Cardiovascular Safety of Rimegepant 75 mg in 3 Randomized Clinical Trials and Systematic Evaluations from In Vitro, Ex Vivo, and In Vivo Nonclinical Assays (2141)

Objective: Characterize the cardiovascular (CV) safety of rimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, in nonclinical assays and clinical trials. Background: 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). Design/Methods: 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. Results: 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. Conclusions: 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. Disclosure: Dr. Conway has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biohaven. Dr. Conway holds stock and/or stock options in Biohaven. Dr. Croop has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biohaven Pharamceuticals, Inc.. Dr. Croop has received compensation for serving on the Board of Directors of Biohaven Pharamceuticals, Inc.. Dr. Croop holds stock and/or stock options in Biohaven Pharamceuticals, Inc. which sponsored research in which Dr. Croop was involved as an investigator. Dr. Croop holds stock and/or stock options in Biohaven Pharamceuticals, Inc.. Dr. Dubowchik has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biohaven. Dr. Dubowchik holds stock and/or stock options in Biohaven. Dr. Coric has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biohaven Pharmaceuticals, Inc.. Dr. Coric has received compensation for serving on the Board of Directors of Biohaven Pharmaceuticals, Inc.. Dr. Coric holds stock and/or stock options in Biohaven Pharmaceuticals, Inc. which sponsored research in which Dr. Coric was involved as an investigator. Dr. Coric holds stock and/or stock options in Biohaven Pharmaceuticals, Inc.. Dr. Lipton has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceuticals. Dr. Lipton has received compensation for serving on the Board of Directors of eNeura and Biohaven. Dr. Lipton holds stock and/or stock options in Biohaven which sponsored research in which Dr. Lipton was involved as an investigator. Dr. Lipton holds stock and/or stock options in Biohaven. Dr. Lipton has received research support from Migraine Research Foundation the National Headache Foundation and Amgen.