Treatment with atogepant, an oral, small-molecule calcitonin gene–related peptide (CGRP) receptor antagonist, is safe and effective for migraine prophylaxis, according to full results of the phase 3 ADVANCE trial, published in the New England Journal of Medicine.
Previous studies have shown increased blood levels of CGRP during migraine attack, suggesting that the molecule plays an important role in the pathophysiology of migraine. Several CGRP-based treatments are available for migraine prophylaxis but all are administered by injection, whereas oral CGRP receptor antagonists are approved for acute migraine but not as a prophylactic treatment option.
A previous phase 2-3 dose-ranging trial supported the efficacy of atogepant in reducing migraine days. The objective of the current phase 3 trial was to determine the safety and efficacy of atogepant administered orally once daily at a dose of 10 mg, 30 mg, or 60 mg, compared with placebo, for migraine prophylaxis in patients with episodic migraine.
The change in the mean number of migraine days per month during the study period was the primary efficacy endpoint.
The multicenter, double-blind, parallel-group, randomized, placebo-controlled trial included 902 patients (safety population, which included all patients who received at least 1 dose of atogepant or placebo; mean age, 41.6 years; 88.8% women) with at least a 1-year history of episodic migraine with or without aura. The participants were randomized to receive a once-daily dose of atogepant (at 10 mg, 30 mg, or 60 mg) or placebo for 12 weeks.
At week 12, the mean reduction from baseline in the mean number of migraine days per month was 3.7 days with 10-mg atogepant, 3.9 days with 30-mg atogepant, 4.2 days with 60-mg atogepant, and 2.5 days with placebo. The differences between each active dose and placebo were statistically significant (P < .001).
There was also a reduction in the mean number of headache days per month across the 12-week treatment period: 3.9 days with 10-mg atogepant, 4.0 days with 30-mg atogepant, 4.2 days with 60-mg atogepant, and 2.5 days with placebo. The differences between each active dose and placebo were statistically significant (P < .001).
A reduction of 50% or greater in the 3-month average of migraine days per month was reported in 55.6% of the participants in the 10-mg atogepant group, 58.7% of those in the 30-mg atogepant group, 60.8% of those in the 60-mg atogepant group, and 29.0% of those in the placebo group (P < .001 for all comparisons with placebo).
The most common adverse events among those treated with atogepant were constipation (6.9% to 7.7% across atogepant doses), nausea (4.4% to 6.1%), and upper respiratory tract infection (1.4% to 3.9%). The incidence of treatment discontinuation due to adverse events was similar across the trial groups.
The study had several limitations. These included its short duration and exclusion of patients with 15 or more headache days per month, exclusion of patients treated with triptans or ergots on 10 or more days per month, and exclusion of patients with clinically significant coexisting conditions, so the results cannot be generalized to these patients. Furthermore, the safety of atogepant in pregnant women was not assessed.
“[A]togepant once daily was effective for reducing the number of migraine days and headache days in the preventive treatment of migraine over 12 weeks. Adverse events included constipation, nausea, and upper respiratory tract infection. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention,” the researchers concluded.
Disclosure: This research was supported by Allergan. Please see the original reference for a full list of disclosures.
Ailani J, Lipton RB, Goadsby PJ, et al, for the ADVANCE Study Group. Atogepant for the preventive treatment of migraine. N Engl J Med. 2021;385(8):695-706. doi:10.1056/NEJMoa2035908