CGRP inhibitors for migraine prophylaxis: a safety review

ABSTRACT

Introduction

Since calcitonin gene-related peptide (CGRP) plays an important role in the pathophysiology of migraine via the activation of the trigeminovascular system, the newest prophylactic treatments directly block CGRP or its receptor. However, the safety of these novel antimigraine drugs is not yet sufficiently established.

Areas covered

Based on the blockade of CGRP or its receptor, this review considers: (i) the effects of the novel prophylactic antimigraine drugs (i.e. gepants and monoclonal antibodies) in clinical trials; and (ii) the potentially negative effects of blocking CGRP or its receptor in terms of safety.

Expert opinion

In the last decade, clinical trials have demonstrated the efficacy of new drugs for the preventive treatment of migraine which aim to (i) block CGRP or its receptor; (ii) increase tolerability as compared to the currently available prophylactics; and/or (iii) be more effective and safer than other treatments. However, these trials are limited to study the safety on the short term, and a cardiovascular risk with prolonged use cannot be excluded. Clearly, basic science experimental studies and long-term clinical trials (i.e. Phase IV) are required to delineate the safety of the newest prophylactic antimigraine drugs without causing unwanted side effects due to chronic CGRP (receptor) blockade.

KEYWORDS:

• Antimigraine drugs
• CGRP
• CGRP blockade
• CGRP receptor
• CGRP receptor blockade
• migraine
• prophylactic treatment

Article highlights

• Migraine is a highly disabling, complex, and multifactorial neurological disorder that involves activation of the trigeminovascular system, resulting in the release of CGRP from the sensory nerves.

• Although there is a wide variety of prophylactic antimigraine drugs that act via different mechanisms of action (e.g. β-blockers, antiepileptics, Ca²⁺ channel blockers, 5-HT receptor antagonists, etc.), CGRP (receptor) blockade is critical for the novel prophylactic treatments of migraine.

• For prophylactic antimigraine treatment based on CGRP (receptor) blockade, the gepants (rimegepant and atogepant) and the monoclonal antibodies (erenumab, eptinezumab, fremanezumab, and galcanezumab) are effective and safe in the short term.

• Regarding the novel antimigraine treatments that involve CGRP (receptor) blockade, basic science experimental studies and long-term clinical trials and/or registries (Phase IV) are required to confirm their safety and effectiveness and to delineate their potential cardiovascular side effects.

Declaration of interest

A Maassen van den Brink has received grants and/or fees from Amgen/Novartis, Lilly, 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. This includes employment, consultancies, honoraria, stock ownership, or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received personal fees or honoraria for lectures and/or advisory boards from Pharm Allergan, BIAL, Desitin, Eli Lilly, Hormosan, Novartis and TEVA. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This article was supported by the following research grants: (i) Consejo Nacional de Ciencia y Tecnología (Postdoctoral Grant No. 740678, Mexico) for E. Rivera-Mancilla; and (ii) the Dutch Research Council (NWO, Vici Grant 09150181910040) for A. MaassenVanDenBrink.