Background/Purpose: Fibromyalgia (FM) is characterized by chronic widespread pain, unrefreshing sleep, fatigue, and cognitive complaints.  TNX-102 SL* is a sublingual (SL) formulation of cyclobenzaprine (CBP) that is rapidly absorbed and bypasses first-pass metabolism, providing for unique pharmacokinetics of the parent CBP and long-lived metabolite norcyclobenzaprine that previous studies have suggested lead to improvements in overall sleep quality. This may lead to improvements in pain and other somatic complaints by a mechanism distinct from existing FM therapies.  This Phase 3 double-blind, randomized, placebo-controlled, multicenter trial (AFFIRM Study) evaluated safety and efficacy of a 2.8 mg dose of TNX-102 SL 2.8 mg in FM.

Methods: A total of 519 patients meeting ACR 2010 FM criteria were enrolled across 35 centers in a 12-week trial.  Patients were randomized 1:1 to receive TNX-102 SL 2.8 mg (N=262) or placebo (N=257). Primary efficacy endpoint was a responder analysis of patients who reported ≥30% reduction in daily diary pain from baseline to endpoint. Secondary outcome measures included analyses of diary mean pain and sleep ratings, Fibromyalgia Impact Questionnaire (FIQ-R), Patient Global Impression of Change (PGIC), and PROMIS Sleep Disturbance (SD) scales.

Results: The study did not achieve statistical significance on the primary efficacy endpoint (TNX-102 SL, 28.6% responders v. placebo 22.6% responders; OR 1.41 [0.94-2.10], P=0.095). TNX-102 SL did show significant effects on pain over placebo when analyzed by other standard approaches including: 30% responder analysis with BOCF/LOCF imputation (P=0.012); 50% responder analysis with BOCF alone (P=0.035); and MMRM of mean change from baseline (P< 0.001).  TNX-102 SL 2.8 mg improved FIQ-R total score: -13.7 compared to -7.5 for placebo (P< 0.001). PGIC responder rate v. placebo: 23.7% v. 16.3%  (P=0.038). Measures of sleep quality improved including PROMIS SD: -8.0 v. -4.7 (P< 0.001); daily diary: 1.8 v. -1.0 (P< 0.001). Systemic adverse events (AEs) were infrequent, with the only AE reported in ≥5% of TNX-102 SL-treated patients of fatigue (5.7% v. 2.3% in placebo).The most common AEs were local oral events: transient oral hypoaesthesia (40.1% v. 0.8% in placebo), glossodynia (9.2% v. 1.6% in placebo), paresthesia oral (7.6% v. 1.2% in placebo), product taste abnormal (6.1% v. 0.8%  in placebo). A total of 77.5% of TNX-102 SL-treated patients completed the study compared with 86.4% on placebo.

Conclusion: Bedtime TNX-102 SL 2.8 mg, although failing to achieve statistical significance on the 30% pain responder analysis primary outcome, had clinically meaningful effects on pain and sleep by several other measures.  Moreover, there were robust effects of TNX-102 SL at 2.8 mg on the broad array of measures of FM symptoms and function, fatigue, and particularly on measures of sleep quality, the hypothesized mechanism of TNX-102 SL in FM. Post-study analyses suggest that a higher dose of TNX-102 SL may be needed to meaningfully improve pain symptoms in a greater percentage of treated patients.

*TNX-102 SL is an Investigational New Drug and has not been approved for any indication.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-phase-3-randomized-double-blind-placebo-controlled-trial-of-bedtime-sublingual-cyclobenzaprine-tnx-102-sl-for-the-treatment-of-fibromyalgia-fm-evidence-for-a-broad-spectrum-of-activity-on-the/