The CGRP Receptor and Migraine: New Treatments

Episodic migraine has long been theorized to occur via a cascading pathway which has at its center release of substances from the trigeminal gangion, which sits at the base of the skull. Just which substances released from that ganglion was chiefly causative of the headache was poorly understood until the past 10 years, when evidence has been increasing regarding the major role of calcitonin gene-related peptide (CGRP), a 37 amino acid length peptide structurally related to the hormone calcitonin. Unlike calcitonin, CGRP has little effect on calcium metabolism Instead, it appears to play a role in signaling for pain and inflammation in many areas of the body, but especially in the head. The trigeminal ganglion is well supplied with CGRP secreting ability. Both triptans like suratriptan and neurotoxins like botulinim toxins inhibit CGRP release from the trigeminal gangion, which suggests a way in which these agents help migraine.

At the AAN meeting this past week in Philadelphia, two similar monoclonal antibodies against CGRP were announced to have migraine prevention ability. Such antibodies are likely binding CGRP before it can bind to pain and inflammation promoting sites. Although both of these medications will be expensive to make and be given by injection, they point the way to a future new class of medication agents for persons with headache.


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AAN PRESENTATION (May 2,2014)

Speaker: David Dodick, MD

Title: CGRP Monoclonal Antibody LY2951742 for the Prevention of Migraine: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study

Brief Talk Description: The rationale, study design, results and conclusion of a recent phase II study evaluating the efficacy and tolerability of a novel anti-CGRP monoclonal antibody for the prevention of migraine.

Biographical Information: David W. Dodick, MD, FRCP (C), FACP, is Professor of Neurology at the Mayo Clinic College of Medicine and a consultant in neurology at the Mayo Clinic, in Phoenix, Arizona. He is the Program Director of the Mayo Clinic Neurology Residency Program and Headache Medicine Fellowship Program....[etc]


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ABSTRACT

Abstract Title: Randomized, Double-blind, Placebo-controlled Trial of ALD403, an Anti-CGRP Peptide Antibody in the Prevention of Frequent Episodic Migraine

Authors: Peter Goadsby; David Dodick; Stephen Silberstein; Richard Lipton; Jes Olesen; Messoud Ashina; Kerri Wilks; David Kudrow; Robin Kroll; Bruce Kohrman; Robert Bargar; Joe Woodinville; Jeff Smith

Objective: To evaluate the efficacy and safety of ALD403, a genetically engineered humanized anti-CGRP antibody (IgG1), for migraine prevention.

Background: Calcitonin gene-related peptide (CGRP) is crucially involved in the pathophysiology of migraine.

Design/Methods: Patients with 5 to 14 migraine days per month were randomized to receive a single intravenous dose of ALD403 1000 mg or placebo in a double-blind fashion. The primary endpoint was the mean change in frequency of migraine days from baseline to migraine days during weeks 5-8. Patients were followed for 24 weeks for additional safety and efficacy analyses

Results: Of 174 patients randomized, 163 patients received either ALD403 (81) or placebo (82). There were no significant differences in baseline demographics or characteristics between the two treatment groups. The mean change in migraine days between weeks 5-8 and baseline was -5.6 days (66% decrease) for ALD403 vs. -4.6 days (52% decrease) for placebo (one-sided p = 0.03). The proportion of patients with a 50%, 75%, and 100% reduction in migraine days at 12 weeks for ALD403 and placebo was 60% vs 33% (p < 0.001); 32% vs 9% (p < 0.001); and 16% vs 0% (p < 0.001), respectively. There were no differences in the type or frequency of adverse events, vital signs, or laboratory safety data between the two treatment groups.

Conclusions: A single intravenous dose of ALD403 1000 mg demonstrated efficacy for the preventive treatment of migraine in patients with a high monthly frequency of migraine days. ALD403 was generally safe and well tolerated. 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.

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