In adults with chronic migraine, the oral calcitonin gene-related peptide (CGRP) antagonist atogepant taken daily was associated with a significant reduction in monthly migraine days (MMD) compared with placebo over a 12-week period, according to findings from the phase 3 PROGRESS study.
The study evaluated the safety, tolerability, and efficacy of atogepant 30 mg taken twice daily and 60 mg taken once daily.
Gepants were developed specifically for preventive migraine treatment and are non-peptide small molocules that target the CGRP receptor in similar fashion to the 4 injectable monoclonal antibodies that also target the CGRP receptor; the latter are approved for prevention of chronic migraine but study authors note that many people with chronic migraine shy away from injectable medications, preferring an oral option.
Traditional oral preventive migraine agents are not migraine-specific; they are associated with a range of side effects and adherence is historically low, said Patricia Pozo-Rosich, MD, PhD, director of the headache and neurological pair research group at Vall d’Hebron University Hospital in Barcelona, and colleagues, writing in Lancet Neurology.
Atogepant was approved by the FDA in October 2021 for prevention of episodic migraine and is 1 of 3 approved in this class. Gepant efficacy in chronic migraine, the "subgroup of the most disabled and difficult to treat migraine patients," has not been evaluated,
The randomized, double-blind, placebo-controlled trial was conducted at 142 international sites and enrolled adults aged 18 to 80 years with at least a 1-year history of chronic migraine with age of onset before age 50 years. Investigators randomly assigned eligible participants in 1:1:1 ratio to receive oral atogepant 30 mg twice a day, oral atogepant 60 mg once a day, or placebo for 12 weeks. The study's primary efficacy endpoint was defined as change in MMD from baseline to end of treatment period and was analyzed in the modified intent to treat population. The safety population was comprised of all participants who received at least one dose of a study drug or placebo.
The researchers assessed potential participants for eligibility between March 11, 2019, and January 20, 2022, and the final cohort numbered 778. Among the safety population the mean age was 42.1 years, 88% were women, and 59% were White. Pozo-Rosich and colleagues reported that 84 participants left the trial with the modified intent-to-treat population comprised of 755 participants n (atogepant 30 mg twice a day n=253, atogepant 60 mg once a day n=256, and placebo n=246).
The investigators reported that change from the baseline MMDs over the 12-week study period was −7.5 (SE 0.4) with atogepant 30 mg twice daily, −6.9 (0.4) with atogepant 60 mg once daily, and −5.1 (0.4) with placebo. The calculated least squares mean difference from placebo was −2.4 with atogepant 30 mg twice daily (95% CI −3.5 to −1.3; adjusted P<.001) and −1.8 with atogepant 60 mg once daily (−2.9 to −0.8; adjusted P=.0009).
Investigators also observed significant reductions in mean number of days a month when acute medication was used as well as clinically significant improvements over placebo in patient reported outcomes.
Constipation was the most common adverse event, reported by approximately 10% of participants in the atogepant 30- and 60-mg arms and 3% in the placebo group followed by nausea reported by approximately 9% in both active treatment groups and 4% of the placebo group. All 3 treatment groups experienced some minimal weight loss.
Among the study’s strengths the authors point out are the multinational multicenter design, the broad age range of the participants, and also that at baseline there were high numbers of participants with acute medication overuse (66%) and who had had poor response to at least 2 previous treatments, suggesting that this cohort may reflect a more severe chronic migraine population. Short treatment duration was noted as a limitation although it was consistent with other RCTs.
Source: Pozo-Rosich P, Ailani J, Ashina A, et al. Atogepant for the preventive treatment of chronic migraine (PROGRESS): a randomised, double-blind, placebocontrolled, phase 3 trial. Lancet Neurol. Published online July 26, 2023. doi:10.1016/S0140-6736(23)01049-8