Gepants for Acute and Preventive Migraine Treatment: A Narrative Review

Abstract

Calcitonin gene-related peptide (CGRP) antagonists are a class of medications that act as antagonists of the CGRP receptor or ligand. They can be divided into monoclonal antibodies and non-peptide small molecules, also known as gepants. CGRP antagonists were the first oral agents specifically designed to prevent migraines. The second generation of gepants includes rimegepant (BHV-3000, BMS-927711), ubrogepant (MK-1602), and atogepant (AGN-241689, MK-8031). Zavegepant (BHV-3500, BMS-742413) belongs to the third generation of gepants characterized by different administration routes. The chemical and pharmacological properties of this new generation of gepants were calculated. The clinical trials showed that the new generation of CGRP antagonists is effective for the acute and/or preventive treatment of migraines. No increased mortality risks were observed to be associated with the second- and third-generation gepants. Moreover, the majority of the serious adverse events reported probably occurred unrelated to the medications. Interesting facts about gepants were highlighted, such as potency, hepatotoxicity, concomitant use with monoclonal antibodies targeting the CGRP, comparative analysis with triptans, and the “acute and preventive” treatment of migraine. Further studies should include an elderly population and compare the medications inside this class and with triptans. There are still concerns regarding the long-term side effects of these medications, such as chronic vascular hemodynamic impairment. Meanwhile, careful pharmacovigilance and safety monitoring should be performed in the clinical practice use of gepants.

Acute Treatment of Migraine

“…Ubrogepant may be repeated once after 2 hours, while rimegepant should not be repeated. 30 Ubrogepant and rimegepant were very well tolerated in clinical trials. The most commonly reported adverse events were dry mouth, nausea, and somnolence, all occurring in less than 4% of the trial population.…”

“…In phase 3 clinical trials of ubrogepant 100 mg or rimegepant 75 mg, 19% to 21% of participants in the active arm experienced pain freedom at 2 hours compared with 9% to 10% in the placebo group, and 35% to 37% showed relief of the most bothersome symptom in the active group compared with 9% to 10% in the placebo group. Ubrogepant may be repeated once after 2 hours, while rimegepant should not be repeated 30 …”

“…Ubrogepant and rimegepant were very well tolerated in clinical trials. The most commonly reported adverse events were dry mouth, nausea, and somnolence, all occurring in less than 4% of the trial population 30 . Ubrogepant should be avoided in patients taking strong CYP3A4 inhibitors and the dose should be limited to 50 mg in patients taking verapamil.…”

Safety and Tolerability of Combining CGRP Monoclonal Antibodies with Gepants in Patients with Migraine: A Retrospective Study

“…Gepants are relatively small CGRP receptor antagonists that have been studied for their efficacy in migraine therapy. They have a mass of 0.2–1 kDa and are typically administered orally except for olcegepant [ 6 ]; their short half-lives and easy use make them more prone for frequent dosing that is more probable in acute treatments [ 7 ]. Fundamentally, gepants bind to the CGRP receptors and inhibit their activation, which reverses CGRP-induced vasodilation, neurogenic inflammation, and sensitization [ 8 ].…”

Shared and independent roles of CGRP and PACAP in migraine pathophysiology

“…These drugs include monoclonal antibodies against CGRP or its receptor and small molecule receptor antagonists that are effective for prevention and treatment of migraine. However, in general only about 40–60% of migraine patients are significantly helped by these agents [ 12 , 14 , 15 ], which suggests involvement of other factors beyond CGRP in migraine pathophysiology, such as PACAP [ 16 ]. In this context, patients who do not respond well to CGRP-based drugs might respond to drugs that target PACAP and similarly, a combinatorial approach targeting both CGRP and PACAP might improve treatment efficacies.…”