Positive Phase 3 Results for Rimegepant in Acute Migraine

Damian McNamara

July 11, 2018

SAN FRANCISCO — The oral calcitonin gene-related peptide (CGRP) rimegepant performed well compared with placebo for treatment of a single acute migraine attack in a double-blind, randomized phase 3 trial.  

"Rimegepant met its co-primary endpoints of pain freedom and relief from most bothersome symptom at 2 hours," study author Richard B. Lipton, MD, professor and vice chair of neurology at the Albert Einstein College of Medicine in the Bronx, New York, said during a late-breaking abstract presentation here at the American Headache Society (AHS) Annual Meeting 2018.

A significantly greater proportion of participants in the active treatment group, 20%, achieved this pain freedom 2 hours after dosing compared with 12% of the placebo group. At the same time, relief from the most bothersome migraine symptom, photophobia, was achieved by 38% of the rimegepant (Biohaven Pharmaceuticals) group vs 25% of the placebo group.

Developing new agents to treat acute migraine could help to address an unmet need, Lipton said.

"You all know well that triptans have been the most widely prescribed treatment for acute migraine now for decades." However, he added, "depending on how you define and study it, perhaps one third of people with migraine do not respond to triptans, 30% to 40% have recurrent attacks, and, according to our estimates, about 3.5 million people have absolute or relative contraindications to triptans out of about 40 million people who get migraines in the United States."

The current research adds to a number of phase 3 trial results announced at the 18th Congress of the International Headache Society (IHC) 2017 from this class of CGRP monoclonal antibodies. In a review reported last year by Medscape Medical News, galcanezumab (Eli Lilly), fremanezumab (Teva Pharmaceuticals), eptinezumab (Alder Biopharmaceuticals), and erenumab (Amgen) all performed similarly in terms of efficacy, depending on the specific endpoints, and in safety and tolerability. The main differences between the agents were in doses, routes of administration, and the target of the antibodies.

In the current investigation, known as Study 302, Lipton and colleagues enrolled 1186 adults with at least a 1-year history of migraine. Participants had two to eight moderate-to-severe attacks per month and fewer than 15 headache days per month. The mean number of migraine attacks per month at baseline was 4.6. Mean age was 41 years, and women made up 89% of the study population.

In the multicenter study, 537 individuals were randomly assigned to receive a single oral dose of rimegepant 75 mg while another 535 received an oral placebo. All participants were instructed to treat a single attack.

In terms of the primary outcomes, "these differences in this large sample were highly statistically significant," Lipton said. Compared with placebo, pain freedom at 2 hours in the rimegepant group reached a significance of P = .0006. Freedom from most bothersome symptom was significant at P < .0001.

A higher proportion of patients in the rimegepant group also reported pain relief at 2 hours, 58%, vs 43% in the placebo group  (P < .0001).

Secondary Endpoints

Patients reported several prespecified secondary findings, which investigators assessed by using a "gatekeeper strategy." With the exception of nausea, there was "clear separation" between rimegepant and placebo, Lipton said.

Table. Prespecified Secondary Endpoints at 2 Hours After Dosing

Secondary Endpoints Rimegepant 75 mg (%) Placebo (%) P Value
Photophobia-free 37 22 <.0001
Phonophobia-free 37 27 .0039
Pain relief 58 43 <.0001
Nausea-free 48 43 .2084


Sustained Effect

Although the primary measures were at 2 hours after dosing, at which point participants could opt to take a rescue medication, the benefits of rimegepant continued to increase up to 8 hours compared with placebo. For example, a single dose of active treatment was associated with significant sustained pain freedom (P = .0181) and pain relief from 2 to 48 hours after dosing (P < .0001).

"A majority of patients achieved pain relief, and there was durability of benefit," Lipton said.

An adverse event occurred in 17% of people receiving active drug and 14% of the placebo group. Common adverse events included nausea, reported by 1.8% the rimegepant group and 1.1% of the placebo group. Urinary tract infections were reported by 1.5% and 1.1% of the groups, respectively. No adverse event was associated with discontinuation.

"The adverse event profile of rimegepant was relatively favorable," Lipton said. Liver safety is an issue in this therapeutic area, but there was no signal of hepatic problems, he added. "The safety profile was favorable, with an excellent safety profile similar to placebo, including liver function tests."

There was one serious adverse event in a person receiving rimegepant that was judged by the investigator to not to be treatment related.

Commenting on the findings for Medscape Medical News, session co-moderator Elizabeth Loder, MD, MPH, chief of the Division of Headache and Pain in the Department of Neurology at Brigham and Women's Hospital in Boston, Massachusetts, said these new medications are clearly more effective than placebo.

The CGRP receptor antagonists "are likely to be priced very high compared to triptans. Use, at least in my clinic, will depend heavily on the price and what the value proposition is," she said.

Also commenting on the study for Medscape Medical News, Huma Sheikh, MD, assistant professor of neurology at the Icahn School of Medicine at Mount Sinai in New York City, described the study design as "well chosen" and noted the investigators used the latest diagnostic criteria.

She said that even though the study met both of its primary endpoints and that side effects were similar in the active treatment and placebo groups, it remains unclear "whether the drug will consistently provide pain relief when used as an abortive, since they tested just one episode of headache relief."

"Many patients have some degree of relief in their headaches just with rest alone. This will also be important in terms of side effects, including liver abnormalities, which may present with multiple doses of the medication. Overall, it does seem to be a promising new way to treat migraines abortively," she added. 

Biohaven Pharmaceuticals funded the study. Lipton is a consultant for, receives honoraria from, and has stockholder/ownership interest in Biohaven. Loder and Sheikh  have disclosed no relevant financial relationships.

American Headache Society (AHS) Annual Meeting 2018. Abstract #IOR-02LB. Presented June 30, 2018.

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