Abstract: Objective The objective of this study was to analyze the evolution of alpha and beta-CGRP circulating levels throughout CGRP monoclonal antibodies (mAbs) treatment in patients with chronic migraine (CM). Methods We recruited patients with CM beginning mAbs along with sex and age paired healthy controls (HCs). Blood was extracted before, 2?weeks (M0.5) and 3?months (M3) after the first dose of mAbs, always in free-migraine periods, and once for HCs. Alpha and beta-CGRP serum levels were measured using enzyme-linked immunosorbent assays (ELISAs) specific for each isoform. Results Baseline alpha-CGRP levels were significantly elevated in 103 patients with CM (median?=?50.3, 95% confidence interval [CI]?=?40.5?57.0 pg/ml) compared to 78 HCs (median?=?37.5, 95% CI?=?33.9?45.0 pg/ml; 95% CI of differences?=?2.85?17.08?pg/ml) and significantly decreased (n?=?96) over the course of mAb treatment (M0.5: median?=?40.4, 95% CI?=?35.6?48.2 pg/ml; and M3: median?=?40.9, 95% CI?=?36.3?45.9 pg/ml). Absolute decrease of alpha-CGRP throughout the treatment positively correlated with the decrease in MMDs. Negative modulation of alpha-CGRP significantly associated with positive scores at the Patient Global Impression of Change scale and with analgesic overuse reversal. Beta-CGRP did not differ at baseline between patients with CM (median?=?4.2, 95% CI?=?3.0?4.8 pg/ml) and HCs (median?=?4.4, 95% CI?=?3.4?5.6 pg/ml; ?1.09 to 0.60) nor was modulated by mAb treatment (n?=?96; M0.5: median?=?4.5, 95% CI?=?3.5?5.2 pg/ml; and M3: median?=?4.6, 95% CI?=?3.7?5.2 pg/ml). Interpretation Treatment with mAbs, regardless of its target, is able to progressively normalize basally increased alpha-CGRP levels in CM and this effect correlates with efficacy measures, which supports a role of this neuropeptide as the first CM biomarker.

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