Intranasal Zavegepant is Effective and Well Tolerated for the Acute Treatment of Migraine: A Phase 2/3 Dose-Ranging Clinical trial (4976)

Objective: Evaluate the efficacy, safety, and tolerability of intranasal zavegepant in the acute treatment of migraine. Background: Zavegepant, a third-generation, high-affinity, selective and structurally unique, small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is the only intranasal CGRP receptor antagonist in late-stage development for the acute treatment of migraine. Findings from a previous single ascending dose study indicated that intranasal zavegepant produced potentially therapeutic systemic exposures. Design/Methods: In this randomized, dose-ranging, placebo-controlled, Phase 2/3 trial in adults with migraine (NCT03872453), subjects treated a single attack of moderate to severe pain intensity with intranasal zavegepant 5, 10, 20 mg, or placebo. The coprimary efficacy endpoints were freedom from pain and the most bothersome symptom (MBS; i.e., photophobia, phonophobia, or nausea) at 2 hours postdose. Endpoints were tested at an alpha level of 0.0167. Results: Of the 1673 subjects randomized, 1588 were treated with study medication and 1581 were included in the modified intention-to-treat population [zavegepant 5 mg (n=387), 10 mg (n=391), 20 mg (n=402), placebo (n=401)]. Overall, median age was 40 years, 85.5% were female, and approximately 14% were taking preventive migraine medication. Zavegepant 10 mg and 20 mg demonstrated statistical superiority to placebo on the co-primary endpoints of pain freedom [placebo: 15.5%; 5 mg: 19.6% (p=0.1214); 10 mg: 22.5% (p=0.0113); 20 mg: 23.1% (p=0.0055)] and MBS freedom [placebo: 33.7%; 5 mg: 39.0% (p=0.1162); 10 mg: 41.9% (p=0.0155); 20 mg: 42.5% (p=0.0094)]. The most common (>5%) adverse events were dysgeusia (13.5%–16.1% with zavegepant vs 3.5% with placebo) and nasal discomfort (1.3%–5.2% with zavegepant vs 0.2% with placebo); The majority of adverse events were mild or moderate. There was no signal of hepatoxicity. Conclusions: Intranasal zavegepant 10 mg and 20 mg were effective for the acute treatment of migraine, with a favorable safety profile. Disclosure: Dr. Croop has received personal compensation for serving as an employee of Biohaven Pharmaceuticals, Inc. Dr. Croop has received stock or an ownership interest from Biohaven Pharmaceutical Holding Co Ltd. Dr. Croop has received intellectual property interests from a discovery or technology relating to health care. Jennifer Madonia has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Jennifer Madonia has received stock or an ownership interest from Biohaven Pharmaceuticals. Charlie Conway has received personal compensation for serving as an employee of Biohaven Pharmaceuticals Inc. Charlie Conway has received stock or an ownership interest from Biohaven Pharmaceuticals. Alexandra Thiry has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Alexandra Thiry has received stock or an ownership interest from Biohaven Pharmaceuticals. Micaela Forshaw has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Micaela Forshaw has received stock or an ownership interest from Biohaven Pharmaceuticals. Abigail Murphy has received personal compensation for serving as an employee of Biohaven Pharmaceuticals . Dr. Jensen has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Dr. Jensen has received stock or an ownership interest from Biohaven Pharmaceuticals. Gene Dubowchik has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Gene Dubowchik has received stock or an ownership interest from Biohaven Pharmaceuticals. Vlad Coric has received personal compensation for serving as an employee of Biohaven. Vlad Coric has received stock or an ownership interest from Biohaven. Vlad Coric has received intellectual property interests from a discovery or technology relating to health care. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Allergan. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Amgen. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biohaven. Dr. Lipton has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Eli Lilly. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GlaxoSmithKline. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Vedanta. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Satsuma. Dr. Lipton has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Eli Lilly. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Grifols. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Allergan. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amgen. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biohaven. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli Lilly. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lundbeck. Dr. Lipton has received stock or an ownership interest from eNeura. Dr. Lipton has received stock or an ownership interest from Biohaven. Dr. Lipton has received stock or an ownership interest from CtrlM Health. The institution of Dr. Lipton has received research support from Teva. The institution of Dr. Lipton has received research support from Amgen. The institution of Dr. Lipton has received research support from Allergan. The institution of Dr. Lipton has received research support from Gammacore. The institution of Dr. Lipton has received research support from Axsome. The institution of Dr. Lipton has received research support from Charleston Labs. The institution of Dr. Lipton has received research support from Eli Lilly. The institution of Dr. Lipton has received research support from Satsuma. The institution of Dr. Lipton has received research support from NIH . The institution of Dr. Lipton has received research support from NIH. The institution of Dr. Lipton has received research support from NINDS. The institution of Dr. Lipton has received research support from NIH. The institution of Dr. Lipton has received research support from NIA. The institution of Dr. Lipton has received research support from NIH. The institution of Dr. Lipton has received research support from NIA. The institution of Dr. Lipton has received research support from NIH. The institution of Dr. Lipton has received research support from Veterans Administration. The institution of Dr. Lipton has received research support from NIH. Dr. Lipton has received publishing royalties from a publication relating to health care.