Early Improvements With Atogepant for the Preventive Treatment of Migraine: Results From 3 Randomized Phase 3 Trials.

Background And Objectives: Three phase 3 trials demonstrated the efficacy and safety of atogepant in episodic migraine (EM) and chronic migraine (CM) across 12-week treatment periods. This analysis evaluates improvements in efficacy and functional outcomes in the first 4 weeks of treatment with the oral calcitonin gene-related peptide receptor antagonist, atogepant, for the preventive treatment of migraine.

Methods: ADVANCE, ELEVATE, and PROGRESS were phase 3, multicenter, randomized, double-blind, placebo-controlled 12-week trials. ADVANCE and ELEVATE included participants aged 18-80 years with >1 year history of EM and 4-14 monthly migraine days (MMDs). ELEVATE required previous treatment failures to 2-4 classes of oral preventives. PROGRESS included participants aged 18-80 years with >1 year history of CM, ≥15 monthly headache days, and ≥8 MMDs. This analysis reports the atogepant 60 mg once daily (QD) and placebo treatment arms. Outcomes included efficacy endpoints (reporting a migraine day on day 1, change from baseline in weekly migraine days [WMDs] at weeks 1-4, and in MMDs in the first 4 weeks) and functional endpoints evaluated by the Activity Impairment in Migraine-Diary (AIM-D) at weeks 1-4 and the European Quality-of-Life 5-Dimension 5-Level (EQ-5D-5L) at weeks 1-2 and 4.

Results: The modified intent-to-treat population included the ADVANCE (atogepant, n = 222; placebo, n = 214), ELEVATE (atogepant, n = 151; placebo, n = 154), and PROGRESS (atogepant, n = 256; placebo, n = 246) studies. Atogepant-treated participants had greater reductions in the proportion of participants with a migraine day on day 1. The odds ratio compared with placebo was 0.39 (95% CI 0.23-0.67; = 0.0006) in ADVANCE, 0.53 (95% CI 0.29-0.94, = 0.031) in ELEVATE, and 0.63 (95% CI 0.43-0.93, = 0.021) in PROGRESS. Atogepant treatment reduced WMDs at weeks 1-4 and MMDs in the first 4 weeks, and improved AIM-D and EQ-5D-5L at all assessed timepoints for weeks 1-4 compared with placebo.

Discussions: Atogepant 60 mg QD demonstrated superiority to placebo in efficacy and functional measures in the first 4 weeks of treatment across 3 preventive studies, 2 in EM and 1 in CM.

Trial Registration: ClinicalTrials.gov NCT03777059; NCT04740827; NCT03855137. Submitted: 12/13/2018; 02/02/2021; 02/25/2019. First patient enrolled: 12/14/2018; 03/05/2021; 03/11/2019 clinicaltrials.gov/ct2/show/NCT03777059. clinicaltrials.gov/ct2/show/NCT04740827 clinicaltrials.gov/ct2/show/NCT03855137.

Classification Of Evidence: This study provides Class II evidence that atogepant 60 mg QD reduces migraine frequency and improves functional outcomes within 4 weeks of initiation in patients with EM and patients with CM.