Can Calcitonin Gene-Related Peptide Change Migraine Treatment?

In a 2013 review of future migraine therapy published in the Annals of Neurology, migraine headache was called a neglected, low-hanging fruit on the neurologic tree. The review was written by Peter J. Goadsby, MD, PhD, director of the National Institute for Health Research—Wellcome Trust King’s Clinical Research Facility in London and professor of neurology at the University of California San Francisco.¹

The review noted that migraine headaches are among the most common and disabling of all neurologic disorders. The World Health Organization has ranked migraine as the third most common disease burden. Despite this, migraine has remained poorly understood, poorly treated, and poorly researched for most of the past 100 years. A neuropeptide called calcitonin gene-related peptide (CGRP) finally may be changing that picture.^1,2

Better Migraine Treatments Are Needed

It was once believed that migraine pain was caused by vasodilation. It is now believed that migraine is a disorder of modulatory networks that gate sensory input. Symptoms like pounding headache, photophobia, and sensitivity to sound or smell are probably a failure of filtering mechanisms. In other words, ordinary stimuli become unbearable.¹

Treatments based on old theories of migraine have not been very effective and have never been developed specifically to treat migraine. Triptans, the backbone of acute migraine treatment, are only partially effective. Various preventive therapies are also not very effective and not very well tolerated.¹

“Triptans are only about 60% effective, and only about half of that 60% become pain free. If we could find a new treatment that was just 5% better, it would be worthwhile,” said James Couch, MD, PhD, professor of neurology at the University of Oklahoma Health Sciences Center in Oklahoma City.³

Could CGRP Fill the Need?

CGRP is not new. For more than 20 years, experts have known that CGRP is elevated during a migraine attack and lower after resolution. “We know that CGRP is an important transmitter both centrally and peripherally and that it activates ganglions that trigger migraine,” said Couch.³Although Goadsby has been tracking CGRP for a long time, not many other researchers were interested until certain recent developments. “For one reason, there was another neurotransmitter candidate called substance P that seemed more interesting. Controlled trials failed. Then came trials to treat migraine with CGRP receptor antagonists. They went off target during phase 2 because they caused liver toxicity. It is only with the recent advances in monoclonal antibody technology that interest has peaked,” Goadsby said.²

Two phase 2 CGRP antibody trials presented at the 2014 meeting of the American Academy of Neurology have raised hopes that real migraine prevention therapy may occur in the future. In one trial, a single dose of intravenously delivered humanized CGRP antibody was given to 81 patients with migraine. Eighty-two patients were given a placebo. Patients receiving the drug had significantly reduced migraine days.

At weeks 9 to 12, 75.3% of the treatment group had a 50% reduction in migraine days compared with 66.7% of the placebo group. Results for 100% reduction were impressive, with 41.1% of the treatment group getting complete reduction compared with 16.7% of the placebo group.⁴

A second trial of bi-weekly injections of CGRP antibody also demonstrated significant results compared with a placebo over 12 weeks. Headache days and number of headaches both decreased.⁵ “We just don’t see these types of results in many clinical trials. To see them in two trials is really impressive,” Goadsby said.²

Where Do We Go From Here?

The CGRP receptor antagonists, also called gepants, could potentially offer a new type of acute treatment for migraine, but they have not fared well. Although gepants have shown proof of efficacy in early trials, two had to be scrapped due to liver toxicity with long-term use.

In 2014, a phase 2 trial reported in the journal Cephalalgia showed that a gepant called BMS-927711 achieved statistical but not clinical significance when compared with a triptan and placebo.⁶

“The gepants may still play a role. They seem to work about as well as the triptans for acute migraine. They could become an alternative if they [researchers] can figure out the hepatotoxicity problem,” Couch said.³

For now the big hope is for migraine prevention with CGRP antibodies. “These drugs have passed the early tests, but we still don’t know about long-term tolerability. We don’t know if they will be better for migraine with aura or migraine without aura. We have a few years to go,” said Couch.³

“There may well be some side effects. These drugs have only been tried in a few hundred people. So far things look good. We have a big condition, a common problem, and a promising solution. That is an uncommon experience. Perhaps in the next decade we will actually have a migraine drug designed to treat migraine. That could be pivotal and extraordinary,” said Goadsby.²

Chris Iliades, MD, is a full-time freelance writer based in Cape Cod, Massachusetts.

This article was medically reviewed by Pat F. Bass III, MD, MS, MPH

References

1. Goadsby PJ. Therapeutic prospects for migraine: can paradise be regained? Ann Neurol. 2013;74(3):423-434.
2. Dodick DW, Goadsby PJ, Silberstein SD, et al. Randomized, double-blind, placebo-controlled, phase II trial of ALD403, an anti-CGRP peptide antibody in the prevention of frequent episodic migraine. Lancet Neurol. In press.
3. Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS. CGRP monoclonal antibody LY2951742 for the prevention of migraine: a phase 2, randomized, double-blind, placebo-controlled study. Lancet Neurol. 2014;13(9):885-892.
4. Bigal ME. BMS-927711 for the acute treatment of migraine. Cephalalgia. 2013; doi:10.1177/0333102413500728.