Oral drug previously approved to treat acute migraine

Rimegepant (Nurtec), an oral calcitonin gene-related peptide receptor (CGRP) antagonist approved to treat acute migraine, reduced migraine frequency when used for migraine prevention, a randomized phase II/III trial found.

“Taken every other day, rimegepant was effective for preventive treatment of migraine,” wrote Robert Croop, MD, of Biohaven Pharmaceuticals in New Haven, Connecticut, and colleagues in Lancet. “Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted.”

A 4-week observation period established a baseline number of monthly migraine days which was compared with migraine frequency during the last 4 weeks of the trial’s double-blind phase (weeks 9-12 of the study). Participants were adults with a 1-year history of migraine randomized to oral rimegepant 75 mg (n=373) or placebo (n=374) every other day for 12 weeks.

Over weeks 9-12, the decrease in mean monthly migraine days from baseline for the rimegepant group was −4.3 days (95% CI –4.8 to –3.9). For placebo, it was −3.5 days (95% CI –4.0 to –3.0; least squares mean difference −0.8 days, 95% CI −1.46 to −0.20, P=0.0099).

Adverse events were reported by 36% of the rimegepant group (2% discontinued the study due to adverse event) and 36% of placebo (1% discontinued the study due to adverse events). There were no deaths.

“The results of our study show the potential for use of rimegepant in preventive treatment of migraine,” Croop and co-authors wrote. “Use of rimegepant for acute and preventive treatment of migraine might reduce the overall burden of illness associated with migraine, and this idea merits further investigation.”

“A constantly high exposure to a CGRP receptor antagonist might not be necessary for all patients,” they continued. “In view of the fluctuating nature of migraine attack frequency, even over relatively short periods, orally-administered rimegepant might give patients the option to adjust drug use to meet individual needs — i.e., regularly for prevention and as-needed for acute treatment.”

The improvement associated with rimegepant relative to placebo — less than 1 mean monthly migraine day — is “disappointing,” wrote Lars Edvinsson, MD, PhD, of Lund University in Sweden, in an accompanying editorial. “Comparing the efficacy of rimegepant 75 mg every other day with that of currently approved and used monoclonal antibodies towards CGRP or the CGRP receptor, the effect of rimegepant is at the lower end of the reported range.”

Croop’s group recruited trial participants between November 2018 and August 2019. Mean participant age was about 41 years, 83% were women, and 82% were white. A history of chronic migraine was present in 21% of the rimegepant group and 26% for placebo, and median age for migraine onset was 18 in both groups. Overall, 40% had migraine with aura.

Monthly migraine days during the 4-week observation period were similar for those ultimately randomized to rimegepant (10.3 days) and placebo (9.9 days).

Adverse events that occurred in at least 2% of participants included nasopharyngitis, nausea, urinary tract infection, and upper respiratory tract infection. Adverse events considered due to the treatment were seen in 11% of the rimegepant group and 9% of placebo. No treatment-related serious adverse events were reported in the rimegepant group.

About half the patients treated with rimegepant had at least a 50% reduction in monthly migraine days (49%, 95% CI 44-54), versus 41% for placebo (95% CI 36-47; difference 8%, 95% CI 0-15; P=0.044). The rimegepant and placebo treatment groups were similar with respect to the least squares mean days of rescue medication per month (3.7 vs 4.0 days; P=0.39).

The dose used in the study was likely adequate to engage CGRP-blocking mechanisms, Edvinsson noted, pointing out that the “gepant” class of drugs has a history of molecular design change to reduce hepatotoxicity seen with earlier gepant molecules such as telcagepant. “Might modernization of the gepants have resulted in reduction of potency or diminished possibility to reach antimigraine targets?” he wrote. “There is still some way to go in understanding how the gepant class of drugs can be most effectively used.”

Rimegepant’s “pharmacokinetic profile (half-life around 11 hours) provides clinicians with greater flexibility for treatment compared with monoclonal antibodies (which have half-lives around 1 month),” the researchers wrote. “The short half-life of rimegepant relative to monoclonal antibodies is especially useful for patients who have a planned or unplanned pregnancy or adverse events that might require rapid cessation of drug exposure.”

Limitations of the study include relatively short duration and small sample of chronic migraine patients in the sample. In addition, the study excluded patients who had more than 18 headache days during observation.

  1. Rimegepant, an oral calcitonin gene-related peptide receptor (CGRP) antagonist approved to treat acute migraine, reduced migraine frequency when used for migraine prevention, a randomized phase II/III trial found.

  2. Comparing rimegepant for migraine prevention with approved monoclonal antibodies towards CGRP or its receptor, “the effect of rimegepant is at the lower end of the reported range,” the editorialist said.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This clinical trial was supported by Biohaven Pharmaceuticals.

Croop is an employee of Biohaven.

Edvinsson received fees for talks at conferences sponsored by Amgen, Novartis, Eli Lilly, TEVA, and Lundbeck on aspects of migraine pathophysiology.

Cat ID: 35

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