Advances in CGRP therapeutic targets for migraine: where do we stand 5 years later?

Introduction The past 5 years of success with calcitonin gene-related peptide (CGRP) based drugs has transformed migraine into a relatively treatable neurological disorder. There are now eight monoclonal antibodies and small-molecule receptor antagonists available for the acute and preventive treatment of migraine. However, while the drugs have been remarkably effective and safe so far, they do not work for everyone, and some adverse effects have become apparent.Areas covered We describe key developments with the CGRP therapeutics regarding real-world effectiveness and safety. Emerging evidence supporting combinatorial treatment strategies within the CGRP drugs and with onabotulinumtoxinA will be discussed.Expert opinion The future of peptides is bright for migraine therapeutics. A monoclonal antibody against pituitary adenylate cyclase–activating polypeptide (PACAP) has shown promise in two clinical trials and evidence suggests that CGRP and PACAP therapeutics may be complementary. A second CGRP receptor, AMY1, which is also activated by another peptide, amylin, is a new therapeutic target validated by clinical and preclinical data. Building on the CGRP story, centrally acting CGRP antagonists are an untapped area that should be explored. We close with a brief speculation on possible future applications of CGRP drugs for other disorders.