New Treatments for Migraines on the Horizon

Major changes may be coming for the prevention of persistent migraines, according to Amaal Starling, MD, of the Mayo Clinic.

At the 69th Annual Meeting of the American Academy of Neurology, Starling gave a plenary address about the difficulties of treating those with chronic migraine, and how monoclonal antibody drugs may soon be an effective preventative treatment.

“There’s an overwhelming number of patients that should be on preventive therapy but are not. In fact, 33% are recommended prevention medications, but only 3% to 13% are using prevention medications,” she said.

Setting up the discussion with a hypothetical patient case, she spoke of typical issues of skepticism and expectations. Epilepsy, blood pressure, and depression drugs like topiramate, propranolol, amitriptyline, and venlafaxine are currently often prescribed for migraine prevention, leading patients to question why a drug with another primary use is being given to them. Such medications also often take some time for their effects to be felt, leading to patient treatment abandonment when they are still having migraines not long after initiation. At one year, such drugs only have a 13 to 16% continuation rate one year after baseline.

Today, Starling says neurology is “several steps closer” to effective migraine prevention medications thanks to developments in monoclonal antibodies (mAbs) that inhibit calcitonin gene-related peptide (CGRP). CGRP is a 37-amino acid neuropeptide believed to be released during migraine that localizes in the trigeminal ganglia and spinal trigeminal nuclei, consistent with a migraine’s central and peripheral manifestations.

“It is found that infusion of CGRP can trigger spontaneous migraine attacks,” said Starling, “and during spontaneous migraine attacks, there is an elevation of CGRP levels.” In addition, there are findings that those with chronic migraines have consistently elevated levels of CGRP compared to healthy controls.

“The hypothesis is that CGRP antagonists can be an effective treatment for migraine,” she said. Earlier forms of CGRP receptor agonists, gepants, were found effective in inhibiting migraines, but in some trials had an unfortunate predisposition to liver toxicity. Starling notes that “the gepant story is not over” and different formulations of such agents are still being explored with different compositions.

Monoclonal antibodies are seen as a potentially better option for CGRP inhibition, as they are large, highly target-specific molecules with long half-lives that allow for monthly administration and thus better potential adherence. Major pharmaceutical companies are currently piloting a host of mAbs for the purpose of inhibiting migraines, including galcanazumab, fremanezumab, eptinezumab, and erenumab.

Starling compared various trials of the mAbs at hand, noting that every one so far had met its primary endpoints, and that “Three of the monoclonal antibodies have undergone not only episodic migraine trials but also chronic migraine trials and still met primary endpoints,” she said.

Across the trials, there were consistent improvements in monthly migraine days, with high rates of patients seeing 50% or 75% reductions in days plagued by them. Unlike with other treatments, as well, many mAbs have shown separation from placebo in less than a week, including one trial of their use on chronic migraine that showed improvements in 3 days.

“In addition, there have been no drug-related serious adverse events that have been reported thus far,” Starling continued, “It has a much better profile, and it makes sense. This is disease-specific, mechanism-based treatment which will have less off-target effects.”

There are still many questions about mAbs for migraine prevention, including where exactly they are working, whether or not they can identify and study super-responders in trials, and what the long-term effects of CGRP modulation are. Still, Starling is exceedingly optimistic about the treatments.

“Welcome to this new era,” she said.

Phase 3 results of a double-blind, placebo controlled trial of one of the drugs, erenumab, will be presented in a highly-anticipated session later in the conference.