The Emperor’s New Gepants: Are the Effects of the New Oral CGRP Antagonists Clinically Meaningful?

Abstract

INTRODUCTION Calcitonin gene-related peptide (CGRP) is most likely involved in migraine. The US Food and Drug Administration and the European Medicines Agency have approved injections of several antibodies to the CGRP receptor or ligand for the prophylactic treatment of migraine. The oral small molecule CGRP receptor antagonist telcagepant was shown to be effective for the acute treatment of migraine attacks in randomized, controlled trials. However, its development was halted when several participants developed liver toxicity in a Phase IIb trial of the drug for migraine prophylaxis. This article focuses on 2 other small molecule CGRP receptor antagonists, ubrogepant and rimegepant, which remain in late phase testing for the acute treatment of migraine. In the first half of 2018, the main results of large Phase 3 trials of these drugs were presented as abstracts at several medical conferences. We review the small effect sizes in these studies, discuss the difference between statistical and clinical significance, and reflect on the lack of candid discussion about the low efficacy of these drugs.