Calcitonin gene-related peptide (CGRP): role in migraine pathophysiology and therapeutic targeting

ABSTRACT

Introduction: The neuropeptide calcitonin gene-related peptide (CGRP) is recognized as a critical player in migraine pathophysiology. Excitement has grown regarding CGRP because of the development and clinical testing of drugs targeting CGRP or its receptor. While these drugs alleviate migraine symptoms in half of the patients, the remaining unresponsive half of this population creates an impetus to address unanswered questions that exist in this field.

Areas covered: We describe the role of CGRP in migraine pathophysiology and CGRP-targeted therapeutics currently under development and in use. We also discuss how a second CGRP receptor may provide a new therapeutic target.

Expert opinion: CGRP-targeting drugs have shown a remarkable safety profile. We speculate that this may reflect the redundancy of peptides within the CGRP family and a second CGRP receptor that may compensate for reduced CGRP activity. Furthermore, we propose that an inherent safety feature of peptide-blocking antibodies is attributed to the fundamental nature of peptide release, which occurs as a large bolus in short bursts of volume transmission. These facts support the development of more refined CGRP therapeutic drugs, as well as drugs that target other neuropeptides. We believe that the future of migraine research is bright with exciting advances on the horizon.

KEYWORDS:

• Migraine
• CGRP
• gepants
• monoclonal antibodies
• trigeminovascular system

Article highlights

• Preclinical and clinical studies have shown that calcitonin gene-related peptide (CGRP) is a critical neuropeptide in migraine pathophysiology, but the mechanisms by which it is involved remain to be elucidated.

• Targeting CGRP or its receptor with antibodies or small molecules is very effective at alleviating migraine symptoms in about half of the patients.

• CGRP antagonizing drugs appear to be safe so far, however, long-term open-label studies are needed to confirm this safety profile.

• Better knowledge of the sites of CGRP action and signaling pathways is likely to lead to improved treatments for patients.

• A second CGRP receptor known as the amylin 1 receptor could be a novel target for migraine treatment.

• Targeting other neuropeptides, such as PACAP and amylin that have similar functions as CGRP, represents an additional avenue for alternative and/or complementary therapeutics.

This box summarizes key points contained in the article.

Declaration of interest

AS Wattiez and LP Sowers are consultants for Pieris Pharmaceuticals. AF Russo serves as a consultant for Alder Biopharmaceuticals, Amgen, Novartis, Lilly, Pharmnovo, Schedule One Therapeutics and receives grant support from Alder Biopharmaceuticals. 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

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

Additional information

Funding

This paper was not funded.