The CGRP Pathway in Migraine as a Viable Target for Therapies

The neuropeptide calcitonin gene-related peptide is well established as a key player in the pathogenesis of migraine. Clinical studies show calcitonin gene-related peptide levels correlate with migraine attacks, and decreases in this neuropeptide can indicate antimigraine therapy effectiveness. Research has revealed a wide distribution of expression sites for calcitonin gene-related peptide in the central and peripheral nervous system. Of these, the calcitonin gene-related peptide receptor, which binds calcitonin gene-related peptide with high affinity, has attracted growing interest as a viable target for antimigraine therapies. An incentive to pursue such research is the continuing unmet medical need of patients. Triptans have offered some clinical benefit, but many patients do not respond and these drugs have important safety considerations. Initial calcitonin gene-related peptide-focused research led to development of the "gepant" small-molecule calcitonin gene-related peptide receptor blockers. Positive efficacy reports concerning the gepants have been tempered by safety findings which led to the discontinuation of some of these agents. Currently, there is considerable excitement regarding monoclonal antibodies against calcitonin gene-related peptide (eptinezumab, galcanezumab, fremanezumab) and the calcitonin gene-related peptide receptor (erenumab). To date, these monoclonal antibodies have shown promising efficacy in clinical trials, with no major safety concerns. If ongoing long-term studies show that their efficacy can be maintained, this may herald a new era for effective antimigraine therapies.