Tonix Pharmaceuticals’ investigational therapy TNX-102 SL (sublingual cyclobenzaprine) safely and effectively eased pain and fatigue in people with fibromyalgia, while also improving their sleep, according to top-line data from the RELIEF Phase 3 trial.
The therapy, given at a dose of 5.6 mg every night at bedtime, met the trial’s main goal and most of its secondary goals, supporting the treatment’s beneficial effects in a patient population with a high unmet need for effective treatments.
“Tonix is dedicated to improving the lives of the millions suffering from fibromyalgia, approximately 90% of whom are female, and the results of the RELIEF trial bring new hope to this community,” Seth Lederman, MD, Tonix’s president and CEO, said in a press release.
“One of the biggest challenges in drug development is finding a dose that balances efficacy and tolerability,” he said, adding that Tonix is pleased with the therapy’s consistent effects on pain and the tolerability of the dose studied.
Gregory Sullivan, MD, Tonix’s chief medical officer, said that “TNX-102 SL could potentially offer fibromyalgia patients, who have multiple disabling fibromyalgia symptoms, a first-line [single therapy] with broad symptom relief, and the compliance advantage of being administered once-a-day (at bedtime).”
The therapy’s active ingredient, cyclobenzaprine, “has no recognized potential for addiction,” he added, in contrast to opioids, which are used by about one-third of fibromyalgia patients “out of desperation and because of dissatisfaction with available therapies.”
A second potential pivotal Phase 3 study, called RALLY (NCT04508621), designed to test a higher dose of TNX-102 SL, is currently enrolling people with fibromyalgia, and top-line data is expected in the second half of 2021.
Should the RALLY study also produce positive data, Tonix may submit a new drug application to the U.S. Food and Drug Administration requesting the therapy’s approval for fibromyalgia in 2022. The company expects to be ready to market the therapy immediately if it’s approved.
Evidence suggests that sleep problems, a common symptom of fibromyalgia, may contribute to the chronic nature and worsening of the disease. As such, therapies targeting sleep disturbances may offer a unique approach to lessen other fibromyalgia symptoms, such as pain and fatigue.
TNX-102 SL is a sublingual (under-the-tongue) reformulation of cyclobenzaprine, a muscle relaxant with the potential to improve sleep quality by targeting three pathways involved in sleep disturbances.
While current oral formulations of cyclobenzaprine can be used only for short periods due to liver toxicity, TNX-102 SL is designed to promote faster absorption into the bloodstream with limited liver toxicity, potentially allowing for longer treatment periods.
Participants were randomly assigned to receive a single tablet of TNX-102 SL (2.8 mg) or a placebo at bedtime for the first two weeks, after which the dose was increased to two daily tablets (5.6 mg of TNX-102 SL or a placebo) for an additional 12 weeks. More than 82% of patients in both groups completed the 14-week treatment period (about 3.5 months).
Top-line results showed that TNX-102 SL significantly reduced patients’ self-reported pain — as assessed with a numerical rating scale — compared with a placebo, meeting the trial’s main goal. Also, significantly more treated patients had a 30% or greater drop in self-reported pain, compared with those on the placebo (46.8% vs. 34.9%).
The therapy also led to significant improvements in all fibromyalgia-specific secondary goals. In particular, TNX-102 SL lessened fibromyalgia symptoms and improved physical functioning — both assessed by the Fibromyalgia Impact Questionnaire — while also reducing fatigue, as measured with PROMIS Fatigue.
Participants receiving TNX-102 SL also showed a significant improvement in sleep, as assessed with both a sleep quality daily diary and the PROMIS Sleep Disturbance Scale.
“These results validate the mechanism that improving sleep quality can lead to [positive] effects on fibromyalgia,” said Harvey Moldofsky, MD, founding director of the University of Toronto’s Centre for Sleep and Chronobiology and a member of Tonix’s scientific advisory board.
Interestingly, while a greater proportion of TNX-102 SL-treated patients reported improvements in the Patient Global Impression of Change (PGIC), compared with those given a placebo, these differences did not reach statistical significance.
While PGIC is not related to any specific fibromyalgia symptom, these findings were “unexpected,” Sullivan said, as previous TNX-102 SL trials showed significant improvements in this measure.
“We speculate that the ongoing COVID-19 pandemic might have affected the participants’ sense of well-being and confounded the PGIC measure,” Sullivan added.
TNX-102 SL was generally well-tolerated, with a safety profile consistent with that reported in previous trials of a lower 2.8 mg daily dose, and with no new safety concerns identified.
The most common adverse events with TNX-102 SL were tongue/mouth numbness (17.3%) and pain or discomfort (11.7%), followed by taste impairment (6.5%), oral tingling (5.6%), and drowsiness (5.6%). Notably, drowsiness is a known side effect of marketed oral cyclobenzaprine.
A higher proportion of patients in the TNX-102 SL group (8.9%) discontinued treatment due to adverse events, compared with those on a placebo (3.9%).
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