Article In Brief
Investigators reported that migraine patients treated with rimegepant, a CGRP receptor antagonist, were free from pain and free from their most bothersome symptom two hours after the dose compared with placebo.
PPHILADELPHIA—New research points to the potential of a new class of agents to treat painful, debilitating headaches, several physician-scientists reported here at the annual meeting of the American Headache Society (AHS).
The “gepants”—as some of the experts referred to the calcitonin gene–related peptide (CGRP) receptor inhibitors—have not yet been approved by the Food and Drug Administration, but a handful of these agents are showing positive outcomes in various clinical trials, researchers reported.
In one study, published in the July 11 issue of The New England Journal of Medicine, to coincide with the AHS meeting, patients who were treated with rimegepant achieved the trial's primary endpoints: freedom from migraine pain at two hours compared with placebo and freedom from their most bothersome symptoms of migraine within two hours of taking the medicine compared with placebo, reported Richard B. Lipton, MD, FAAN, the Edwin S. Lowe professor and vice chair of neurology at the Albert Einstein College of Medicine in New York.
Within two hours, 19.6 percent of the patients taking rimegepant were free of pain compared with 12 percent of patients who were on placebo, a statistically significant difference (p>0.001), said Dr. Lipton.
In addition, he reported that 37.6 percent of patients on rimegepant said their most bothersome migraine symptom— photophobia—was relieved within two hours compared with 25.2 percent of patients who had been assigned to placebo in the randomized clinical trial (p<0.001).
“This trial showed that among patients with migraine, treatment of an attack with rimegepant, which acts through inhibition of the CGRP receptor, resulted in a moderately higher percentage of patients who were free from pain and free from their most bothersome symptom two hours after the dose than placebo,” Dr. Lipton said.
One of his colleagues, Jelena Pavlovic, MD, PhD, assistant professor in the Saul R. Korey department of neurology at Albert Einstein, told Neurology Today that for people with migraine, the secondary endpoint may be the most important.
“Getting people completely pain free in two hours is a high bar, and achieving 19.6 percent is a modest effect, but in my patients' experience getting rid of their most bothersome symptom within two hours is more important. And in this study 37.6 percent of patients were able to achieve that.”
No Vasoconstrictive Effects
CGRP plays a role in the pathophysiological features of migraine, and small-molecule CGRP receptor antagonists (“gepants”) have been shown to be effective in acute migraine treatment in several previous trials, the researchers reported. “Gepants may be effective in patients whose symptoms do not respond to triptans [5-HT receptor agonists], owing to their different mechanisms of action,” Dr. Lipton and colleagues reported.
“Unlike triptans, which are contraindicated in patients with cardiovascular disease because of the possibility of vasoconstriction, rimegepant does not have vasoconstrictive effects,” the researchers suggested.
That finding was borne out in experiments conducted by Eloisa Rubio-Beltran, MSc, a PhD student at Erasmus University Medical Center in Rotterdam, the Netherlands. Rubio-Beltran tested the reactions of human heart and brain arteries to the CGRP inhibitors ubrogepant and atogepant, comparing their vasoconstriction to what happens to those arteries when introduced to zolmitriptan. Rubio-Beltran presented the findings of the study, which was sponsored by Allergan, at the AHS annual meeting.
She illustrated that the proximal coronary artery and the distal coronary artery do not respond to the gepants administration, but there is a significant contractility with the use of zolmitriptan. The triptans are not recommended for patients with cardiovascular disease.
“Ubrogepant and atogepant are devoid of vasoconstrictive properties,” she said in her oral presentation.
The NEJM Study
In the NEJM study, Dr. Lipton and his research team enrolled 1,186 patients and randomly assigned 594 to receive rimegepant 75 mg in a single dose at the onset of migraine and 592 patients to receive placebo. For the report, 537 rimegepant patients and 535 placebo patients were evaluated.
The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7 percent were women; 74 percent were white and 21.4 percent were black; and the patients averaged 4.6 migraine attacks a month, with attacks normally lasting an average of 32 hours when untreated.
Photophobia was the most common bothersome symptom, with 51.9 percent of the patients reporting that symptom as most bothersome; 29.6 percent reported nausea as most bothersome symptom while 15.3 percent of the patients said phonophobia was most bothersome.
Dr. Lipton reported that rimegepant was superior to placebo in the secondary endpoints of two-hour freedom from photophobia (p<0.001), two-hour freedom from phonophobia (p=0.004), and pain relief at two hours (p<0.001). He reported that rimegepant did not prove superior than placebo in reducing symptoms of nausea.
The researchers also reported that in other secondary endpoints more patients (37 percent) required rescue medication in the placebo group than those taking rimegepant (21 percent); more patients on rimegepant (42.6 percent) achieved pain relief through 24 hours than patients on placebo (26.5 percent) and more patients on rimegepant (32.6 percent) were able to function normally two hours after taking a dose compared with 23.4 percent of patients on placebo.
Biohaven Pharmaceuticals sponsored the trial, supplied the trial agents, reviewed the trial design, collected the data, and performed data management and analysis. The manuscript was written with the assistance of a medical writer funded by Biohaven Pharmaceuticals. All the authors have confidentiality agreements with Biohaven Pharmaceuticals, either as a condition of employment or in their role as consultants. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.
Commenting on the study, Noah Rosen, MD, director of Northwell Health's Headache Center in Great Neck, New York, told Neurology Today, “This has been a banner couple of years for new treatments for headache. When you look at the raw data without context, the treatment with rimegepant may not look that wonderful, especially when you look at pain freedom as opposed to pain reduction. But these numbers for two-hour pain freedom have never been very robust. I think the figures we see here are equivalent for two-hour pain freedom as we saw with the triptans.”
“This drug might be a good drug to take if a patient could not tolerate or didn't find triptans effective, although it is hard to say because we don't have head-to-head comparisons,” Dr. Rosen added.
He also said that, because FDA requires treatment to be tested on people with moderate to severe migraine, the drugs are often tested while the attacks are already well entrenched, making effective treatment more difficult.
“Most patients take these drugs earlier in the attack than was done in the clinical trial, and response rates have been better as our experience with triptans has shown,” he said.
Dr. Lipton suggested, “Larger and longer trials are needed to determine the consistency of response and the safety and effectiveness of the drug as compared with other migraine treatments.”
Dr. Lipton disclosed relationships with Acorda Therapeutics, Inc., Alder, Allergan, Amgen, Avanir Pharmaceuticals, Inc., Biohaven, CVS Health, Dr. Reddy's, Eli Lilly and Company, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Sun Pharmaceutical Industries, Inc., Supernus Pharmaceutical, Inc., and Teva. Rubio-Beltran received a research grant from Allergan and travel expenses for the AHS meeting. Dr. Pavlovic reported relationships with Allergan, Alder, Biohaven and Dr. Reddy's. Dr. Rosen disclosed relationships with Eli Lilly & Co., Adler, and Teva.