TNX-102 SL was well tolerated and consistent with prior trials, with no new safety signals observed. Among participants

randomized to the TNX-102 SL and placebo arms, 81.0% and 79.2%, respectively, completed the 14-week dosing period. As expected based

on prior TNX-102 SL studies, administration site reactions were the most commonly reported adverse events and were higher in the TNX-102

SL treatment group (Table 2). Hypoaesthesia oral and paraesthesia oral, or tongue and mouth numbness or tingling, product taste abnormal

(typically a bitter aftertaste upon dosing), and tongue discomfort were local effects nearly always temporally related to dose administration

and transiently expressed (<60 minutes) in most occurrences. The only treatment-emergent adverse events that occurred at a rate of

3.0% or greater in either arm were these four oral adverse events, along with COVID-19, somnolence, and headache (Table 2). Adverse events

resulted in premature study discontinuation in 6.1% of those who received TNX-102 SL compared with 3.5% of placebo recipients. There

were a total of seven serious adverse events in five patients, five of which were experienced by three patients in the placebo arm, and

two of which were in the TNX-102 SL arm. Of the two in the TNX-102 SL arm, one was renal cancer, deemed unrelated to study drug, and

the other was acute pancreatitis with onset 14 days after dosing was completed and reported as possibly related to study drug.

2. Treatment-Emergent Adverse Events at a Rate of 3% or Greater in Either Treatment Arm

Changes in Sexual Functioning Questionnaire short form (CSFQ-14) served as a safety measure for assessing potential adverse effects on

sexual functioning. In females, the total score on the CSFQ-14 at Week 14 improved (indicating better sexual functioning) in the TNX-102

SL group compared with placebo (nominal p=0.010 by analysis of covariance). This potentially indicates an important tolerability advantage

over pharmacotherapeutics which potently inhibit reuptake of serotonin. The low percentage of males in the safety population (<5%)

did not allow meaningful analysis of the CSFQ-14 data.