Efficacy and Safety of Oral Zavegepant in Migraine Prevention: A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study in Patients with Chronic Migraine.

INTRODUCTION: This study aimed to assess the efficacy and safety of once daily oral zavegepant as a preventive treatment for chronic migraine. METHODS: This multicenter, randomized, double-blind, placebo-controlled phase 2/3 study consisted of a 12-week double-blind treatment (DBT) phase and a 52-week open-label extension (OLE). Adults with ≥ 1-year history of chronic migraine (with or without aura), ≥ 15 headache days/month, ≥ 8 migraine days/month, and ≥ 1 headache-free day/month during the 3 months prior to screening were randomly assigned 2:2:1:1 to zavegepant 100 mg, 200 mg, placebo for zavegepant 100 mg, or placebo for zavegepant 200 mg. Following a 28-day observation phase (OP), participants took the study treatment every calendar day. The primary endpoint was mean change from the OP in number of migraine days/month in the DBT phase. This study was stopped prematurely due to recruitment challenges. RESULTS: Of 1753 screened participants, 522 were treated and 411 completed the DBT phase. Participants were predominantly female (n = 391, 79.5%) and mean (SD) age of chronic migraine onset was 26.5 (11.7) years. The mean (97.5% CI) changes from the OP in number of migraine days/month in the DBT phase were - 7.0 (- 8.10, - 5.92), - 6.3 (- 7.45, - 5.10), and - 5.6 (- 6.80, - 4.37) for zavegepant 100 mg, 200 mg, and placebo groups, respectively. The corresponding least squares (LS) mean change differences (zavegepant-placebo pooled; 97.5% CI) were - 1.4 (- 2.72, - 0.12) and - 0.7 (- 2.07, 0.69) for zavegepant 100 mg and zavegepant 200 mg groups, respectively. During DBT, 21 (12.1%) and 14 (8.0%) participants had at least one adverse event considered zavegepant-related in the zavegepant 100 mg and 200 mg groups, respectively, with corresponding rates of nine (5.8%) and nine (6.3%) participants during the OLE. CONCLUSIONS: Oral zavegepant had a favorable safety and tolerability profile for up to 200 mg daily. Additional research is needed to determine the effectiveness of oral zavegepant as a preventive migraine treatment. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT04804033.