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Abstract Details

Cardiovascular Safety of Rimegepant 75 mg in 3 Randomized Clinical Trials and Systematic Evaluations from In Vitro, Ex Vivo, and In Vivo Nonclinical Assays
Headache
S8 - Migraine Therapeutics (3:54 PM-4:06 PM)
003
Characterize the cardiovascular (CV) safety of rimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, in nonclinical assays and clinical trials.
Approximately 3.5 million individuals with migraine have had a CV event, condition, or procedure that contraindicates triptan treatment. A single oral 75 mg dose of rimegepant has demonstrated efficacy in 3 Phase 3 trials for the acute treatment of migraine (Studies 301, 302, and 303).
Rimegepant’s CV safety profile was evaluated using in vitro, ex vivo, and in vivo assays. Nonclinical data were compared with clinical exposures from 75 mg oral rimegepant and pooled data for CV AEs from 3 Phase 3 trials administering 1762 rimegepant 75 mg oral doses versus 1769 placebo doses.
In vitro, rimegepant up to 30 µM was a weak inhibitor in the human ether-a-go-go related gene (hERG) assay and had no effects on rabbit Purkinje fiber action potentials. This concentration is >20× the human Cmax for repeat-dose oral 75 mg rimegepant (1.46 μM, Phase 1 Day 14). Ex vivo, rimegepant showed no vasoconstriction of human coronary or cerebral arteries up to 3-10 µM. In vivo, cynomolgus monkeys receiving 60 mg/kg rimegepant showed exposures (16.5 µM, 8 hr) >10× the repeat-dose human Cmax with no effects on hemodynamic/electrocardiographic parameters, and 9 month daily dosing showed no changes in CV parameters at AUC[0-24h] of 75,473 ng•h/mL, 20× the human repeat-dose AUC (3729 ng•h/mL). Pooled results from the 3 clinical trials showed zero CV AEs.
Nonclinically, rimegepant showed an absence of undesirable CV safety signals at multiples of 10-20× (Cmax) and 20× (AUC) the oral 75 mg repeat-dose human exposure. In Phase 3 clinical trials, there were no on-treatment CV AEs. Rimegepant 75 mg may be a new treatment option in patients with migraine and CV contraindications to triptans.
Authors/Disclosures
Charlie Conway
PRESENTER 		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.
Robert Croop, MD Dr. Croop has received personal compensation for serving as an employee of Biohaven Pharmaceuticals, Inc. Dr. Croop has received personal compensation for serving as an employee of Pfizer Inc.. Dr. Croop has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Collima LLC. Dr. Croop has stock in Biohaven Pharmaceutical Holding Co Ltd. Dr. Croop has stock in Biohaven Ltd.. Dr. Croop has stock in Actio Biosciences, Inc. . Dr. Croop has received research support from Pfizer Inc. Dr. Croop has received intellectual property interests from a discovery or technology relating to health care. Dr. Croop has received intellectual property interests from a discovery or technology relating to health care.
Gene Dubowchik Gene Dubowchik has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Gene Dubowchik has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Morrison Foerster.
Vladimir Coric Vladimir Coric has received personal compensation for serving as an employee of Biohaven. Vladimir Coric has received personal compensation in the range of $1,000,000+ for serving as an officer or member of the Board of Directors for Bioahven. Vladimir Coric has stock in Biohaven. Vladimir Coric has received intellectual property interests from a discovery or technology relating to health care.
Richard B. Lipton, MD, FAAN (Albert Einstein College of Medicine) Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Allergan/Abbvie. 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 $10,000-$49,999 for serving as a Consultant for Lundbeck. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for GlaxoSmithKline. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 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 $10,000-$49,999 for serving as a Consultant for Grifols. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Pfizer. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Axon. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Satsuma. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cool Tech. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BDSI. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Linpharma. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Axsome. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Clexio. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Shiratronics. 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/Abbvie. 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 $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lundbeck. Dr. Lipton has stock in Biohaven. Dr. Lipton has stock in Manistee. Dr. Lipton has stock in Axon. Dr. Lipton has stock in CoolTech. 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/Abbvie. 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 Veterans Administration. Dr. Lipton has received publishing royalties from a publication relating to health care.