Novel, Orally Dissolving Agent May Offer More Rapid Migraine Pain Relief

Damian McNamara

July 15, 2019

PHILADELPHIA — An orally dissolving tablet (ODT) formulation of an acute migraine drug in development may offer more rapid relief from migraine pain, new research suggests.

In a large, double-blind, phase 3 trial, the small molecule calcitonin gene–related peptide (CGRP) receptor antagonist rimegepant (Biohaven Pharmaceuticals) provided significantly greater freedom from pain at 2 hours than placebo among adults with acute migraine.

If approved, this speed of onset could be an advantage for patients with migraine, lead investigator Richard Lipton, MD, professor of neurology, psychiatry, and behavioral sciences and the Edwin S. Lowe chair of neurology at Albert Einstein College of Medicine, New York City, said.

"In contrast to the currently available ODT medications for migraine, rimegepant ODT actually gets absorbed more quickly," he told Medscape Medical News.

This formulation can reach peak levels in the blood 30 minutes faster than the rimegepant tablet, with a reported Tmax of 1.5 hours, in contrast to the 2-hour Tmax reported a prior phase 1 study, which is "something patients really care about," Lipton said.

"People ask me if 30 minutes or 1 hour really makes a difference. I tell them to ask someone with terrible pain if it matters how long it takes to get rid of it. It matters," he added.

The findings were presented here at the American Headache Society (AHS) Annual Meeting 2019 and were simultaneously published online July 13 in the Lancet.

Faster, More Convenient

Lipton noted that greater convenience is another potential advantage. Because the ODT formulation can be taken without water, a person who, for example, is attending a meeting at work and feels a migraine coming on could take the formulation more discreetly than would be the case if that person had to swallow a tablet with water, Lipton said. The ODT formulation would also be convenient, for example, for a patient who is driving a car at the time an attack occurs.

"We know migraine medicines work best when you treat early," he said.

In the study, known as Study 303, the investigators evaluated 1351 adults with episodic migraine.

The participants (85% women; mean age, 40 years) reported having from two and eight severe migraine attacks per month. Rimegepant or placebo was used to treat a single attack. Use of preventive medications with stable doses was allowed.

One of the primary outcomes, freedom from pain at 2 hours, was achieved by 21% of the rimegepant group and 10% of the placebo group, which was significantly different (P < .0001).

Another primary outcome, freedom from most bothersome migraine symptom at 2 hours, was reported by 35% of the rimegepant group vs 27% of the placebo group (P = .0009).

Photophobia, nausea, and phonophobia were the most bothersome symptoms reported in the study.

The proportion of patients who achieved the primary outcomes was similar to the proportion reported in Study 302, as previously reported by Medscape Medical News.

Unique Study Design

Lipton said he was surprised the investigators found statistically significant differences on 21 consecutive factors when comparing rimegepant to placebo. "That's never happened before," he noted.

A "gatekeeper approach" was used to evaluate each factor on its own, but only if the prior factor was significant in comparison with placebo. In other words, because freedom from pain was significant compared with placebo, the researchers could move on to assess most bothersome symptom. If this endpoint was also significant, they could proceed to another factor, and so on, until a given endpoint was not significant.

Pain relief at 60 minutes, freedom from functional disability, and use of rescue medications are examples of these additional factors used in the study.

Lipton said he was unsure why the manufacturer is simultaneously developing a 75-mg tablet and a 75-mg ODT formulation. He noted that the company is developing another small molecule CGRP receptor antagonist, BHV-3500, as a nasal spray, "which might be even quicker than the ODT clinically.

"Formulation choice is clinically desirable," he said.

Forty million Americans experience migraine.

"For some people, the only thing that matters is how quickly it works, and they might use the nasal spray. There might be other people who don't want to spray anything up their nose, and they can use the ODT," Lipton said.

Another Tool in the Toolbox

Commenting on the findings for Medscape Medical News, Kathleen Digre, MD, professor of neurology and ophthalmology at the John A. Moran Eye Center, Salt Lake City, Utah, who is president of the AHS, noted the novelty of the drug's formulation.

"This is the first time I'm learning about this new study on the orally dissolving tablet. But, as a clinician, I need as many tools in my toolbox as I can get," said Digre, who is also chief of the Division of Headache and Neuro-ophthalmology at the University of Utah in Salt Lake City.

Some patients with migraine will like an orally dissolvable tablet, she added.

"The other thing I was interested in is the Tmax was faster, so there is actually a pharmacologic difference in this ODT tablet," Digre said. She added that the shorter Tmax time could be an advantage.

"I'm going to have to try it [with my patients]," she said, although she noted that the agent is not yet available.

The manufacturer notes on its website that it submitted a new drug application to the US Food and Drug Administration for rimegepant in the second quarter of 2019.

The study was funded by Biohaven. Lipton is a consultant for and owns stock options in Biohaven. Digre has reported no relevant financial relationships.

American Headache Society (AHS) Annual Meeting 2019: Abstract IOR05. Presented July 13, 2019.

Lancet. Published online July 13, 2019. Abstract

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