Atogepant for Migraine Prevention Meets Primary, Secondary Endpoints

The oral calcitonin gene-related peptide inhibitor atogepant demonstrated statistically significant reduction in mean monthly migraine days across 12 weeks in patients experiencing 4 to 14 migraine days per month. This primary endpoint was met in all active treatment arms of atogepant - 10 mg, 30 mg, and 60 mg once-daily doses.

The study also found that a greater proportion of atogepant-treated participants achieved at least a 50% reduction in mean monthly migraine days for all doses compared to placebo and met other key secondary endpoints.

The findings, based on the phase 3 ADVANCE trial, were published August 19, 2021, in the New England Journal of Medicine. Atogepant is under FDA investigation for prevention of episodic migraine.

"Too many people around the world face the incapacitating challenges of migraine, which place undue burden on patients, care partners, and health systems," said Michael Gold, MD, vice president, neuroscience development, at atogepant manufacturer AbbVie, in a press statement. "At AbbVie, we are resolutely committed to advancing new treatment options across the migraine continuum. These data reinforce our confidence in atogepant as a potential option for the preventive treatment of migraine."

The ADVANCE Trial

Led by Jessica Ailani, MD, professor of clinical neurology, director, Medstar Georgetown Headache Center, MedStar Georgetown University Hospital in Washington, DC, ADVANCE was a phase 3, multicenter randomized placebo-controlled trial designed to evaluate atogepant safety, efficacy, and tolerability for migraine headache prevention in adults with 4 to 14 migraine headache days per month.

Investigators screened 2270 potential participants and randomized 910 patients in 1:1:1:1 ratio to receive a once-daily dose of oral atogepant at 3 doses, 10 mg (n=214), 30 mg (n=223), 60 mg (n=222), and placebo (n=214) for 12 weeks. At baseline measurement, the mean number of migraine days per month ranged from 7.5 to 7.9 across the 4 groups.

The study’s primary end point was change from baseline in mean number of migraine days per month over 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine–Diary (AIM-D).

Efficacy analyses were based on the modified intent-to-treat population of 873 patients.

Results

All atogepant dose groups met the primary endpoint and demonstrated statistically significant reductions in mean monthly migraine days compared to placebo. Patients treated in the 10 mg, 30 mg, and 60 mg atogepant arms experienced a decrease of 3.7, 3.9, and 4.2 days respectively vs a decrease among patients in the placebo arm of 2.5 days (all dose groups vs placebo, p<.0001).

Significant improvements also were seen in secondary endpoints. Atogepant 10 mg, 30 mg, and 60 mg doses demonstrated statistically significant reductions in acute medication use. For the 30 mg and 60 mg doses, significantly greater improvements vs placebo were seen in the mean monthly AIM-D Performance of Daily Activities domain score and in the Physical Impairment domain score.

"Migraine symptoms can vary in frequency and severity from person to person and from attack to attack, which is why they can impact people's daily lives in so many different ways," said ADVANCE co-author Peter Goadsby, MD, neurologist, and professor at University of California (Los Angeles) and King's College, London, in NEJM. 

"The novel AIM-D functional scale administered in the ADVANCE study and the Migraine-Specific Quality of Life Questionnaire helped us monitor the effects of migraine on ability to perform daily activities and functions. These data, along with the primary endpoint and other secondary endpoints, help further our understanding of atogepant as a potential treatment option for people living with migraine."

All doses were well tolerated. The most common adverse events reported with a frequency ≥5% in at least one atogepant treatment arm, and greater than placebo, were constipation, nausea, and upper respiratory tract infection. The majority of cases were mild/moderate and did not lead to study discontinuation.

AbbVie states in the release that a regulatory decision from the FDA is expected late in the third quarter of 2021. If approved, atogepant would be the first orally administered gepant developed specifically for preventive treatment of episodic migraine.