Gepants for the treatment of migraine

ABSTRACT

Introduction: Migraine is the most common of all neurological disorders. A breakthrough in migraine treatment emerged in the early nineties with the introduction of 5-HT1B/D receptor agonists called triptans. Triptans are used as the standard of care for acute migraine; however, they have significant limitations such as incomplete and inconsistent pain relief, high rates of headache recurrence, class- specific side effects and cardiovascular contraindications. First- and second-generation calcitonin gene-related peptide (CGRP) receptor antagonists, namely gepants, is a class of drugs primarily developed for the acute treatment of migraine. CGRP is the most evaluated target for migraine treatments that are in development.

Areas covered: This article reviews the available data for first- and second-generation CGRP receptor antagonists, the role of CGRPs in human physiology and migraine pathophysiology and the possible mechanism of action and safety of CGRP-targeted drugs.

Expert opinion: Available data suggest that second generation of gepants has clinical efficacy similar to triptans and lasmiditan (5-HT1F receptor agonist) and has improved tolerability. Future studies will assess their safety, especially in specific populations such as patients with cardiovascular disease and pregnant women.

KEYWORDS:

• Atogepant
• calcitonin gene-related peptide
• CGRP
• gepant
• migraine
• migraine acute treatment
• rimegepant
• ubrogepant

Article Highlights

• Calcitonin gene-related peptide (CGRP) is released in parallel with pain; successful treatment of migraine attacks aborts both the associated pain and the CGRP release.

• Triptans are the gold standard of acute migraine treatment but have class contraindications that limit their use in patients with cardiovascular diseases.

• CGRP antagonism does not cause vasoconstriction, making it safe for patients with migraine who cannot use triptans.

• CGRP receptor antagonists (gepants) do not have vasoconstrictive properties; in phase 2 and phase 3 trials they have demonstrated similar efficacy to- and fewer side effects than triptans.

• The development of the first gepants (olcegepant, telcagepant, MK-3207 and BI 44,370 TA) was discontinued because of difficulties in developing an oral formulation or liver toxicity concerns.

• Three new gepants (rimegepant, ubrogepant and atogepant) are still in the development pipeline; results from phase 2 and phase 3 RCTs show they are effective, well tolerated and safe in terms of liver toxicity. Currently ongoing RCTs, which are expected to be completed in 2019, will provide definite conclusions on the efficacy and safety of these promising molecules.

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Declaration of interest

A Negro has received speaking honoraria from and has served on the Advisory Board of Allergan and Novartis. P Martelletti has received speaking honoraria from, and has served on the Advisory Board of Allergan, Eli Lilly, Novartis and TEVA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.