Background The importance of nonrestorative sleep in the pathophysiology of fibromyalgia (FM) suggests that treatments that improve sleep quality may improve FM globally by a mechanism distinct from that of centrally acting analgesics. TNX-102 SL is a sublingual formulation of cyclobenzaprine (2.8 mg) designed for rapid absorption and bedtime use. The current study was designed to evaluate the safety and efficacy of TNX-102 SL in the treatment of FM.

Objectives The BESTFIT study was designed to evaluate whether the sleep quality improvement associated with TNX-102 SL treatment would lead to improvement in the pain and other symptoms of FM.

Methods BESTFIT was a 12-week, randomized, double-blind, placebo-controlled trial conducted at 17 investigational US sites. Under a US Investigational New Drug Application, 205 participants were randomized 1:1 to receive TNX-102 SL (N=103) or matching placebo (N=102). Outcome measures included daily diary assessment of pain and sleep (0-10 NRS), the Fibromyalgia Impact Questionnaire (FIQ-R), Patient Global Impression of Change (PGIC), PROMIS Sleep Disturbance scale (PROMIS), and mood (Beck Depression Inventory, BDI). Data were analyzed by mean change from baseline using Mixed Effects Model Repeated Measures (MMRM) unless otherwise noted.

Results TNX-102 SL treatment improved multiple domains of FM. Treatment improved the FIQ-R total score by -17.2 compared to -9.1 for placebo, p=0.015. PGIC response rate was improved vs. placebo (30.1% vs. 16.7%, p=0.025 by logistic regression). Several measures of sleep quality improved, including the PROMIS with a -9.5 improvement on active compared to -6.1 on placebo, p=0.004. Sleep as measured by daily diary (change from baseline to endpoint) was improved by -1.9 compared to -1.0 on placebo; p<0.001. TNX-102 improved sleep quality on FIQ-R by -2.9 compared to -1.2 on placebo; p<0.0001. Treatment decreased pain by -1.6 compared to -1.1 for placebo on the daily diary; p=0.086. The same week 12 pain data analyzed for 30% improvement from baseline (responder analysis) was significant with a 34% response rate compared to 20% for placebo; p=0.03. Pain reported at clinic visits (7 day recall NRS) was also significantly improved (p=0.014) as was the pain item on FIQ-R (7 day recall), p=0.004. The most common local adverse event was transient tongue or mouth numbness occurring in 42% of treated patients. Systemic adverse events were very infrequent, none of which occurred at a 5% or greater rate in the treated population. This excellent AE profile is consistent with the decision to use very low doses of cyclobenzaprine to optimize the risk-benefit ratio of this therapeutic approach.

Conclusions Bedtime TNX-102 SL improved sleep quality by multiple measures. Nonrestorative sleep has been linked to central sensitization, which is a process in which regional chronic pain leads to changes in central pain processing and interpretation. The improvement in sleep quality resulting from bedtime treatment with TNX-102 SL was associated with improvements in multiple other symptoms and domains of fibromyalgia.

Acknowledgements Study sponsored by Tonix Pharmaceuticals. TNX-102 SL is an Investigational New Drug and has not been approved for any indication.

Disclosure of Interest None declared