By Alina Masters-Israilov, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Atogepant, an oral small-molecule inhibitor of the calcitonin gene-related peptide pathway, administered once daily, effectively reduced migraine days in the preventive treatment trial of migraine over a period of 12 weeks.
SOURCE: Ailani J, Lipton RB, Goadsby PJ, et al. Atogepant for the preventive treatment of migraine. N Engl J Med 2021;385:695-706.
Calcitonin gene-related peptide (CGRP) has been shown to be involved in migraine pathophysiology and has been targeted in new migraine therapies. CGRP monoclonal antibodies (mAbs) affecting the receptor or ligand have been developed and in clinical use since 2018 for the prevention of migraine. Oral CGRP receptor antagonists (gepants) have been available more recently for abortive therapy of migraine attacks, although rimegepant also has been available for prevention since earlier in 2021. Ailani et al conducted a multicenter, double-blind, randomized, placebo-controlled trial with atogepant, an oral small-molecule CGRP receptor antagonist, for the prevention of episodic migraine. Atogepant reaches maximum plasma concentrations in one to two hours and has a half-life of approximately 11 hours.
The trial included a screening period (four weeks), baseline period (four weeks), double-blind treatment period (12 weeks), and a safety follow-up period (four weeks). Participants were between the ages of 18 and 80 years and had episodic migraine (four to 14 migraine days per month in the three months leading up to screening and in the 28-day baseline period). They were randomly assigned in a 1:1:1:1 fashion to receive either 10 mg, 30 mg, or 60 mg of atogepant or placebo daily during the treatment period. Exclusion criteria included patients with chronic migraine, history of inadequate response to more than four oral preventive medications, medication overuse headache, or plans to become pregnant. They were allowed to treat migraine attacks with abortive therapies but were not allowed to take any migraine preventive medication starting 30 days before their screening visit and throughout the duration of the trial. Participants recorded efficacy assessments in an electronic diary throughout the trial, documenting headache duration, clinical features of their headaches, and abortive therapies used. Additional data were collected through questionnaires and diaries. The primary endpoint was the change from baseline in the mean number of migraine days per month across the 12-week treatment period. Adverse events were reported by the participants, and laboratory tests, vital stastistics, and electrocardiograms were checked as well.
A total of 910 participants were randomized, with 805 of them completing the trial. Baseline characteristics were comparable among the groups; participants had an average of 7.4 migraine days per month in the three months before randomization. The mean change from baseline in the mean number of migraine days per month across the 12-week treatment period was -3.7 with 10 mg atogepant, -3.9 with 30 mg atogepant, -4.2 with 60 mg atogepant, and -2.5 with placebo. The mean difference from placebo with all three doses of atogepant showed statistically significant results. A reduction of 50% or more in the three-month average of migraine days per month, an important secondary efficacy endpoint, occurred 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 < 0.0001 for all comparisons with placebo). Differences from placebo were observed within the first four weeks after initiation of treatment.
Adverse events were reported by 52.2% to 53.7% of the participants in the atogepant groups and by 56.8% of those in the placebo group. Constipation, nausea, and upper respiratory tract infection were the most commonly reported adverse events in the atogepant groups. The incidence of constipation was higher in the atogepant groups compared to placebo, although none of the cases of constipation were determined to be serious. A total of five participants in the atogepant groups and four participants in the placebo group had elevated alanine transaminase (ALT) or aspartate aminotransferase (AST) levels.
COMMENTARY
Atogepant, at all three doses studied, was effective in reducing monthly migraine days compared to placebo over a 12-week trial period. The population studied had episodic migraine, so it is unclear if the same benefit would be seen in patients with chronic migraine. Long-term safety studies are needed, as well as inclusion of a more diverse group of participants. Atogepant may be an effective alternative for migraine prevention for patients who are anxious about self-injecting CGRP mAbs. It also may be considered instead of CGRP mAbs in women who may want to become pregnant in the very near future who would otherwise have to wait at least four to six months after stopping a CGRP mAb before conceiving, as opposed to several days after stopping atogepant. There also were fewer reported side effects with atogepant than with many historically used migraine prevention treatments, making it an attractive option for prevention. As with other new CGRP-based medications, drug cost and insurance drug coverage will be important factors in the practical availability of this medication to patients living with migraine.
