Background <p>Real-world data on calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) are essential to determine whether a class effect exists and to assess the benefit of switching between treatments. Available data remain limited as most studies focused exclusively on patients who failed previous CGRP mAbs and evidence regarding newer agents such as eptinezumab are still scarce.</p> Methods <p>This prospective real-world study included all adult patients enrolled in the FHU InovPain registry who received intravenous eptinezumab 100 mg and after prior treatment with one or more subcutaneous CGRP mAbs, regardless of their response to previous CGRP mAbs. According to the 50% response rate (in terms of monthly migraine days) after 6 months of treatment, a descriptive analysis of switching from subcutaneous CGRP mAbs to eptinezumab was performed. Patients were classified into three subgroups: cross-effectiveness (all CGRP mAbs used were effective), cross-ineffectiveness (all CGRP mAbs used were ineffective), and no cross-response (different responses across CGRP mAbs used). Factors associated with response to CGRP mAbs were investigated by comparing patients with cross-ineffectiveness (with the CGRP mAbs used) to those who responded to at least one CGRP mAb (cross-effectiveness and no cross-response), followed by multivariate logistic regression.</p> Results <p>A total of 190 patients (83.7% women; mean age 52.2 ± 13.7 years) were included. The 50% responder rate to eptinezumab was 76.0% (95% CI: 67.3-83.1) in patients who had responded to at least one previously used CGRP mAb, compared with 30.4% (95% CI: 20.2-42.8) in patients with no prior response to CGRP mAbs. Cross-effectiveness, cross-ineffectiveness, and no cross-response were observed in 46.8% (95% CI: 39.6-54.2), 28.9%, (95% CI: 22.7-36.0) and 24.2% (95% CI: 18.4-31.7) of patients, respectively. Only two factors were associated with response to at least one CGRP mAb: a lower helplessness score on the Pain Catastrophizing Scale (AdjOR 0.91, 95% CI: 0.86-0.97, p=0.004) and a lower allodynia score on the ASC-12 (AdjOR 0.91, 95% CI: 0.84-0.98, p=0.010).</p> Conclusion <p>This real-world study confirms the clinical benefit of switching to eptinezumab in nearly one-third of patients who did not respond to previous subcutaneous CGRP mAbs. It also demonstrates a class effect that is not absolute, as nearly one-quarter of patients showed no cross-response between CGRP mAbs.</p> Clinical trial number <p>Not applicable.</p>