Late response to anti-CGRP therapy for migraine.

Abstract

Migraine is a debilitating neurological disorder affecting 1 billion people worldwide. Traditional preventive drugs showed low efficacy and poor tolerability. Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptors offer a new efficacious and safe therapeutic option for migraine patients. According to randomized controlled trials, these disease-specific drugs reduce migraine frequency by ≥ 50% within 3 months. However, real-world studies show that some patients require a longer treatment duration (6 or 12 months). This narrative review aimed to investigate the occurrence of late and ultra-late responses to anti-CGRP therapy, exploring their potential mechanisms and clinical significance. A literature search was performed [PubMed, Web of Science and Google Scholar; publications up to July 2025] to identify relevant studies for this narrative review. Across 10 real-world studies, a proportion of patients who did not respond at 3 months achieved a meaningful clinical response at later time points: some between 3 and 6 months ("late responders") and others between 6 and 12 months ("ultra-late responders"). Around one-third of initial non-responders improved by 6 months, and among those who remained non-responsive at that point, a further proportion benefited by 12 months. The pathophysiological mechanism behind late response is a field of investigation, and the interaction of anti-CGRPs on the process of central desensitization seems to be crucial. Our review underscores the need to extend treatment beyond the typical 3-month period to attain meaningful benefits from anti-CGRP therapies.