Migraines are among the most common disorders around the world, and they are also one of the leading causes of disability. And yet, the current list of preventive medications for migraines primarily includes drugs that were developed for other indications and co-opted for migraine therapy.
However, research presented at the 2016 American Academy of Neurology annual meeting reveals new therapeutic targets for headache. Combined with a growing awareness of this complex brain event through functional imaging studies, this is a hopeful time for patients with migraines and for neurologists alike.
“These are particularly exciting times for migraine. For the first time, migraine-specific targets are in development,” said Andrew Charles, MD, Director, Goldberg Migraine Program, University of California, Los Angeles.
Calcitonin Gene-Related Peptide a Prime Target for Migraine
A ubiquitous peptide that is produced in neural cells throughout the body, calcitonin gene-related peptide (CGRP) has multiple functions—it is involved in pain transmission, the dilation of blood vessels, inflammation, and regeneration of motor neurons.
According to Dr Charles, the connections between CGRP and migraines are manifold:
- CGRP is released into the circulation in patients during a migraine attack
- CGRP infusion in patients with migraines evoked a migraine attack 2 to 3 hours later
- Serum CGRP levels may be elevated in patients with chronic migraine
- CGRP receptor antagonists as fast-acting agents effectively abort migraine attacks.
Currently, 4 anti-CGRP monoclonal antibodies (humanized and human antibodies) are in development for migraine (Table).
Overall, 5 phase 2 clinical trials with these monoclonal antibodies have been completed thus far in patients with episodic and chronic migraines. Phase 3 studies and other phase 2 studies are underway for chronic and episodic migraines, as well as for cluster headaches.
“These are large, well-powered studies, with more than 1400 patients enrolled overall,” said Dr Charles, noting that each antibody met the primary end point of significant reduction in headache days for at least 1 of the doses in the clinical trials.
Furthermore, no pattern of serious adverse events has emerged with these novel agents, and no effects on heart rate or blood pressure have been observed.
“Importantly, there’s no evidence of elevation of liver enzymes, which was a concern because of prior studies with small molecules,” said Dr Charles.
Of note, the responder analysis for some of the studies suggested subsets of patients for whom these therapies are very effective, with a 75% or 100% reduction in headache days.
“Obviously, based on this kind of potential efficacy, these studies are generating a considerable amount of excitement,” said Dr Charles.
Finally, because CGRP receptors are found in multiple locations that may be involved in migraine, there are many potential sites of action, including the dural mast cells and the dural arterioles. There may also be >1 receptor that responds to CGRP, Dr Charles noted.
Other Potential Targets and Precision Medicine
One of multiple potential therapeutic targets based on antibodies, pituitary adenylate cyclase-activating polypeptide (PACAP) has also generated considerable interest for treating migraines.
As with CGRP, a variety of evidence implicates this peptide in migraines. For example, the infusion of PACAP triggers migraines in susceptible individuals, and PACAP levels are elevated in circulation during migraines and cluster headache attacks. In addition, PACAP is co-localized with CGRP in many anatomic regions, and shares an accessory protein with CGRP. PACAP may work synergistically or in parallel with CGRP, or with distinct sites of action, Dr Charles said.
“The results of these studies have an enormous potential to teach us about the basic pathophysiology of migraine. We can begin to understand how a migraine attack evolves, and how it evolves from an episodic into a chronic state,” said Dr Charles.
Given the heterogeneous nature of this disorder, researchers are discussing the idea of tailoring fast-acting or preventive migraine therapy to individual patients based on their specific migraine mediators.
“Perhaps most exciting of all, though, is that we’re able to offer new hope for patients who are suffering terribly from this extraordinarily common problem,” said Dr Charles.