PurposeTo evaluate efficacy and safety of efdamrofusp alfa compared with aflibercept in neovascular age-related macular degeneration (nAMD). DesignRandomized, double-masked, multicenter, active-controlled, non-inferiority phase 2 study ParticipantsA total of 231 treatment-naïve and previously treated participants with active choroidal neovascularization secondary to nAMD were enrolled. MethodsEligible participants were randomized (1:1:1) to 2 mg efdamrofusp alfa, 4 mg efdamrofusp alfa or 2 mg aflibercept groups. Participants in all groups received three initial monthly loading doses, followed by treatment every 8 weeks with assessment every 4 weeks up to week 52. Main outcome measuresThe primary endpoint was the mean BCVA change from baseline to week 36. The pre-specified noninferiority margin was set as –5 letters (80% CI). ResultsEach treatment group included 77 participants. The mean BCVA changes from baseline to week 36 for 2 mg efdamrofusp alfa, 4 mg efdamrofusp alfa and aflibercept groups were +10.6, +11.4, +12.0 letters, respectively; Least Squares (LS) mean difference were –1.4 (80% CI: –3.5 to 0.7) between 2 mg efdamrofusp alfa and aflibercept, and –0.6 (80% CI: –2.7 to 1.6) between 4 mg efdamrofusp alfa and aflibercept. Mean central retinal thickness changes were consistent across groups. Adverse event rate was comparable among the groups. ConclusionsEfdamrofusp alfa demonstrated noninferiority to aflibercept in BCVA improvement, accompanied by a similar safety profile.