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Will Acute Migraine Get Its Due in 2019?

By many standards, 2018 was a banner year for migraine prevention. A novel class of drugs designed to prevent migraine by inhibiting calcitonin gene-related peptide (CGRP) was launched, with the FDA approving three anti-CGRP treatments: erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality). But treatments to shut down acute migraine remain unsatisfactory.

Will that change in 2019? We asked four headache specialists to weigh in.

“In the next period, providers caring for patients with migraine will see two completely novel classes of acute migraine therapies: gepants and ditans,” predicted Peter Goadsby, MBBS, of King’s College London in England and the University of California, San Francisco.

The gepant drugs — rimegepant and ubrogepant — are oral CGRP receptor antagonists for acute migraine treatment. Both have completed phase III trials and “both have shown effectiveness for the two endpoints the FDA requires: 2-hour pain freedom in comparison to placebo and 2-hour relief of the most bothersome migraine symptom,” said Stewart Tepper, MD, of the Geisel School of Medicine at Dartmouth College in Hanover, New Hampshire.

Their efficacy is gentle and modest, “more like the slow-acting triptans,” Tepper noted. And the gepants are well-tolerated without any plausible basis for producing medication overuse issues, Goadsby added.

But this novel class of drug presents an unusual question: if a patient is using one of the new CGRP inhibitors for migraine prevention, will gepant drugs work?

“That is an unknown at the moment,” Goadsby said. But given the popularity of the new preventive drugs — over 100,000 patients have received the CGRP receptor inhibitor erenumab (Aimovig) since it was approved in May, for example — it’s a likely question to be investigated.

Also completing successful phase III trials in 2018 was the first “ditan” for acute migraine treatment — lasmiditan, a serotonin 5-HT1F receptor agonist. In November, drugmaker Eli Lilly reported the company had filed a new drug application for lasmiditan with the FDA.

“The presumed mechanism of action of lasmiditan is to terminate migraine in the brain stem and prevent processing of the migraine centrally,” Tepper explained. That may be why lasmiditan appears to have central nervous system adverse effects, including dizziness and drowsiness.

“These side effects are of concern for a drug that will be used repeatedly over many years by otherwise healthy young people — mostly women — who need to drive and work,” said Elizabeth Loder, MD, MPH, of Brigham and Women’s Hospital in Boston.

Both lasmiditan and gepants “clearly are better than placebo, but they have not, as far as I am aware, been compared head-to-head with other commonly-used treatments,” Loder pointed out. “It seems unlikely, looking at the effect sizes in the trials, that they are more effective than existing treatments, including some inexpensive over-the-counter treatments.”

Neither lasmiditan nor gepants are associated with vasoconstriction, Tepper stated: “These drugs will not be contraindicated in patients with known vascular disease.”

But marketing campaigns for them may overstate the cardiovascular dangers of triptans, Loder observed: “This could potentially scare people away from triptans, many of which are generic and inexpensive, to new higher-priced drugs whose safety advantages are mostly speculative.”

And the new drugs have other caveats, she added: long-term safety remains to be demonstrated by widespread use in thousands of people and safety in pregnancy is uncertain, which is “a major consideration for a treatment that will be used mostly by women of childbearing age,” she said.

Other treatment possibilities in 2019 may include innovative neuromodulation therapies like the Nerivio Migra device, a wireless armband that uses smartphone-controlled electrical stimulation controlled to block migraine pain signals. In a pivotal trial, Nerivio Migra met its primary endpoints and in November, device maker Theranica Bioelectronics announced it had filed for FDA approval.

“Remote electrical stimulation and hand stimulation devices are especially attractive options given that they are portable, relatively discreet devices that may be used while the patient is at work or performing other daily activities,” noted Amaal Starling, MD, of the Mayo Clinic in Scottsdale, Arizona.

These techniques offer patients with contraindications to standard oral or injection therapies a non-drug treatment option, Starling said. And emerging neuromodulation therapies show promise: “I expect the innovation of treatment devices to continue to grow as we learn more about migraine and other headache disorders,” she added.


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