Plasma CGRP but not PACAP-38 concentrations are associated with response to anti-CGRP monoclonal antibodies in migraine

Background: Monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway have revolutionized migraine prophylaxis. However, a subset of patients does not respond to these therapies, highlighting an urgent need for predictive biomarkers. This study investigates whether baseline plasma levels of CGRP or pituitary adenylate cyclase activating peptide (PACAP)-38 may predict the clinical response to anti-CGRP mAbs in patients with high-frequency episodic migraine (HFEM) or chronic migraine (CM). Methods: A prospective, longitudinal study was conducted on migraine patients treated with erenumab, fremanezumab, or galcanezumab. Clinical outcomes, including monthly migraine days (MMD), Migraine Disability Assessment (MIDAS), and monthly medication intake (MMI), were assessed at baseline (T0), 3 months (T1), and 6 months (T2). A group of healthy subjects was used as controls. Plasma CGRP and PACAP-38 levels were measured using an enzyme-linked immunosorbent assay (ELISA). Treatment responses were tested using bivariate and multivariate analyses. Results: 30 females, 7 males (17 HFEM, 20 CM), and 16 healthy controls were included in the study. Baseline plasma CGRP and PACAP-38 concentrations were higher in migraine patients than in controls (p<0.01 and p<0.001, respectively). Baseline CGRP levels significantly correlated with worse clinical outcomes at 6 months: higher CGRP was associated with greater MMD (r=0.470, p=0.003), MIDAS scores (r=0.601, p<0.001), and MMI (r=0.410, p=0.010) at T2. Additionally, higher baseline CGRP levels were associated with a lower likelihood of achieving a ≥50% reduction in MIDAS scores. Multivariate regression confirmed that elevated CGRP independently predicted poorer response, particularly in CM patients. Conversely, PACAP-38 levels did not emerge as significant predictors of any clinical outcome measures. Conclusions: Our study shows that higher baseline plasma CGRP levels predict a reduced clinical response to anti-CGRP mAbs in patients with HFEM and CM after 6 months, supporting CGRP as a potential biomarker for treatment stratification. PACAP-38 levels did not influence treatment outcomes, indicating a distinct role in migraine pathophysiology. These results encourage further research into personalized treatment approaches based on neuropeptide profiling.