OC-09 | Atogepant in treatment-refractory chronic migraine: is a revision of current criteria for refractory migraine appropriate?

Background: Despite the emergence of novel targeted therapies, refractory migraine remains a major clinical challenge. According to the 2020 European Headache Federation (EHF) Consensus, patients experiencing ≥8 debilitating headache days per month are classified as "resistant" if they have failed at least three classes of preventive treatments, and as "refractory" if they have failed all available classes. Notably, treatments targeting the calcitonin gene-related peptide (CGRP) pathway—monoclonal antibodies and small-molecule antagonists—are currently grouped together within this classification. However, recent real-world evidence suggests that atogepant, a small-molecule CGRP receptor antagonist, may be effective in patients with resistant migraine phenotypes, including those who have failed anti-CGRP monoclonal antibodies. This study aimed to evaluate the effectiveness, safety, and tolerability of atogepant 60 mg daily over 24 weeks in patients with refractory migraine. Methods: This was an observational, prospective, non-randomized, open-label study conducted over a 24-week period. Twenty patients with treatment-refractory chronic migraine received atogepant 60 mg once daily. The co-primary effectiveness endpoints were: (i) change in monthly migraine days (MMDs) from baseline to Weeks 12 and 24; and (ii) the proportion of responders, defined as patients achieving a ≥50% reduction in MMDs from baseline at each time point. Results: MMDs decreased by a mean of 3.7 days at Week 12 (SD 5.8; p=0.049) and 4.1 days at Week 24 (SD 6.0; p=0.047). The proportion of patients achieving a ≥50% reduction in MMDs was 30% at Week 12 and 35% at Week 24.  Conclusion: These findings support the effectiveness of atogepant 60 mg daily as a preventive treatment in patients with refractory migraine. Notably, the observed clinical benefit in individuals who had failed all available migraine preventive drug classes challenges current EHF criteria, suggesting that atogepant and CGRP-targeting monoclonal antibodies should be considered as distinct therapeutic options. Several molecular mechanisms may explain the enhanced inhibition of CGRP signalling with atogepant. Unlike monoclonal antibodies, atogepant is co-internalized with the CGRP receptor, allowing it to inhibit signalling within endosomes. Additionally, atogepant binds to receptors for amylin and adrenomedullin, neuropeptides implicated in migraine pathophysiology, as supported by provocation studies.