Atogepant Safe and Effective in Treatment-Resistant Episodic Migraine: ELEVATE Phase 3b Trial

Atogepant, an oral calcitonin gene-related peptide (CGRP) antagonist, was associated with significant and clinically relevant reductions in mean monthly migraine days in a 12-week study of individuals with episodic migraine for whom 2 to 4 classes of oral preventive migraine treatments were ineffective.

Dosed once daily at 60 mg, atogepant was found safe and was well tolerated, according to findings of the phase 3b ELEVATE trial published in The Lancet Neurology.

Approximately 27% of individuals with episodic migraine will have more than 3 headache days per month, Cristina Tassorelli, MD, a professor in the department of brain and behavioral science at the University of Pavia in Italy, and colleagues wrote. “Scientific and expert consensus is generally that treating physicians should consider initiating preventive treatment when migraine attacks are severely disabling,” added the researchers.

Atogepant is approved in the US for prevention of migraine but there have been no clinical trials dedicated to evaluating its safety and efficacy in migraineurs whose headaches have been resistant to conventional oral preventive treatments, Tassorelli and colleagues wrote.

ELEVATE was a randomized, double-blind, placebo-controlled parallel-group phase 3b trial conducted at 73 study sites in North America and Western and Eastern Europe. Investigators randomly assigned adults aged 18 to 80 years with episodic migraine resistant to up to 4 classes of oral migraine preventives, in 1:1 fashion, to receive either atogepant 60 mg or placebo once a day for 12 weeks. They further stratified the treatment group by baseline number of migraine days per month, number of ineffective treatment classes, and by geographic region. A total of 309 participants in the off-treatment hypothetical estimand (OTHE) population were randomly assigned to the same treatment regimens.

The primary endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period in the OTHE population, which included participants in the safety population (all participants who received ≥1 dose of study intervention) who had evaluable data available for the baseline period and for at least 1 of the 4-week post-baseline periods (whether on treatment or off treatment).

Tassorelli et al screened 540 participants between March 5, 2021, and August 4, 2022, finally randomly assigning 315 to active or placebo treatment; 313 participants (89% women, 96% White) received at least 1 dose of atogepant.

Findings

Among the 309 participants in the OTHE population, researchers reported least squares mean (LSM) changes from baseline in monthly migraine days across 12 weeks of −1.9 (standard error 0.4) with placebo and −4.2 (SE 0.4) with atogepant 60 mg (LSM difference −2.4; 95% CI −3.2 to −1.5; adjusted P <.001).

Among atogepant-treated participants diarrhea was the most common treatment-emergent adverse event, reported by 10% vs by 3% of participants receiving placebo. There were 4 serious adverse events among 156 participants in the atogepant group and none in the placebo group. Treatment-emergent adverse events resulting in discontinuation were reported in 3 participants in the atogepant group and 2 in the placebo group.

“This is, to our knowledge, the first study for an oral, small molecule [calcitonin gene-related peptide] receptor antagonist to show high efficacy, safety and tolerability for this difficult-to-treat population,” Tassorelli and colleagues wrote. “Atogepant may be an effective preventive treatment option.”

Source: Tassorelli C, Nagy K, Pozo-Rosich P, et al. Safety and efficacy of atogepant for the preventive treatment of episodic migraine in adults for whom conventional oral preventive treatments have failed (ELEVATE): a randomised, placebo-controlled, phase 3b trial. Lancet Neurol. Published online February 13, 2024. doi:10.1016/S1474-4422(24)00025-5