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ABSTRACT & COMMENTARY
By Dara Jamieson, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Jamieson reports no financial relationships relevant to this field of study.
Synopsis: In a Phase 2 trial, antibodies to calcitonin gene-related peptide resulted in a significant decrease in migraine days measured from baseline to weeks 5 to 8 after one intravenous infusion of the medication, as compared to a placebo infusion. But the high-rate of placebo response (50%) warrants caution in the interpretation of the study results and requires more investigation.
Source: Dodick DW, et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: A randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 2014;13:1100-1107.
Calcitonin gene-related peptide (CGRP) is a neuropeptide that contributes to the intracranial vasodilation and nociceptive activation of the trigeminovascular system that occurs with migraine. In this randomized, double-blind, placebo-controlled, exploratory, proof-of-concept Phase 2 trial, ALD403, a genetically engineered humanized antibody to CGRP, was assessed for safety and efficacy in migraine prevention. Alder Biopharmaceuticals was the sponsor of the study and took responsibility for the collection, processing, and reporting of the data. Adults with monthly episodic migraine were randomly assigned to receive a 1-hour intravenous infusion of ALD403 1000 mg or of placebo.
The primary efficacy endpoint was the change in the frequency of migraine headache days from baseline to weeks 5 to 8 after infusion, although patients were followed for up to 24 weeks after the one-time infusion. Of the 174 patients randomized at 26 centers in the United States, 163 eventually received either ALD403 (n = 81) or placebo (n = 82). Five patients in the ALD403 group and two patients in the placebo group were lost to follow-up during study. The mean change in migraine days between baseline and weeks 5 to 8 after infusion was -5.6 (SD 3.0) in the ALD403 group, as compared with -4.6 (3.6) in the placebo group (difference -1.0; 95% confidence interval, -2.0 to 0.1; one-sided P = 0.0306). For all time points from the date of infusion and for all percentages of reduction in migraine headache days, the ALD403 treatment group had numerically higher response rates, generally around 20% higher than the placebo treatment group response rate. Of the 143 patients who were able to complete the required electronic headache diary consistently, 11 out of 67 patients treated with ALD403 and none of the 76 patients treated with placebo were 100% migraine free for weeks 1 to 12 of the study. The placebo response rates were high, especially in the 50% migraine-free responder group where the placebo response rate was 50% at 1 to 4 weeks, increasing to 67% at 9 to 12 weeks. Adverse events were experienced by 46 (57%) of 81 patients in the ALD403 group and 43 (52%) of 82 patients in the placebo group. The most frequent adverse events were upper respiratory tract and urinary tract infections, fatigue, back pain, arthralgias, and nausea and vomiting. Six serious adverse events in three patients were judged to be unrelated to study drug. There were no differences in vital signs or laboratory safety data between the two treatment groups. Pharmacokinetic assays of ALD403 indicted that the mean maximum concentration occurred 4.8 hours after the start of the 1-hour infusion and that the mean apparent terminal elimination half-life was 27.9 days (range 19.9-46.5). Eleven (14%) of 81 patients in the ALD403 group may have formed anti-ALD403 antibodies during the study.
CGRP, the current "it" compound in migraine treatment, is the target for both acute and preventive therapy. Oral CGRP receptor antagonists have shown efficacy in Phase 2 and Phase 3 trials for acute abortive treatment and may eventually be the first CGRP-targeted intervention to be approved for use in migraine patients. This trial, reported by Dodick et al, indicates potential for another novel anti-CGRP strategy, with an intravenous infusion every as-yet-to-be-determined number of months for migraine headache prevention. However, adoption of this nascent treatment needs further investigation as these preliminary results come from only 163 patients treated for a relatively short period of time, with a robust placebo response as well. That only 174 patients could be recruited into the study from 26 centers is surprising, given the millions of adults in the United States who suffer from migraine headaches. The research protocol was time consuming, with seven visits to the local study center from screening to 24 weeks after the treatment dose, which may have been burdensome to time-stressed patients. An intravenous infusion for headache prevention is a new treatment paradigm but is less painful than onabotulinum toxin injections every 3 months. The authors speculated that intravenous therapy and the novelty of the therapy might have contributed to the high placebo response. The increase in the placebo response over time after infusion may be due to implementation of lifestyle changes that are known to decrease headache frequency and therapy.
The long half-life of the antibody adds to the challenges of the therapy. Possible teratogenic effects of long-term exposure in a population of women of child-bearing age need to be explored. Migraine patients take multiple medications for headaches and comorbidities, so they should be aware of theoretic drug-antibody interactions. The side effect profile appears promising, but any adverse effect may take time to dissipate. These preliminary results are intriguing. However, more studies, with a much larger number of patients who are treated and followed for a much longer period of time, need to be performed before a visit to an infusion center every few months becomes routine for millions of migraine sufferers.