Ten open questions in migraine prophylaxis with monoclonal antibodies blocking the calcitonin-gene related peptide pathway: a narrative review

Abstract

The monoclonal antibodies (mAbs) blocking the calcitonin-gene related peptide (CGRP) pathway, collectively called here “anti-CGRP/rec mAbs”, have dramatically improved preventive migraine treatment. Although their efficacy and tolerability were proven in a number of randomized controlled trials (RCTs) and, maybe even more convincingly, in real world settings, a number of open questions remain. In this narrative review, we will analyze published data allowing insight in some of the uncertainties related to the use of anti-CGRP/rec mAbs in clinical practice: their differential efficacy in migraine subtypes, outcome predictors, switching between molecules, use in children and adolescents, long-term treatment adherence and persistence, effect persistence after discontinuation, combined treatment with botulinum toxin or gepants, added-value and cost effectiveness, effectiveness in other headache types, and potential contraindications based on known physiological effects of CGRP. While recent studies have already provided hints for some of these questions, many of them will not find reliable and definitive answers before larger studies, registries or dedicated RCTs are available.

Beyond Pain Relief: Unveiling the Multifaceted Impact of Anti-CGRP/R mAbs on Comorbid Symptoms in Resistant Migraine Patients

“…Previous failures of preventive treatments, according to most trials, do not represent a negative predictor of anti-CGRP/R antibodies success, and our study confirms the evidence [ 41 , 65 ]. It should be noted that an inverse relationship between the responder rate and number of prior treatments was reported in other real-world studies [ 43 , 67 , 68 ].…”

“…We did not assess the pediatric (children and adolescents) population of migraineurs. The opportunity to treat these young patients with anti-CGRP/R drugs is one of the unsolved questions for the novel treatments [ 65 ]. One of the main issues is the physiological role of CGRP in bone formation.…”

Atogepant: Mechanism of action, clinical and translational science

“…Now, an assessment of a patient as a responder following treatment with a gepant can be obtained within a couple of days to a week at the relevant efficacious dose. Current efforts aim to predict nonresponders and super‐responders for all modalities of CGRP‐targeting therapeutics 5 . In some cases, dose‐escalation with mAbs improves patient response, suggesting that some patients require a higher level of CGRP blockade.…”

“…For example, the combination of atogepant with onabotulinumtoxin A (NCT05216263) is currently being evaluated. Studies are also currently evaluating CGRP mAb switching between a CGRP receptor mAb and a CGRP ligand mAb 5 . These questions arise from the fundamental differences in the mechanism of action of these drugs; however, recent studies have also revealed differences in the physiological response to these drugs.…”

“…MOH has not been observed with CGRP‐targeting therapeutics. Recent longitudinal studies on cessation of CGRP monoclonal antibodies (mAbs) demonstrate that migraine frequency and disability gradually increase after treatment interruption 4,5 . These data demonstrate that long‐term use of CGRP‐targeted therapeutics is needed; and thus, the improvements in the safety profiles of CGRP‐targeting therapeutics compared to non‐migraine‐specific medications expand treatment options to patients with cardiovascular risk factors and have the potential to improve patient adherence and migraine management.…”