Targeted CGRP Small Molecule Antagonists for Acute Migraine Therapy

Migraine is a highly prevalent, severe, and disabling neurological condition with a significant unmet need for effective acute therapies. Patients (~50%) are dissatisfied with their currently available therapies. Calcitonin gene-related peptide (CGRP) has emerged as a key neuropeptide involved in the pathophysiology of migraines. As reviewed in this manuscript, a number of small molecule antagonists of the CGRP receptor have been developed for migraine therapy. Incredibly, the majority of the clinical trials conducted have proven positive, demonstrating the importance of this signalling pathway in migraine. Unfortunately, a number of these molecules raised liver toxicity concerns when used daily for as little as 7 days resulting in their discontinuation. Despite the clear safety concerns, clinical trial data suggests that their intermittent use remains a viable and safe alternative, with 2 molecules remaining in clinical development (ubrogepant and rimegepant). Further, these proofs of principle studies identifying CGRP as a viable clinical target have led to the development of several CGRP or CGRP receptor-targeted monoclonal antibodies that continue to show good clinical efficacy.