Serum alpha and beta-CGRP levels in chronic migraine patients before and after monoclonal antibodies against CGRP or its receptor

Objective: To analyse the evolution of alpha and beta-CGRP circulating levels throughout CGRP monoclonal antibodies (mAb) treatment in chronic migraine (CM) patients. Methods: We recruited CM patients beginning mAb along with sex and age paired healthy controls (HC). Blood was extracted before, two-weeks (M0.5) and three months (M3) after first dose of mAb, always in free-migraine periods, and once for HCs. Alpha and beta-CGRP serum levels were measured using ELISAs specific for each isoform. Results: Baseline alpha-CGRP levels were significantly elevated in 103 CM patients (median [95% CI]: 50.3 [40.5-57.0] pg/mL) compared to 78 HC (37.5 [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: 40.4 [35.6-48.2] pg/mL; M3: 40.9 [36.3-45.9] pg/mL). Absolute decrease of alpha-CGRP throughout the treatment positively correlated with the decrease in monthly migraine days. 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 CM patients (4.2 [3.0-4.8] pg/mL) and HC (4.4 [3.4-5.6] pg/mL; -1.09 to 0.60) nor was modulated by mAb treatment (n=96) (M0.5: 4.5 [3.5-5.2] pg/mL; M3: 4.6 [3.7-5.2] pg/mL). Interpretation: Treatment with mAb, 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