Real world considerations for newly approved CGRP receptor antagonists in migraine care

ABSTRACT

Introduction

Migraine is the leading cause of years lived with disability in people under 50. Electrophysiological phenomena at the basis of prodromal and headache attack phases and of chronification processes involve calcitonin-gene related peptide (CGRP) as a fundamental player become a game changer of migraine pharmacotherapy.

Areas covered

The purpose of the present review is to retrace fundamental stages of CGRP from its discovery to the role in migraine pathogenesis and therapy to underscore the change of paradigm offered by the newly approved small molecules to antagonize CGRP receptor, the gepants. In particular, the development of this new class is gone over from the initial synthesis of C-terminus truncated CGRP antagonists to the development of the first generation of gepants ending with Zavegepant that can be considered the third generation.

Expert opinion

The history of CGRP in migraine draws the successful road to follow for key signaling pathways of modulation of nociceptive facilitation by diencephalic and brainstem nuclei, including dopaminergic neurotransmission, orexin A and the large-conductance calcium-activated potassium (BK_Ca) and ATP-sensitive potassium (K_ATP) channels also investigating the potential of essential oils and the role of polymorphisms. Real-world post marketing long-term data are needed for gepants.

KEYWORDS:

• Atogepant
• CGRP antagonists
• gepants
• migraine
• rimegepant
• ubrogepant
• vazegepant

Article Highlights

• Migraine is the leading cause of years of life lived with disability in people under 50

• The calcitonin-gene related peptide (CGRP) has been implicated in migraine pathophysiology and chronification

• The newly approved small molecules to antagonize CGRP canonical receptor gepants offer relief from attack and prevention being well tolerated

• Ubrogepant, rimegepant and atogepant have recently been approved being effective and devoid of the hepatotoxicity characteristic of the first generation gepants

• The development of CGRP-targeting therapeutic options is a success to repeat for key signaling pathways of modulation of nociceptive facilitation by diencephalic and brainstem nuclei for novel drugs discovery

• Real-world long-term data about the pharmacotherapy with gepants are needed.

Declaration of interests

D Scuteri is a researcher in the frame of the project supported by the Italian Ministry of Health: NET-2016-02361805 (WP 5). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has received honoraria for contribution to advisory boards or oral presentations from Lilly, Lundbeck, Novartis, Pfizer and Teva. The German Research Council (DFG), the German Ministry of Education and Research (BMBF) and the European Union support his headache research. He also serves on the editorial boards of Cephalalgia, Lancet Neurology and Drugs and is a member of the Clinical Trials Committee of the IHS. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose

Additional information

Funding

This paper was not funded.