AT IHC 2015

VALENCIA, SPAIN (FRONTLINE MEDICAL NEWS)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.

“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.

“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.

“An antibody having this high an affinity will shut down the biology of CGRP very quickly. The same is true for the very high–affinity anti-TNF and anti-interleukin-6 antibodies used in rheumatology. ALD403 will not only bind to free CGRP, it will actually pull CGRP off the receptor. Everything goes towards the antibody; it acts as a sink,” Dr. Smith replied.

This study was too small to identify predictors of hyperresponsiveness. Investigators hope to hunt down useful biomarkers in the large upcoming phase III studies, he added.

TEV-48125: Dr. Bigal presented the first-ever clinical trial of any CGRP-inhibiting antibody in patients with chronic migraine, defined as 15 or more headache days per month. All other studies to date have been conducted in patients with episodic migraine, who typically have far less cardiovascular disease and other comorbidities. Another unique feature of this trial was that current users of migraine preventive medications weren’t excluded; indeed, roughly half of participants were current users.

In this 263-patient, multicenter, double-blind, placebo-controlled, 3-month, phase II study, once-monthly subcutaneous TEV-48125 at 900 mg resulted in a 6.3-day reduction in the monthly number of moderate to severe headache days, while a regimen consisting of a 675-mg loading dose followed by 225 mg achieved a 6-day reduction, compared with baseline. Both of these outcomes were significantly better than the 4-day reduction seen with placebo.

Moreover, efficacy was evident just 1 week into the study. At that point, patients on either the high or low dose of TEV-48125 already showed a significantly greater reduction in the number of headache hours recorded in an electronic headache diary than did controls.

The monoclonal antibody–treated patients also resorted to acute medications significantly less frequently than did controls by a margin of roughly 2 fewer days per month.

The benefit of both TEV-48125 dosing regimens was equally robust regardless of whether they were on conventional prophylactic medications.

A 75% or greater reduction in monthly headache days was achieved in 32% of patients on the 900-mg dose, in nearly 30% of those on 675/225 mg, and in 16% of controls.

“These patients had suffered with frequent migraine for an average of 18 years, and now they come in and say, ‘I’m basically free of headaches for the first time in my life,’” Dr. Bigal said.

AMG 334: This fully human monoclonal antibody to the CGRP receptor was the focus of a multicenter, phase IIb, double-blind, dose-ranging study in 483 patients with 4-14 migraine days per month at baseline. Patients with comorbid depression and/or anxiety disorders were eligible to participate.

The most effective dose, and the one being carried forward into phase III, was 70 mg given subcutaneously once per month. The mean number of monthly migraine days was reduced by 3.4 days in patients on that regimen from a baseline of 8.7 days, significantly better than the 2.28-day reduction with placebo. In a prespecified secondary analysis, there was no difference in efficacy between patients with more than 8 monthly migraine days at baseline and those with fewer than 8 days, reported Dr. Robert Lenz of Amgen in Thousand Oaks, Calif.

The safety data showed no signal of any adverse event. Fewer than 3% of patients of the AMG 334 group discontinued treatment for any reason.