Pauline Anderson

July 03, 2014

LOS ANGELES — There is growing anticipation in the headache community about the arrival of a variety of monoclonal antibodies that target the calcitonin gene-related peptide (CGRP) pathway to prevent migraine headaches.

CGRP is involved in the pathophysiology of migraine. Levels of CGRP are elevated during migraine attacks and decrease with resolution of the attacks.

Several pharmaceutical companies are developing agents that block CGRP activity, with relevant research being showcased here at the American Headache Society (AHS) 56th Annual Scientific Meeting.

Revolutionary

Although approval is likely 5 or more years away, when these drugs do become available, it will be "revolutionary," commented Peter Goadsby, MD, PhD, Director, Headache Center, University of California, San Francisco. "This is the first mechanism-based, migraine-specific therapy for prevention that we have ever had."

Although triptans represent acute treatments for migraine, "these new agents are preventive, which we have not had before," he added.

One of the agents, ALD403 (Alder BioPharmaceuticals Inc), is a genetically engineered humanized CGRP antibody delivered intravenously. A double-blind trial that randomly assigned patients to receive either the drug (n = 81) or placebo (n = 82) found that more participants receiving the drug had reduced migraine days compared with those receiving placebo.

At week 9 to 12, for example, 75.3% of the ALD 403 and 66.7% of the placebo groups had a 50% reduction in migraine days (P = .1603). The respective percentages for a 75% and 100% reduction in migraine days were 53.4% vs 30.8% (P = .0039) and 41.1% vs 16.7% (P = .0008), respectively.

"We regard a 50% reduction in headaches as a success, but in this study, there were a significant proportion of people who had a 75%, and even a 100% reduction in headaches, so it's very exciting," said Dr. Goadsby.

Another agent, LY2951742 (Eli Lilly and Company), a fully humanized monoclonal antibody to CGRP, also enjoyed positive phase 2 trial results. In this double-blind study, 106 participants received the treatment and 110 received a placebo, administered subcutaneously. The mean change in migraine headache days at 3 months was −4.2 for the drug and −3.0 for the placebo group (P = .003).

As well, the drug was superior to placebo for all secondary endpoints, including headache days, migraine attacks, and 50% responder rate. Adverse events that were reported more frequently in the treatment group included upper respiratory tract infections, injection site pain, neck pain, abdominal pain, dizziness, injection site erythema, rash, hypertension, and pain in extremities.

In a presentation during the meeting, Cen Xu, PhD, scientific director, Amgen Inc, explained the science behind a third drug, Amgen's AMG 334. Although the other antibodies act by "mopping up" the CGRP peptide, rendering it inactive, according to Dr. Goadsby, AMG334 binds to the CGRP receptor itself, effectively disabling it.

Amgen, said Dr. Xu, had decided to target the receptor despite the fact that this would mean a more complicated and time-consuming route. "After several years of trying, we are pleased to let you know that we have overcome the technical difficulties and have generated a panel of CGRP receptor antibodies," said Dr. Xu.

She explained how one of the company's star antibodies (AMG 334, a fully human monoclonal antibody) is "highly selective for the CGRP receptor" and works to prevent the CGRP signal, presumably blocking its function.

The company has 2 ongoing phase 2 studies. One is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and safety of the drug in migraine prevention, and the other is evaluating the efficacy and safety of the drug in chronic migraine prevention.

"We are anxiously awaiting results," said Dr. Xu.

No Safety Concerns

After the presentation, Werner Becker, MD, professor, neurology, University of Calgary, Alberta, Canada, and founding director, Calgary Headache Assessment and Management Program, noted that CGRP is widely distributed throughout the body.

"You would assume that it has some important functions other than producing migraines, perhaps maintaining cardiac circulation," said Dr. Becker. He wondered whether any serious adverse effects have been uncovered with the use of this antibody.

Dr. Xu responded by saying that from the accumulated evidence on the AMG 334 molecule and from research on related drugs, "we haven't seen any significant concerns or safety signals from blocking the signalling pathway."

Indeed, in a study that compared cardiovascular parameters in healthy women volunteers receiving yet another monoclonal antibody against CGRP (LBR-101; Labrys Biologics Inc) or placebo via infusion, effects on blood pressure, heart, rate, and electrocardiogram parameters were similar.

Together, the research indicates that these agents are "well tolerated," as well as "mechanism-specific" and "highly targeted," commented Dr. Goadsby.

Today, patients with migraine are given everything from epilepsy treatments to blood pressure treatments and depression treatments, but nothing targeted specifically at preventing migraine, according to Dr. Goadsby. That there is nothing now available to prevent migraine "is crazy," he said.

But that could all change when these new agents reach the market, he added. "There will come a time when patients will come in with a migraine and we will give them a migraine treatment."

Dr. Goadsby called this a "huge" development that will be "completely revolutionary."

"For the first time," he said, "physicians can diagnose migraine and treat it preventatively with a migraine drug."

The research also tells pharmaceutical companies that "it is possible to make highly specific, well-tolerated preventives for the most common neurological problem," noted Dr. Goadsby.

Once these drugs are available, Dr. Goadsby foresees that patients will get a regular infusion or injection to reduce the frequency and severity of their migraine attacks.

Although not all patients with headache will benefit from these monoclonal antibodies, "from what we have seen so far, we can just about guarantee they will make a huge difference for a proportion of people" suffering the devastating effects of migraine headaches, said Dr. Goadsby.

Dr. Goadsby has received consulting fees and/or honoraria from AlderBio, Allergan Inc, Amgen, Arteaus, Autonomic Technologies Inc, Bristol-Myers Squibb, Colucid, Dr. Reddy, Eli Lilly, eNeura, Impax Labs, Medtronic, Merck and Co Inc, Nevrocorp, Pfizer Inc, Sharpe & Dohme, Zogenix, and Zosano. He is on the speaker's bureaus of Allergan Inc and Pfizer Inc. He receives a salary from the University of California, San Francisco. He has received other financial benefit, as an expert witness from Journal Watch Neurology (manuscript preparation), Medico (legal advice, patient advice), and the American Headache Society (presentation development).

American Headache Society (AHS) 56th Annual Scientific Meeting. Presented June 27, 2014.

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