Novel therapy for acute migraine awaits FDA approval

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A drug belonging to a new generation of acute migraine headache treatments was found to eliminate pain and reduce bothersome symptoms for people with migraine in a large-scale trial. The drug, rimegepant, is awaiting US Food and Drug Administration approval and may offer advantages over currently available migraine medications. The study was led by researchers at Albert Einstein College of Medicine and Montefiore Health System.

“For the first time in nearly three decades, people with migraine not helped by existing medications may have a new option to find relief during attacks,” said Dr Richard B Lipton, the study’s first author and Edwin S Lowe professor and vice chair of the Saul R Korey department of neurology at Einstein and director of the Montefiore Headache Centre.

Migraine headache affects about 12 to 14% of people, or more than a billion individuals worldwide. This chronic neurologic disorder involves periodic attacks of head pain along with symptoms that may include nausea as well as sensitivity to light and sound. More than three-quarters of migraine sufferers experience at least one migraine attack per month, and more than half are severely impaired during their attacks.

Currently, many people with migraine take triptan drugs (examples include sumitriptan, eletriptan, and rizatriptan), which were introduced in the 1990s. Triptans halt acute migraines by stimulating serotonin receptors, which in turn reduces inflammation and constricts blood vessels. But triptans don’t help everyone, they can produce intolerable side effects, and – since they constrict vessels – shouldn’t be taken by people with cardiovascular disease (CVD) or major CVD risk factors.

People not helped by triptans, or those who can’t take them, may benefit from the new class of drugs called, gepants, which includes rimegepant. Gepants work by targeting the receptors for a small protein, called CGRP, long implicated in migraine. During migraine attacks, CGRP is released resulting in pain. Gepants relieve the pain and other symptoms of migraine by blocking the CGRP pathway.

The trial assessed rimegepant, in a randomized double-blind trial involving more than 1,000 men and women with migraine at 49 centres in the US. The participants were instructed to take a tablet of rimegepant, or a matching placebo tablet, during a migraine attack, once moderate or severe pain developed. Before taking the tablet and for 48 hours afterwards, patients answered questions in an electronic diary concerning their pain and their most bothersome symptoms. Participants chose their most bothersome symptom from a list, including intolerance to light, intolerance to loud sounds, or nausea.

Two hours after taking their tablets, 19.6% of patients in the rimegepant group were free from pain compared with 12.0% in the placebo group – a statistically significant difference. Freedom from their most bothersome symptoms occurred in 37.6% of patients in the rimegepant group and 25.2% in the placebo group. Side effects were minimal, with nausea and urinary tract infections the only adverse effects reported in more than 1% of patients in each group and no adverse CVD effects observed.

“These results confirm that rimegepant’s mechanism of action – blocking the CGRP pathway – effectively relieves pain and associated symptoms that occur during acute migraine attacks,” said Lipton. “As someone who has studied CGRP blockers for more than a decade, I’m gratified to see their benefits confirmed in a large-scale clinical trial.”

The clinical trial, led by Lipton, was sponsored by Biohaven, which makes rimegepant and may benefit financially from the results. Lipton is a paid consultant and a stockholder of Biohaven.

Background: Calcitonin gene–related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene–related peptide receptor antagonist that may be effective in acute migraine treatment.
Methods: In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least a 1-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month to receive rimegepant orally at a dose of 75 mg or matching placebo for the treatment of a single migraine attack. The primary end points were freedom from pain and freedom from the most bothersome symptom (other than pain) identified by the patient, both of which were assessed 2 hours after the dose of rimegepant or placebo was administered.
Results: A total of 1186 patients were randomly assigned to receive rimegepant (594 patients) or placebo (592 patients); of these, 537 patients in the rimegepant group and 535 patients in the placebo group could be evaluated for efficacy. The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7% were women. In a modified intention-to-treat analysis, the percentage of patients who were pain-free 2 hours after receiving the dose was 19.6% in the rimegepant group and 12.0% in the placebo group (absolute difference, 7.6 percentage points; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after the dose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001). The most common adverse events were nausea and urinary tract infection.
Conclusions: Treatment of a migraine attack with the oral calcitonin gene–related peptide receptor antagonist rimegepant resulted in a higher percentage of patients who were free of pain and free from their most bothersome symptom than placebo.

Richard B Lipton, Robert Croop, Elyse G Stock, David A Stock, Beth A Morris, Marianne Frost, Gene M Dubowchik, Charles M Conway, Vladimir Coric, Peter J Goadsby

Albert Einstein School of Medicine material
New England Journal of Medicine abstract

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