Atogepant for the preventive treatment of episodic migraine in Japanese participants: A phase 2/3, randomized, double-blind, placebo-controlled trial with an active treatment extension (RELEASE)

Background Atogepant is an oral calcitonin gene–related peptide receptor antagonist approved in the US and EU for the preventive treatment of migraine in adults. We evaluated the efficacy, safety, and tolerability of atogepant for the preventive treatment of episodic migraine (EM) in Japanese participants. Methods RELEASE was a phase 2/3, multicenter, randomized, double-blind, placebo-controlled study enrolling adult participants with a ≥1-year history of migraine, <50 years of age at time of migraine onset, history of 4–14 monthly migraine days (MMDs), and <15 monthly headache days in the three months prior to screening and during the screening/baseline period. The study included a four-week screening/baseline period, 12-week double-blind treatment period (DBTP), 12-week active treatment extension period, and 30-day safety follow-up. Participants were randomized 1:1:1:1 to placebo, atogepant 10 mg once daily (QD), 30 mg QD, or 60 mg QD for the 12-week DBTP. Completers of the DBTP could continue to the 12-week active treatment extension period where the placebo group was rerandomized 1:1:1 to atogepant 10 mg, 30 mg, or 60 mg; atogepant groups continued the same dose. The primary endpoint was the change from baseline in mean MMDs across the 12-week DBTP. Results Of 807 participants screened, 523 were treated in the 12-week DBTP (Safety Population 1 [placebo, N = 134; atogepant 10 mg, N = 126; 30 mg, N = 131; 60 mg, N = 132]; modified intent-to-treat population [placebo, N = 133; atogepant 10 mg, N = 127; 30 mg, N = 130; 60 mg, N = 131]). The least square mean difference (95% confidence interval) from placebo in mean MMDs across 12 weeks was −1.57 (−2.24, −0.89) for atogepant 10 mg, −1.90 (−2.57, −1.22) for 30 mg, and −2.10 (−2.78, −1.43) for 60 mg (all p < 0.0001). Treatment-emergent adverse events (TEAEs) in the DBTP occurred in 46.3%, 45.2%, 38.9%, and 43.2% of participants receiving placebo, atogepant 10 mg, 30 mg and 60 mg, respectively. During the DBTP, TEAEs occurring ≥5% were constipation and nasopharyngitis, and there was one serious TEAE in the atogepant 10 mg group considered not related to treatment. TEAEs resulting in treatment discontinuation were infrequent in all treatment groups in the DBTP. Safety was consistent in the 12-week active treatment extension period. Conclusions Atogepant treatment demonstrated statistically significant and clinically meaningful reductions in mean MMDs compared with placebo across the 12-week DBTP in Japanese participants with EM. The safety profile of atogepant in Japanese participants was consistent with the known safety profile in the global population. No new safety signals were identified. Trial registration ClinicalTrials.gov NCT05861427; https://clinicaltrials.gov/study/NCT05861427