Abstract & Commentary
Source: Olesen J, et al. N Engl J Med. 2004;350:1104-1110.
The accumulated evidence that 5-HT (serotonin) plays a role in migraine ultimately led to the development of the 5-HT1B/1D receptor agonists. Further research into the mechanism of action of these drugs then led to the discovery of other vasoactive and neuroinflammatory peptides. Several targets have emerged as promising. Calcitonin gene-related peptide (CGRP) is a neuropeptide that is a potent vasodilator of cerebral and dural vessels. CGRP has been shown to be elevated during a migraine and infusion of CGRP can induce a migraine. CGRP antagonists have been obvious agents to pursue. Olesen and associates report on a phase II study of BIBN 4096 to evaluate the safety and efficacy of a first in class non-peptide, parenteral CGRP-receptor antagonist.
A total of 126 patients with acute moderate-to-severe migraine without aura aged 18-65 with 1-6 migraines per month were enrolled. Besides placebo, a range of intravenous doses (.25, .5, 1, 2.5, 5, 10 mg) were studied. A group-sequential adaptive treatment-assignment design was chosen to compare relatively few patients across this wide range of doses. The primary end point was "headache response" defined as the reduction in severe or moderate headache to mild or no headache at 2 hours. Several secondary end points were also measured such as 24 hours sustained pain relief; relief of nausea, vomiting; clinical disability; use of rescue medication; and rates of adverse events. The group sequential analysis yielded the 2.5 mg dose as the optimal one. At this dose the 2-hour pain relief response was 66% vs 27% for placebo (P < 0.001). The recurrence rate was 19% for the 2.5 mg dose vs 46% for placebo. The use of rescue meds was lower across all doses of BIBN 4096. The adverse events were higher in the treatment group 20% vs 12% (P value not provided). The most frequent complaint (8% vs 0%, no P value provided) was paresthesias. No serious side effects were reported. Overall Olesen et al conclude that as a "proof-of-concept" study, intravenous BIBN-4096- a first in class CGRP receptor antagonist, is both safe and effective.
Commentary
Since, the world needs more migraine drugs, this trial should be seen as hopeful for an emerging new class of treatment. Several points, some of which Olesen et al raise, are worth reiterating here. The current study was small and we do not really know how to compare it with the thousands of patients studied with triptans. Sumatriptan delivered subcutaneously demonstrates 2-hour pain relief efficacy results in the 70-80% range. Would BIBN-4096 need to compete with those numbers? Probably not, especially if the mechanism of action and the clinical results proved synergistic. The fact that the drug does not appear to have vasoconstrictive effects could prove to be a major distinguishing feature from almost every other acute migraine medication on the market. Furthermore, treatment effect was seen as far as 6 hours into the attack, and this could prove quite an advantage over currently approved remedies. Now that Boehringer Ingelheim has a dose to move forward we look ahead to larger more comprehensive phase III data. — Jeffery Reich, MD
Dr. Reich, Assistant Professor of Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.
Olesen and associates report on a phase II study of BIBN 4096 to evaluate the safety and efficacy of a first in class non-peptide, parenteral CGRP-receptor antagonist.
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