Rimegepant

Rimegepant is a potent, selective, competitive, orally bioavailable small-molecule antagonist of the calcitonin gene-related peptide (CGRP) receptor, belonging to the gepant pharmacological class. Originally discovered at Bristol-Myers Squibb as BMS-927711 and subsequently licensed to Biohaven Pharmaceuticals in 2016, rimegepant was the second oral gepant approved by the United States Food and Drug Administration for the acute treatment of migraine (February 2020) and the first oral gepant approved for the preventive treatment of episodic migraine (May 2021), marketed as Nurtec ODT in the United States and as Vydura in the European Union. Pfizer completed the acquisition of Biohaven in October 2022, bringing rimegepant into the Pfizer portfolio.

At the molecular level, rimegepant binds the human CGRP receptor with a Ki of 0.027 nM and produces functional antagonism with an IC50 of 0.14 nM in CGRP-stimulated cAMP accumulation assays. The compound also antagonizes the AMY1 (amylin 1) receptor, a second receptor through which CGRP signals in the trigeminovascular system, with a pA2 of 8.07 (approximately 8.5 nM), representing approximately 30-fold lower potency than at the canonical CGRP receptor (pA2 9.56, approximately 0.28 nM). Activity at the adrenomedullin receptors AM1 and AM2 is negligible (pA2 less than 5). The dual CGRP and AMY1 receptor antagonism distinguishes rimegepant pharmacologically from simple CGRP receptor-selective agents and may contribute to its clinical efficacy in the trigeminovascular pathway.

Pharmacokinetics in humans are characterized by rapid oral absorption (median time to maximum plasma concentration 1.5 hours), absolute oral bioavailability of approximately 64 percent, plasma protein binding of approximately 96 percent, an elimination half-life of approximately 11 hours, and a volume of distribution at steady state of approximately 120 liters. Metabolism is primarily by cytochrome P450 3A4 (CYP3A4) with a minor contribution from CYP2C9; rimegepant is also a substrate of the efflux transporters P-glycoprotein and breast cancer resistance protein (BCRP). Approximately 77 percent of the administered dose is excreted unchanged (42 percent in feces, 51 percent in urine), indicating that the parent compound is the predominant circulating species with no major active metabolites detected in plasma.

Clinical efficacy for the acute treatment of migraine was established across three pivotal Phase 3 randomized, double-blind, placebo-controlled trials (Studies 301, 302, and 303) enrolling a total of 3,507 subjects with migraine of moderate to severe intensity. Pooled two-hour pain freedom rates were 19 to 21 percent for rimegepant 75 mg versus 11 to 12 percent for placebo; freedom from the most bothersome symptom at two hours was 35 to 38 percent versus 25 to 27 percent. For migraine prevention, the Phase 2/3 Study 305 demonstrated that rimegepant 75 mg every other day reduced monthly migraine days by 4.3 days versus 3.5 days on placebo over weeks 9 to 12, a statistically significant difference. The compound is well tolerated; the most common adverse events are nausea (2.7 percent versus 0.8 percent on placebo) and abdominal pain or dyspepsia (2.4 percent versus 0.8 percent). Unlike the first-generation gepant telcagepant, rimegepant has shown no signal of clinically significant hepatotoxicity across preregistration and long-term safety studies enrolling thousands of patients. Rare hypersensitivity reactions (rash, dyspnea) have been reported.

This monograph documents the chemistry, synthesis, and stereochemistry of rimegepant; the dual-receptor CGRP and AMY1 antagonist pharmacology; the comprehensive human pharmacokinetic record; the clinical evidence base across acute and preventive migraine indications and emerging dermatological research applications; sourcing and quality verification considerations; reconstitution and handling; drug interaction implications; adverse event signal; and a comparative assessment of five alternative CGRP pathway therapeutics (ubrogepant, atogepant, zavegepant, galcanezumab, erenumab) against rimegepant on five competency standards. The compound is approved by the FDA and by the European Medicines Agency for migraine indications. Investigators exploring CGRP pathway pharmacology for non-migraine research applications should obtain analytical confirmation of identity and purity on every lot.