Migraine therapeutics have shifted from largely repurposed treatments towards mechanism-based interventions following the recognition of calcitonin gene–related peptide (CGRP) as a key mediator of migraine pathophysiology. Monoclonal antibodies targeting CGRP or its receptor, together with small-molecule CGRP receptor antagonists (gepants), have expanded preventive and acute treatment options and changed clinical decision-making. Nevertheless, treatment response remains heterogeneous, and the biological basis of efficacy and non-response is not fully understood. Important questions also persist regarding cerebrovascular safety, blood pressure and vascular effects, reproductive and perinatal exposure, and use during childhood and adolescence. Current clinical trials and real-world studies provide encouraging evidence of effectiveness and generally favourable tolerability, but long-term, comparative and population-specific data remain limited. Further investigation is needed to clarify how CGRP therapies should be personalised, sequenced and monitored, particularly in patients with vascular comorbidities, those who are pregnant or breastfeeding, younger patients, and individuals with less common primary headache disorders.

This Research Topic aims to strengthen the evidence base for CGRP-targeted therapies by examining their mechanisms, efficacy, real-world effectiveness and safety across diverse populations and life stages. It will address predictors of response and non-response, including clinical, imaging, genetic and molecular biomarkers; evaluate treatment sequencing, switching and combination strategies; and clarify the positioning of CGRP therapies alongside other pharmacological, device-based and emerging targeted approaches. Particular emphasis will be placed on cerebrovascular outcomes, reproductive and perinatal considerations, paediatric and adolescent use, long-term follow-up, and the implications of these treatments for clinical practice. The Research Topic also seeks to advance evidence-informed approaches to access, health economics, policy and shared decision-making.

To gather further insights in CGRP-pathway–targeted treatment for migraine and other primary headache disorders, this Research Topic will focus on therapeutic, mechanistic, clinical and safety research with a clear connection to CGRP-based care. Comparative or adjunctive interventions will be considered when they inform the use, sequencing or selection of CGRP-targeted therapies, including for patients who do not respond to or cannot receive them. Themes include, but are not limited to:

Pharmacokinetics, pharmacodynamics, tissue distribution and blood–brain barrier considerations for CGRP monoclonal antibodies and gepants.
- The role of CGRP in vascular homeostasis, neurovascular coupling and treatment-related cerebrovascular effects.
- Efficacy, durability, adherence, persistence and real-world effectiveness in episodic and chronic migraine.
- Mechanisms and predictors of response, non-response and loss of response, including clinical and molecular biomarkers.
- Treatment sequencing, switching and combination strategies within the CGRP class and with other relevant therapies.
- Cerebrovascular safety, blood pressure, vasomotor tone, endothelial function and vascular comorbidities.
- Fertility, pregnancy, lactation, hormonal contraception and peripartum management.
- Paediatric and adolescent dosing, developmental outcomes, long-term safety, ethics and regulatory considerations.
- Neuromodulation, ditans, nutraceuticals and behavioural interventions as CGRP-relevant adjuncts or alternatives.
- PACAP, AMPA and other emerging targets positioned as alternatives or rescue strategies for CGRP non-responders.
- Health economics, affordability, access, health equity, formulary policy and implementation in routine care.
- Safety registries, minimum data elements, pharmacovigilance methods and standards for long-term follow-up.

Submissions should have a clear therapeutic focus in migraine or another primary headache disorder and explicitly address CGRP mechanisms, CGRP-targeted interventions or outcomes directly relevant to CGRP-based care.

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Optimising CGRP-targeted therapies in migraine and primary headache disorders