To evaluate the long-term real-world effectiveness of eptinezumab through a four-year longitudinal analysis of subjects initiating therapy.

Eptinezumab demonstrated clinical efficacy in trials. However, real-world data on long-term treatment persistence, dose escalation, and headache outcomes (both in subjects who maintained therapy and those who discontinued) remain limited.

We conducted a retrospective chart review of 112 subjects who initiated eptinezumab at the Jefferson Headache Center between January 2019 and December 2021. Monthly headache days (MHD), Migraine Disability Assessment (MIDAS), and average pain intensity (API) were extracted at baseline and every 6 months for up to 48 months. Longitudinal changes were analyzed using generalized estimating equations clustered by subject with an unstructured correlation matrix, adjusting for age, sex, and BMI. Baseline served as reference to estimate marginal mean (EMM) changes (least significant difference) at each follow-up interval. No imputation or censoring for treatment discontinuation was applied. Treatment persistence, dose escalation, and discontinuation reasons were also characterized.

Among 112 subjects (age 50.2±13.8; 87 female; baseline MHD: 26.6±6.4), nearly all had prior anti-CGRP mAb exposure (99.9% ≥1 failure; 58.9% ≥2 failures). Treatment persistence at each year was 56.2%, 41.1%, 35.7% and 29.5%. Discontinuation was primarily due to inadequate response (55.7%) and insurance issues (17.7%). Dose escalation to 300 mg occurred in 87 patients (27/29/16 after 1^st/2^nd/3^rd cycles). Compared to baseline, EMM reductions in MHD were observed at 6, 18, 24, 30, 36 months (-0.055 to -0.078, all p<0.05), and API at 24  (-0.622, p=0.001) and 48 months (-0.611; p=0.003); other time points were not significantly different. MIDAS EMM increased at the 6 months (0.272, p=0.021) and decreased at 48 months (–0.273; p=0.039).

In this highly refractory cohort (all eptinezumab initiators), modest benefit on headache frequency was observed, but disability improvement was limited, and discontinuation rates were high.