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• W2100034504 abstract "Calcitonin gene-related peptide (CGRP) is a wellstudied neuropeptide found at the very centers of the migraine processes, both centrally and peripherally (1,2). Its role in migraine pathophysiology was suggested more than 20 years ago (3,4) and, since then, our knowledge of the peptide has increased substantially, leading to a robust interest in targeting CGRP to treat migraine. At present, CGRP remains the most actively evaluated, and probably best validated target for currently in-development migraine medications (5). CGRP receptor antagonists disrupt the interaction of CGRPwith its receptor and are being developed primarily for the acute treatment of migraine. Free CGRP and CGRP receptors can also be targeted using monoclonal antibodies which are being developed for the preventive treatment of episodic and chronic migraine (6). Four distinct CGRP receptor antagonists (the ‘gepants’) had proof of efficacy for the acute treatment of migraine. Of them, olcegepant (BIBN4096BS) was discontinued because of difficulties in developing an oral formulation (7); telcagepant (MK-0974) was discontinued because of concerns of liver toxicity after frequent use (6,8); MK-3207, a molecule that was significantly more potent than telcagepant (9), was also discontinued because of concerns of liver toxicity (10); and BI44370A had efficacy demonstrated in a Phase 2 clinical study (11). In addition to demonstrating proof of efficacy, CGRP receptor antagonist clinical trials demonstrated the tolerability of the class with acute dosing and that, as opposed to triptans, their use is not associated with vasoconstriction (12–14). A fifth ‘gepant’ just joined the club by its own merits. In the current issue of Cephalalgia, Marcus and colleagues report the result of a large Phase 2b study testing BMS-927711 for the acute treatment of migraine (15). The study used an adaptive design to test six doses of BMS-927711 (10, 25, 75, 150, 300 and 600mg) against placebo. Sumatriptan 100mg was used as an active comparator. Endpoints were those recommended by the International Headache Society (16). The primary efficacy endpoint was the proportion of pain-free subjects at 2 hours post dose. In addition to testing the primary endpoint for statistical significance compared with placebo, the authors attempted to define a measure of clinical relevance, or clinical response of at least 15% greater than the response of placebo. Several of their findings are worth mentioning and commenting on. First and foremost: the drug was clearly effective at multiple doses, meaning that all CGRP receptor antagonists tested to date have demonstrated efficacy in Phase 2 and Phase 3 studies. For the primary endpoint (pain-free at 2 hours), doses of 75mg, 150mg and 300mg (as well as sumatriptan) were superior to placebo. Efficacy was numerically inferior to sumatriptan for this endpoint for all doses (although the study was not powered for direct comparisons). The drug also passed the bar of the secondary endpoints where most (and sometimes all) doses were superior to placebo, and most effective doses were also numerically superior to sumatriptan. Accordingly, certain doses of BMS-927711 seem to deliver levels of efficacy that are similar to those delivered by the highest dose of an effective triptan. Overall, the efficacy of the drug increased up to the dose of 75mg when a plateau effect seemed to have been reached for doses between 75mg and 300mg. The highest tested dose (600mg) demonstrated no additional benefit over the doses of 75mg and 150mg. Although the drug clearly achieved statistical significance, it did not achieve ‘clinical significance’ (response of at least 15% greater than the response of placebo) for any of the reported endpoints. This apparent discrepancy could be explained by the design of the study. Adaptive designs using Bayesian models allow better" @default.
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• W2100034504 date "2013-08-13" @default.
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• W2100034504 title "BMS-927711 for the acute treatment of migraine" @default.
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• W2100034504 doi "https://doi.org/10.1177/0333102413500728" @default.
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