Real-World Response and Super-Response to Eptinezumab over 48 Weeks in Migraine: The Prospective Multicenter EMBRACE III Study

Introduction: Long-term (> 24 weeks) real-world evidence of eptinezumab's effectiveness is limited. We evaluated >= 50% and >= 75% response rates over 48 weeks in patients with high-frequency episodic migraine (HFEM) or chronic migraine (CM). Methods: EMBRACEIII (NCT05570149) is a prospective, multicenter, observational study. Adults with HFEM or CM who experienced >= 3 preventive treatment failures received eptinezumab 100 mg intravenously every 12 weeks, with optional 300 mg escalation after week 12 for inadequate response. Co-primary endpoints were >= 50% and >= 75% reductions in monthly migraine/headache days (MMD/MHD) at weeks 45-48 versus baseline. Secondary endpoints were changes in MMD/MHD, monthly analgesic intake (MAI), pain intensity (assessed using the numeric rating scale [NRS]), migraine-related disability and impact (assessed using the Headache Impact Test-6 [HIT-6], Migraine Disability Assessment [MIDAS], the Migraine Interictal Burden Scale-4 [MIBS-4]), patient-reported global treatment response (assessed using the Patient Global Impression of Change [PGI-C] questionnaire), and 100% response. Exploratory analyses assessed dose escalation, prior anti-calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) treatment failures, responders without adverse events, >= 30% reduction in the NRS during residual attacks, and clinically complex subgroups. Results: Among the 261 patients (safety population) included in the study, 124 completed >= 48 weeks of treatment with eptinezumab. At week 48, the response rates for >= 50%, >= 75%, and 100% were 82.3%, 51.6%, and 9.7%, respectively. All secondary endpoints improved significantly (p < 0.001), with significant reductions from baseline: MMD/MHD, - 15.5; MAI, - 14.9; NRS, - 3.3; HIT-6, - 20.6; MIDAS, - 74; and MIBS-4, - 4.3. Also, 94.8% of patients reported PGI-C improvement. Dose escalation occurred in 69.4% of patients. Patients receiving >= 3 doses of 300 mg eptinezumab achieved outcomes comparable to responders receiving 100 mg. Among patients with prior anti-CGRP mAb treatment failures (51.6%), >= 50% and 100% responders were similar to mAb-na & iuml;ve patients, whereas >= 75% response was lower (37.5%; p = 0.002). Response rates of >= 50%, >= 75% and 100% were achieved by 81.2%, 50.4%, and 8.5%, respectively, in patients without adverse events; 85.7%, 51.4%, and 8.6% in patients with psychiatric comorbidities; 87.8%, 54.9%, and 7.3% in patients with CM with medication overuse; and 89.2%, 50.0%, and 7.1% in patients with CM with both conditions. Conclusions: Eptinezumab demonstrated sustained 48-week effectiveness, with high response rates of >= 75% and 100% in a difficult-to-treat population. Effectiveness was preserved in patients with prior anti-CGRP mAb failures after 300 mg escalation and in clinically complex subgroups. Many patients achieved >= 30% reduction in NRS during residual migraine attacks. Trial Registration: ClinicalTrials.gov: NCT05570149.