Background & Aims
Fibromyalgia (FM) is a common nociplastic syndrome characterized by core symptoms of widespread pain, nonrestorative sleep, fatigue, and cognitive dysfunction and by functional impairment. Non-restorative sleep is hypothesized to be an obstacle to recovery. TNX-102 SL is a sublingual, transmucosal formulation of cyclobenzaprine (CBP) designed for daily administration at bedtime to improve sleep quality. CBP is a tricyclic antagonist of 5-HT2A serotonergic, ?1 adrenergic, H1 histaminergic and M1 muscarinic receptors, each of which plays roles in sleep quality. The mechanistic hypothesis for bedtime TNX-102 SL is that improving sleep quality in FM can lead to syndromal improvement. RESILIENT was the second positive Phase 3 trial of TNX-102 SL 5.6 mg for FM. In addition to significantly improving sleep quality and the primary endpoint of pain, treatment with TNX-102 SL resulted in syndromal improvement, including significant improvements in a broad array of symptoms and function.
Methods
RESILIENT was a double-blind, placebo (PBO)-controlled study that enrolled 457 patients meeting 2016 American College of Rheumatology criteria for FM at 33 U.S. sites. Patients received 2 weeks TNX-102 SL 2.8 mg, followed by 12 weeks of TNX-102 SL 5.6 mg (N=231), or matching PBO (Safety N=226; ITT N=225) for 14 weeks. The primary endpoint was Week 14 change from baseline (CFB) in the weekly average of daily diary numeric rating scale pain scores. Key secondary measures included Patient Global Impression of Change (PGIC), FM Impact Questionnaire-Revised (FIQR)-Symptoms, FIQR-Function, PROMIS Fatigue, PROMIS Sleep Disturbance scales and a daily sleep quality diary. Primary and continuous key secondary efficacy endpoints were analyzed by mixed model repeated measures (MMRM) with multiple imputation (MI) whereas other continuous endpoints by MMRM without MI. Safety assessments included adverse events (AE) and Changes in Sexual Functioning Questionnaire short form (CSFQ-14).
Results
TNX-102 SL reduced daily pain at Week 14 (least squares (LS) mean (SE) difference vs PBO of ?0.7 (0.16); P=0.00005; effect size 0.38), which was the primary endpoint. Statistically significant improvements were also observed in all six pre-specified key secondary endpoints of PGIC, FIQR-Symptoms, FIQR-Function, PROMIS Fatigue, PROMIS Sleep Disturbance and the daily sleep diary. The FIQR cognition item improved on TNX-102 SL vs PBO (LS mean (SE) difference of ?0.8 (0.23); P=0.001; effect size 0.31, no correction for multiple comparisons). The local administration site reaction of oral hypoaesthesia was the most common AE with TNX-102 SL (23.8%) versus placebo (0.4%), and was transient, self-limited, and generally rated as mild (22.1%), occasionally moderate (1.7%), and never severe. Systemic AEs (headache and somnolence) were low (3%) on active, and there were no changes in weight or blood pressure. Females on TNX-102 SL showed an improvement in sexual function by the CSFQ-14.
Conclusions
Bedtime TNX-102 SL treatment targets non-restorative sleep in FM and resulted in broad spectrum or syndromal improvement in both symptoms and function. TNX-102 SL showed significant effects on the pain primary endpoint, and sleep quality, fatigue, cognitive function, patient global, FIQR-symptoms and FIQR-function. As importantly, TNX-102 SL was well tolerated without side effects relating to cognition, weight, blood pressure or sexual dysfunction. TNX-102 SL improved sexual function in female participants. The central role of nonrestorative sleep in the pathogenesis and persistence of FM was recognized by Dr. Harvey Moldofsky.1,2 The benefits of TNX-102 SL therapy in the RESILIENT study support the hypothesis that addressing FM sleep disturbance leads to syndromal improvement. Together, these findings are consistent with the concept that disturbed sleep in FM is an obstacle to recovery and pharmacological targeting of disturbed sleep has the potential to facilitate recovery.
References
*TNX-102 SL has not been approved for any indication.
1. Moldofsky H et al, Psychosom Med 1975;37:341-51
2. Moldofsky H and Scarisbrick P. Psychosom Med 1976;38:35-44.
Presenting Author
Seth Lederman
Poster Authors
Seth Lederman
MD
Tonix Pharmaceuticals
Lead Author
Annie Iserson
MA
Tonix Pharmaceuticals
Lead Author
Gregory Sullivan
MD
Tonix Pharmaceuticals
Lead Author
Mary Kelley
MPH
Tonix Pharmaceuticals
Lead Author
Ben Vaughn
Rho
Lead Author
Jean Engels
MS
Tonix Pharmaceuticals
Lead Author
Topics
- Treatment/Management: Pharmacology: Non-opioid