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If approved, cyclobenzaprine hydrochloride (HCl) will be the first member of a new class of analgesic drugs for fibromyalgia.
The FDA accepted the filing of a new drug application (NDA) for cyclobenzaprine hydrochloride (HCl; TNX-102 SL; Tonix Pharmaceuticals) sublingual tablets for the management of fibromyalgia.1 The NDA is supported by data from 2 different 14-week phase 3 trials, RELIEF (NCT04172831)2 and RESILIENT (NCT05273749).3
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Cyclobenzaprine HCl is a 5.6 mg, non-opioid, centrally acting investigational drug designed for chronic use. According to experts, the FDA is expected to assign a Prescription Drug User Fee Act (PDUFA) target action date in a Day 74 Letter, and at that time, the FDA will also communicate whether priority review has been granted. Additionally, cyclobenzaprine HCl was granted a fast track designation for fibromyalgia in July of 2024.1
“The FDA’s acceptance of our NDA represents another step forward as we pursue our goal of delivering the first member of a new class of medicines for the management of fibromyalgia, a condition affecting over 10 million adults in the US,” said Seth Lederman, MD, CEO of Tonix Pharmaceuticals, in a news release.1
RELIEF (NCT04172831) is a randomized, parallel-group, double-blind, placebo-controlled, 14-week phase 3 trial designed to evaluate the safety and efficacy of cyclobenzaprine HCl in patients with fibromyalgia. Enrolled patients were randomly assigned to receive either 5.6 mg of cyclobenzaprine HCl (2.8-mg sublingual tablets; n=248) or placebo (n=255). Both groups received 1 tablet on day 1 for 2 weeks, and at the time of the week 2 visit, increased to 2 tablets for 12 weeks.2,4
The primary end point was change from baseline at week 14 in weekly average of daily pain scores, and secondary end points included Patient Global Impression of Change (PGIC) scores, Fibromyalgia Impact Questionnaire Revised (FIQR) scores, Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance and Fatigue scores, and daily sleep quality. Safety was assessed by adverse event (AE) reporting.2,4
According to results published in Arthritis Care Research (Hoboken) in 20234, patients receiving cyclobenzaprine HCl experienced greater reductions in daily pain from baseline to week 14 (mean change: −1.9 [95% CI −2.1, −1.7]) compared with placebo (mean change: −1.5 [95% CI −1.7, −1.3]; P = .01). Additionally, cyclobenzaprine HCl was not shown to be associated with significant improvement in PGIC at week 14; however, it was associated with improvements in FIQR and PROMIS scores as well as daily sleep quality.4
Additionally, approximately 59.7% of patients receiving cyclobenzaprine HCl compared with 46.3% of those on placebo reported treatment-emergent AEs. The most common were oral hypoesthesia (cyclobenzaprine HCl: 17.3%; placebo: 0.4%), oral paresthesia (cyclobenzaprine HCl: 5.6%; placebo: 0.4%), and abnormal taste of the product (cyclobenzaprine HCl: 4.4%; placebo: 0.4%).4
RESILIENT (NCT05273749) is another randomized, parallel-group, double-blind, placebo-controlled, 14-week phase 3 also designed to evaluate the safety and efficacy of cyclobenzaprine HCl in patients with fibromyalgia. Like in the RELIEF trial2, patients were randomly assigned to receive either the investigational therapy (n = 231) or placebo (safety population: n = 226; intent to treat population: n = 225; same dose and method of administration). Additionally, both the primary and secondary end points were the same.3
According to findings published in Annals of Rheumatic Diseases in 20245, deduction in daily pain from baseline at week 14 was significantly greater with cyclobenzaprine HCl (mean change −1.82 [95% CI, −2.04 to −1.59]) compared with placebo (mean change: −1.16 [−1.40 to −0.93]; P =.00005). Additionally, those on the investigational drug also demonstrated significant improvements in PGIC, FIQR domains, PROMIS instruments, and daily sleep quality. Memory by FIQR memory item was also more improved on cyclobenzaprine HCl.5
RELIEF
RESILIENT
The most common treatment-emergent AEs were transient, sporadic, self-limited oral administration site reactions. These were present in both groups and included oral hypoesthesia (cyclobenzaprine HCl: 23.8%; placebo: 0.4%), abnormal product taste (cyclobenzaprine HCl: 11.7%; placebo: 0.9%), and oral paresthesia (cyclobenzaprine HCl: 6.9%; placebo: 0.9%). Tongue discomfort was only reported by those receiving cyclobenzaprine HCl (6.9%). Additionally, there were no drug-associated changes in systolic or diastolic blood pressure, weight or sexual side effect AEs.5
“The fibromyalgia community, comprised of patients and their families and support groups, has been waiting for a new drug for over 15 years. Analysis of insurance claims in the US…have shown that 18 months after diagnosis, fibromyalgia patients were more likely to be prescribed addictive opioids than all 3 of the FDA-approved drugs combined,” said Lederman in the news release. “We look forward to working closely with the FDA throughout the NDA review period with the goal of bringing [cyclobenzaprine HCl] to the market to address the significant unmet needs of the fibromyalgia community as quickly as possible.”1
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