VALENCIA, SPAIN – In the lecture halls and corridors at the International Headache Congress, far and away the dominant topic of conversation was the latest highly promising data for the CGRP (calcitonin gene–related peptide)-inhibiting monoclonal antibodies being developed for migraine prophylaxis.
“The question of efficacy, to me, has been resolved: They’re spectacularly effective. The whole reason for the phase III studies is to establish safety,” Dr. Marcelo E. Bigal, a vice president at Teva Pharmaceuticals, said in the opening plenary session.
Dr. Marcelo E. Bigal
“This is the second revolution in the history of migraine therapy,” declared another opening plenary speaker, Dr. Messoud Ashina, professor of neurology at the University of Copenhagen.
“It is a really exciting emerging field. It kind of reminds me of the triptan story,” observed Richard J. Hargreaves, Ph.D., vice president for discovery science at Biogen in Cambridge, Mass.
With a long track record of success in new drug development and having conducted research on CGRP for more than 2 decades, it fell to Dr. Hargreaves to provide an introductory overview of the CGRP inhibitors. Each of the monoclonal antibodies has a different mechanism of action. However, they share several key characteristics: They are highly specific in their mechanisms of action, they have long circulating plasma half-lives, they are largely peripherally restricted rather than acting at the level of the central nervous system, and they typically have a low toxicity profile. Indeed, in phase I and -II studies the type and frequency of adverse events was essentially indistinguishable from placebo.
Now advancing through the developmental pipeline are three CGRP ligand-neutralizing antibodies and one CGRP receptor antibody.
“The race is on. It’s estimated that 40% of migraine patients are candidates for prophylaxis. That’s 14 million U.S. patients. And preventive therapy represents a significant unmet medical need,” Dr. Hargreaves said at the meeting sponsored by the International Headache Society and the American Headache Society.
“Clearly the CGRP monoclonal antibodies aren’t going to be used for acute migraine therapy. That’s going to be the province for oral small-molecule CGRP inhibitors because of the need for rapid activity. But if the antibodies prevent well, then hopefully the need for acute medications will go down,” he continued.
A particularly impressive feature of the investigational agents is that a substantial proportion of treated patients are hyperresponders – that is, individuals who experience at least a 75% and in some cases a 100% reduction in migraine days per month.
“Understanding these hyperresponders in the antibody trials is a real goal for the field. What’s the biomarker that predicts you can cure a patient of migraine headaches? How can you match an individual’s phenotype to the pharmacology of the medicine you’re giving them and get a better outcome?” he asked.
Dr. Hargreaves left his audience of headache specialists with another question to ponder: “If triptans inhibit CGRP release, and CGRP modulators, such as the monoclonal antibodies block CGRP’s action, then why aren’t triptans useful preventive agents? It’s something for the field to think about. I’ll leave you with the thought that maybe CGRP is the volume control for trigeminovascular sensory transmission.”
New data on three CGRP inhibitors was presented at the congress:
ALD403: A single 1,000-mg IV dose of this humanized IgG1 CGRP antibody produced lasting efficacy for 6 months in a phase II, randomized, double-blind, placebo-controlled study.
The study, conducted at 28 U.S. sites, included 163 patients with high-frequency episodic migraine, defined as an average of 5-14 migraine days per month.
One month post infusion, 51% of ALD403-treated patients and 24% of controls had a 75% reduction in monthly migraine days; in addition, 26% of the ALD403 group and 5% of controls had a 100% response, meaning they had no migraines.
At 12 weeks, 33% of the ALD403 group and 9% of controls had a 75% response, while 16% of ALD403-treated patients and zero controls had a 100% response.
At 24 weeks – again, after just a single dose – 26% of the ALD403 group and 7% of controls had a 75% response, while 11% of the active treatment group and no controls had a 100% response.
Dr. Jeffrey T.L. Smith
“There is relatively little difference between the 3-month and 24-week data. So in initial responders, the antibody is still working at 6 months. Some patients simply never had a migraine from the end of the needle to the end of the study,” said Dr. Jeffrey T.L. Smith, senior vice president at Alden BioPharmaceuticals in Bothell, Wash.
One audience member asked how the antibody can reduce the frequency of migraines so swiftly – starting within the first several weeks – when conventional prophylactic medications take months and months to work.