Investigational oral agent for migraine prevention appears safe, well tolerated

Atogepant, an investigational oral small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, reduced monthly episodic migraine days compared with placebo, a phase IIb/III migraine prevention trial showed.

“All doses of oral atogepant were associated with a significant decrease in monthly migraine days over 12 weeks compared with placebo,” reported Peter Goadsby, MD, of King’s College in London, and coauthors, in Lancet Neurology. “Atogepant was safe and well tolerated over 12 weeks, supporting its phase III development for the preventive treatment of migraine.”

The primary efficacy analysis was based on 795 adults with at least 1 year of migraine history and 4 to 14 migraine days per month, randomized to one of five doses or placebo and followed over 12 weeks.

For patients in the placebo group (n=178), mean monthly days fell by -2.9 days. Among atogepant-treated patients, reductions were:

  • 10 mg once daily, n=92: −4.0 days (P=0.024).
  • 30 mg once daily, n=182: −3.8 days (P=0.039).
  • 60 mg once daily, n=177: −3.6 days (P=0.039).
  • 30 mg twice daily, n=79: −4.2 days (P=0.0034).
  • 60 mg twice daily, n= 87: −4.1 days (P=0.0031).

No serious adverse effects were attributed to atogepant.

“Atogepant was well tolerated and treatment-related adverse events showed a dose-dependent association,” noted Linda Al-Hassany, MD, and Antoinette Maassen van den Brink, MD, both of Erasmus University Medical Center in Rotterdam, the Netherlands. “These results show the preliminary efficacy and tolerability of this new gepant; long-term safety, including hepatotoxic effects, which were reported for the first-generation of gepants, but are not necessarily a class effect, are under investigation,” they wrote in an accompanying editorial.

CGRP plays an important role in migraine pathophysiology. CGRP receptor antagonists (“gepants”) are used for acute migraine treatment (such as the recently approved drug, ubrogepant). Monoclonal antibodies against CGRP (eptinezumab, fremanezumab, and galcanezumab) or against the CGRP receptor (erenumab) are used for migraine prevention.

A 2019 review of gepants in migraine treatment looked at the long-term safety of the first generation of gepants, including hepatoxicity. Expert consensus was that second-generation gepants have improved tolerability versus the first-generation, with efficacy similar to triptans.

In this trial, Goadsby and collaborators randomized 795 migraine patients to different oral doses of the atogepant versus placebo between September 2016 and April 2018. The cohort was 87% female and 76% white. Patients had median migraine duration of 17.5 years, and preventive treatment had been used by 28%. Mean baseline monthly headache days ranged from 7.4 to 7.8 across all treatment groups.

Adverse event frequency ranged by dose, from 18% at 10 mg daily to 26% at 60 mg twice daily (compared with 16% for placebo). The most common adverse events were nausea (from 5% at 10 mg daily to 12% at 60 mg daily; 5% for placebo) and fatigue (from 1% at 10 mg daily to 10% at 60 mg twice daily; 3% for placebo).

Adverse events leading to discontinuation were reported in 5% of patients who received atogepant and 3% for placebo, most commonly nausea (four people receiving atogepant-treated and none on placebo), with three each for constipation, dizziness, and fatigue (all receiving atogepant).

Serious treatment-emergent adverse events included ureterolithiasis (placebo), Hodgkin’s disease (placebo), cholecystitis (10 mg once daily), ureteritis (30 mg once daily), migraine (30 mg once daily), elective abortion (60 mg once daily), major depression (60 mg once daily), and acetaminophen overdose (60 mg once daily). Major depression and acetaminophen overdose occurred in the same participant. “All serious treatment-emergent adverse events were unrelated to treatment,” Goadsby and colleagues wrote.

“Given the wide variability of anti-CGRP and anti-CGRP receptor drugs that are now available, with different half-lives, the gepants could almost be considered to form a continuum between acute and prophylactic migraine treatment,” the editorialists observed. “This concept would be a departure from the distinction between acute and prophylactic treatment of migraine, and might help to address the fact that regular overuse of acutely acting drugs can induce medication-overuse headache.”

“If future studies confirm that gepants can be used in this way, the availability of more drugs that meet individual needs will provide a substantial improvement for migraine patients,” they added.

Limitations include a study cohort that was mostly white and mostly women, limiting generalizability to other populations. Also, the 12-week treatment design cannot determine long-term safety and discontinuation. “Long-term safety of atogepant will be evaluated in an open-label study where any potential for hepatotoxicity can be carefully monitored,” Goadsby and colleagues noted.

This trial looked only at patients with 4 to 14 monthly headache days and did not study atogepant in patients with chronic migraine, which will be in a subsequent study.

  1. Atogepant, an investigational oral small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, reduced monthly episodic migraine days compared with placebo, a phase IIb/III migraine prevention trial found.

  2. The drug appeared to be well tolerated and treatment-related adverse events showed a dose-dependent association in this 12-week trial. No serious adverse effects were attributed to atogepant.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study was funded by Allergan (before its acquisition by AbbVie).

Goadsby reported personal fees from AbbVie, during the conduct of the study; personal fees from Alder Biopharmaceuticals, Autonomic Technologies, Biohaven Pharmaceuticals, Clexio, electroCore, eNeura, Epalex, Impel Neuropharma, MundiPharma, Novartis, and Teva Pharmaceuticals; personal fees from WL Gore, outside the submitted work; grants from Celgene; grants and personal fees from Amgen and from Eli Lilly; other from Trigemina; a patent magnetic stimulation for headache licensed to eNeura without fee; fees for advice through Gerson Lehrman Group and Guidepoint; and fees for publishing from Oxford University Press, Massachusetts Medical Society, and Wolters Kluwer, and for medicolegal work.

Al-Hassany had no conflicts of interest to declare. Maassen van den Brink reported grants and personal fees from Amgen–Novartis, grants and personal fees from Eli Lilly, and personal fees from Teva and Allergan.

Cat ID: 35

Topic ID: 82,35,730,35,192,925