Novel Agents for Migraine Prevention Look Good in Phase 2

April 25, 2014

PHILADELPHIA — Two new agents representing a novel mechanism of action for the prevention of migraine are generating much interest after showing promising results in phase 2 studies.

Studies with the 2 new agents — which are both monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) — were presented here at the American Academy of Neurology (AAN) 66th Annual Meeting.

"This is the first time a mechanism based treatment specifically for migraine prevention has ever been tested," Peter Goadsby, MD, professor of neurology at University of California San Francisco and Kings College London, United Kingdom, who was involved in both studies, commented to Medscape Medical News. "This heralds a new era for migraine. It is very exciting."

Professor Goadsby explained that CGRP is a crucial transmitter in pathways involved in migraine in the brainstem, the midbrain, and the thalamus.

The new preventive drugs are monoclonal antibodies targeting CGRP and are given by subcutaneous injection twice a month or intravenous (IV) injection once every 3 months. Both showed significant reductions in migraine attacks vs placebo in these phase 2 studies.

"Huge" Need

Professor Goadsby does not believe the necessity of having injections will put patients off these new agents.

"The need for new preventative medications is huge," he said. "I don't think having to have an injection every now and then is a big deal. Frequent migraine is a massively disabling condition. It has a major effect on quality of life. If patients have to have two injections a month to normalize their lives I don't think they will hesitate."

He noted that all the current preventive treatments for migraine have come from other therapeutic areas — anticonvulsants, antidepressants, β-blockers — and have not been developed to focus specifically on migraine.

"They also all bring their own baggage with regards to side effects — β-blockers and antidepressants can make you feel tired and anticonvulsants can be associated with cognitive effects and weight gain."

He says that so far the new CGRP-targeted antibodies have been remarkably free of adverse effects. "There may be a little mild nausea in the first few days after the injection. But patients will cope with that to have fewer migraines."

The 2 drugs are ALD403 (Alder Pharmaceuticals) and LY2951742 (Arteaus).

ALD403

For the study of ALD403, 163 patients who had migraine from 5 to 14 days per month received a placebo or a single IV dose of ALD403, 1000 mg. The main outcome measure was the mean change in migraine days between baseline and weeks 5 to 8. This was a reduction of 5.6 days for ALD403 vs a decrease of 4.6 days for placebo (P = .03).

The proportion of patients with a 50%, 75%, or 100% reduction in migraine days at 12 weeks also increased with ALD403.

Table 1. Patients With 50%, 75%, or 100% Reductions in Migraine Days at 12 Weeks

Endpoint ALD403 (%) Placebo (%) P Value
50% reduction 60 33 <.001
75% reduction 32 9 <.001
100% reduction 16 0 <.001

 

The type or frequency of adverse events, vital signs, and laboratory safety data did not differ between the 2 treatment groups.

The researchers conclude that these results support the conduct of larger randomized, placebo-controlled studies and may potentially represent a new era in disease-specific and mechanism-based preventive therapy for migraine.

LY2951742

For the study of LY2951742, which was led by David Dodick, MD, from Mayo Clinic Arizona, Phoenix, 217 patients with 4 to 14 migraine headache days per month were randomly assigned to receive biweekly subcutaneous injections of LY2951742 (150 mg) or placebo for 12 weeks.

The primary endpoint — the change in number of migraine days per 28-day period assessed at 12 weeks — was a reduction of 4.2 days for the active drug vs a reduction of 3.0 days for placebo (P < .003).

LY2951742 was superior to placebo for all secondary endpoints, including headache days, migraine attacks, and responder rate, and also in an exploratory analysis of complete responders (100% reduction in migraine days).

Table 2. Secondary/Exploratory Endpoints

Endpoint LY2951742 Placebo
Headache days –4.9 –3.7
Migraine attacks (n) –3.1 –2.3
Responder rate (%) 70 45
100% reduction in migraine days (%) 33 17.3

 

Adverse events seen more frequently with LY2951742 than placebo included injection site pain, upper respiratory tract infections, and abdominal pain.

The researchers conclude that, "The safety and robust efficacy results in this study are promising and justify the conduct of larger, randomized, placebo-controlled, phase 3 studies and the expression of cautious optimism that a new era of mechanism-based migraine prevention is beginning."

Good News

Asked for comment on these findings, Andrew H. Ahn, MD, PhD, assistant professor of neurology at the University of Florida College of Medicine, Gainesville, said they provide early preliminary data that these agents are effective in reducing the number of headache days in people with frequent migraine.

"This is good news for each of these 2 antibody drugs individually, but together, the news is really big," Dr. Ahn told Medscape Medical News.

The development of these agents represents the culmination of 3 decades of development, he noted, that has been a "roller coaster ride, from the interesting discovery that CGRP appears to be a specific signal associated with migraine, to the exhilarating success of 2 separate CGRP receptor agonists in aborting migraine, to the disappointment when toxicology studies appeared to have killed the development program," he said.

"The results from these 2 early (phase 2) trials represent the discovery that a different strategy altogether, an antibody to the CGRP signal, can modulate the course of migraine disease and again offer a glimmer of hope to a field that continues to struggle with a huge unmet clinical need from a disabling and economically significant neurological disorder," Dr. Ahn said. "These 2 studies are together more powerful because they provide independent and confirmatory data supporting this treatment rationale."

 

The study of ALD403 was funded by Alder Pharmaceuticals. The study of LY2951742 was supported by Arteaus. The study of LY2951742 was supported by Arteaus. Dr. Goadsby reports grants and personal fees from Allergan, eNeura, and Amgen and personal fees from Autonomic Technologies Inc, BristolMyerSquibb, AlderBio, Pfizer, Zogenix, Nevrocorp, Impax, DrReddy, Zosano, Colucid, Eli-Lilly, Medtronic, Avanir, Gore, Ethicon, Heptares, Nupathe, and Ajinomoto.

American Academy of Neurology (AAN) 66th Annual Meeting. To be presented May 1, 2014.

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