By Matthew S. Robbins, MD, FAAN, FAHS

Neurology Residency Program Director; Associate Professor of Neurology, Weill Cornell Medical College, NewYork-Presbyterian Hospital

Dr. Robbins reports no financial relationships relevant to this field of study.

SYNOPSIS: Atogepant, an oral calcitonin gene-related peptide antagonist, was shown to be effective and safe for migraine prevention.

SOURCE: Goadsby PJ, Dodick DW, Ailani J, et al. Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: A double-blind, randomised phase 2b/3 trial. Lancet Neurol 2020;19:727-737.

Goadsby et al conducted a multicenter, randomized controlled trial (RCT) of atogepant, a novel small molecule antagonist to the calcitonin gene-related peptide (CGRP) receptor, to prevent migraine. The study included patients ages 18-75 years with preexisting migraine with or without aura for at least one year and a frequency of four to 14 migraine days per month.

The trial enrollment included 825 subjects who ultimately received at least one dose of study medication. Participants were randomized to twice-daily placebo or the study medication of varying doses at once or twice daily over a 12-week treatment period after a four-week run-in period. All groups receiving the study medication reached the primary endpoint vs. placebo, ranging from a reduction of -3.6 to -4.2 monthly migraine days, with slightly higher efficacy in twice-daily dosing. Atogepant was safe; adverse events were infrequent and most commonly manifested as nausea (3% to 9%), with lower rates for constipation and fatigue and no serious adverse events deemed related to the study drug.

COMMENTARY

CGRP is an inflammatory neuropeptide that is fundamentally involved in migraine pathophysiology. Gepants, small molecule CGRP receptor antagonists, represent an important treatment advance for migraine. Their development, although initially limited by hepatotoxicity, led to the successful development of monoclonal antibodies that target CGRP or its receptor as preventive treatments. The FDA recently approved two gepants, rimegepant and ubrogepant, and are available for acute migraine treatment. Although rimegepant also is under investigation as a preventive treatment, atogepant is the first gepant to demonstrate both efficacy and safety for migraine prevention in a large-scale RCT. Its safety profile in the study was encouraging, with neither hepatotoxicity nor cardiovascular events apparent.

Gepants provide distinct advantages over existing preventive treatments. Their tolerability seems excellent, although long-term cardiovascular safety questions remain. They may be a true blend of acute and preventive treatments, since the same medication class has demonstrated efficacy in both paradigms. They also do not seem to cause medication overuse headache, a common complicating factor in patients with frequent or chronic migraine. Compared to CGRP monoclonal antibodies, which have half-lives of approximately one month, their short half-life (10 hours) enables rapid dose changes and medication cessation in certain circumstances, such as side effects or a planned or unplanned pregnancy. Many patients do not like the injections required of CGRP monoclonal antibodies; atogepant may be more tolerable.

There were study limitations. Real-world patients may not be well represented, since most patients were not on preventive therapy previously; such a population would be unlikely to receive atogepant as first-line therapy in clinical practice. The therapeutic gain for atogepant (-0.7 to -1.4 monthly migraine day reduction) is comparable to CGRP monoclonal antibodies and other oral preventive treatments, but is not superior to such therapies. Further studies of atogepant, including RCTs of patients with episodic and chronic migraine, are ongoing.