POS0324 TARGETING NON-RESTORATIVE SLEEP IN FIBROMYALGIA WITH BEDTIME TNX-102 SL (SUBLINGUAL CYCLOBENZAPRINE HCL) SIGNIFICANTLY IMPROVES PAIN IN RESILIENT, A CONFIRMATORY PHASE 3 RANDOMIZED CLINICAL TRIAL
Authors: I. Iglehart, S. Lederman, M. Kelley, B. Vaughn, J. Engels, G. Sullivan
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Fibromyalgia (FM) is a chronic nociplastic disorder characterized by widespread pain, nonrestorative sleep, fatigue, and cognitive disturbance. The central role of nonrestorative sleep in the pathogenesis and persistence of FM was initially recognized by Dr. Harvey Moldofsky[1]. Cyclobenzaprine, a tricyclic, potently binds and antagonizes 5-HT2A serotonergic, α1 adrenergic, H1 histaminergic and M1 muscarinic receptors. In RESILIENT, nonrestorative sleep in FM was targeted with a sublingual, transmucosal formulation of cyclobenzaprine (TNX-102 SL) administered at bedtime. A previous Phase 3 study, RELIEF, reported in 2020, showed significant pain improvement (p=0.010) over placebo, making RESILIENT the second positive Phase 3 trial, potentially supporting NDA filing with U.S. FDA. <h3>Objectives:</h3> To evaluate efficacy and safety of TNX-102 SL* for reducing pain in FM and to test the hypothesis that improved sleep quality provides syndromal benefits. <h3>Methods:</h3> Across 33 U.S. sites, the double-blind RESILIENT study enrolled 457 FM patients; each received 2 weeks TNX-102 SL 2.8 mg, followed by 12 weeks 5.6 mg (N= 231), or matching placebo (Safety Pop N=226; ITT Pop N=225). The primary endpoint was change from baseline at Week 14 in weekly average of daily diary numeric rating scale (NRS) pain scores. Six key secondary endpoints included Patient Global Impression of Change (PGIC), Fibromyalgia Impact Questionnaire - Revised (FIQR) Symptoms and Function domains, PROMIS Sleep Disturbance (SD) and Fatigue instruments, and daily diary sleep quality NRS ratings. Efficacy endpoints were analyzed by mixed model repeated measures with multiple imputation, or, for PGIC responder analysis by Pearson's chi-squared test. Safety was assessed by adverse events (AEs), vital signs, weight, and physical exams. <h3>Results:</h3> Reduction in daily pain from baseline at Week 14 was significantly greater with TNX-102 SL (LS mean change [95% CI], –1.82 [−2.04 to −1.59]) vs placebo (−1.16 [−1.40 to −0.93]; <i>P</i>=0.00005; effect size [ES] 0.38). TNX-102 SL demonstrated significant improvement in PGIC, FIQR domains (Symptoms ES 0.44; Function ES 0.30), PROMIS instruments (SD ES 0.50; Fatigue ES 0.37), and daily sleep quality (ES 0.32) (all six <i>P</i>≤ 0.001). Memory by FIQR memory item was also more improved on TNX-102 SL (<i>P</i>=0.001, uncorrected). The most common treatment-emergent AEs were transient, sporadic, self-limited oral administration site reactions: oral hypoaesthesia (23.8% TNX-102 SL vs 0.4% placebo), product taste abnormal (11.7% vs 0.9%), oral paraesthesia (6.9% vs 0.9%), and tongue discomfort (6.9% vs 0%). There were no drug-associated changes in systolic or diastolic blood pressure, weight or sexual side effect AEs. <h3>Conclusion:</h3> In this confirmatory Phase 3 trial, TNX-102 SL treatment significantly improved sleep quality, which demonstrates target engagement. The improvement in nonrestorative sleep was associated with a highly statistically significant reduction in the pain primary endpoint. Also, TNX-102 SL demonstrated broad spectrum syndromal improvement in FM, with an overall favorable safety and tolerability profile. Together, these data strongly establish nonrestorative sleep as a target for broad-spectrum therapy in FM and implicate nonrestorative sleep as a factor in FM persistence. <h3>REFERENCES:</h3> [1] Moldofsky H et al, <i>Psychosom Med</i> 1975;37:341-51. *TNX-102 SL has not been approved for any indication. <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> Iredell Iglehart, III I own stock in Tonix Pharmaceuticals, Inc., I have worked as a consultant for Tonix Pharmaceuticals, Inc., Seth Lederman I own stock and stock options in Tonix Pharmaceuticals, Inc., I am the CEO of Tonix Pharmaceuticals, Inc., Mary Kelley I have stock options in Tonix Pharmaceuticals, Inc., I am an employee of Tonix Pharmaceuticals, Inc., Ben Vaughn I am a salaried employee of a contract research organization that is paid for my consulting. My salary, bonuses, raises are not tied to my performance on this project., Jean Engels I own stock options in Tonix Pharmaceuticals, Inc., I am an employee of Tonix Pharmaceuticals, Inc., Gregory Sullivan I own stock and stock options in Tonix Pharmaceuticals, Inc., I am the CMO at Tonix Pharmaceuticals, Inc.