Targeting CGRP for migraine treatment: mechanisms, antibodies, small molecules, perspectives

ABSTRACT

Introduction

Calcitonin Gene-Related Peptide (CGRP) has gradually emerged as a suitable therapeutic target to treat migraine. Considering the social and economic burden of migraine, it is fundamental to optimize the disease management with efficacious and safe treatments. In this scenario, drugs targeting GCRP, monoclonal antibodies (MoAbs) and gepants, represent new therapeutic strategies.

Areas covered

In the present work, the authors aim at appraising the main insights and implications of treatments targeting CGRP by reviewing pathophysiology and clinical information.

Expert opinion

Anti-CGRP MoAbs are the first migraine-specific preventive treatments representing a suitable option especially for difficult-to-treat patients. They can be safely administered for long periods even in association with preventatives acting on different targets. Gepants are a safe alternative to triptans for the acute management of migraine and are currently being tested for prevention, thus representing the first transitional molecules for disease therapy. In the future, it might be possible to adapt the treatment according to patients’ characteristics and disease phenotype even combining the two treatments targeting the CGRP pathway.

KEYWORDS:

• Migraine
• Calcitonin Gene-Related Peptide
• GCRP
• erenumab
• galcanezumab
• fremanezumab
• eptinezumab
• atogepant
• rimegepant
• ubrogepant

Article highlights

• Calcitonin Gene-Related Peptide (CGRP) is a neuromodulator and vasodilator peptide playing a key role in migraine genesis. Gepants and monoclonal antibodies are specific migraine treatments, which act peripherally at the levels of trigeminal ganglion and afferents.

• Monoclonal antibodies targeting the CGRP pathway achieved good results in migraine prevention, even in the most difficult-to-treat patients and in those with medication overuse. Indeed, they are particularly indicated in who suffers from high-frequency episodic migraine and chronic migraine.

• Monoclonal antibodies proved to have several advantages compared to old oral preventatives, such as ease of use and a high safety and tolerability profile, which might ensure greater therapeutic adherence rate.

• Gepants induce a blockade of CGRP pathway binding to its receptor and have a short half-life and a good tolerability profile. The new generation of these drugs, rimegepant and ubrogepant proved to be effective in controlling acute migraine symptoms, whereas atogepant is under study as a preventive treatment.

• Gepants might be transitional molecules leading to a completely new therapeutic strategy. Their ease of use in prevention and during the acute attacks of migraine could allow a patient self-regulated treatment.

• Further studies are needed to deeper understand the mechanisms at the basis of disease, as well as the CGRP pathway itself. They are fundamental to explain the partial or absent response of some patients to these treatments opening up new therapeutic strategies.

• For difficult-to-treat patients, a possible therapeutic approach is the add-on therapy with treatments acting on peripheral and central targets combining new and old preventatives. In the future, it might even be possible to combine gepants and monoclonal antibodies and/or switching the antibody class used.

• The treatment duration of anti-CGRP treatments has not been defined yet. Even if the guidelines suggest discontinuing the therapy after 6–12 months, a longer timespan might be necessary to downregulate the pathogenetic mechanisms and subsequently avoid rebound after drug discontinuation. Further data are necessary to clarify this issue. Long treatment durations are justified by the excellent tolerability profile of those drugs.

Declaration of interest

R Ornello has received sponsorship to attend meetings from Novartis and Teva. S Sacco has received speaking honoraria from and has served on Advisory Boards of Abbott, Allergan, Eli-Lilly, Medscape, Novartis, Teva. P Martelletti has received speaking honoraria from and has served on the Advisory Board of Eli-Lilly, Allergan, Novartis, Teva. 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

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

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was not funded.