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-naïve 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.