Antiangiogenesis therapies targeting vascular endothelial growth factor (VEGF) have revolutionized the treatment of neovascular ocular diseases, including neovascular age-related macular degeneration (nAMD). Compelling evidence has implicated the vital role of complement system dysregulation in AMD pathogenesis, implying it as a potential therapeutic strategy for geographic atrophy in dry AMD and to enhance the efficacy of anti-VEGF monotherapies in nAMD. This study reports the preclinical assessment and phase 1 clinical outcomes of a bispecific fusion protein, efdamrofusp alfa (code: IBI302), which is capable of neutralizing both VEGF isoforms and C3b/C4b. Efdamrofusp alfa showed superior efficacy over anti-VEGF monotherapy in a mouse laser-induced choroidal neovascularization (CNV) model after intravitreal delivery. Dual inhibition of VEGF and the complement activation was found to further inhibit macrophage infiltration and M2 macrophage polarization. Intravitreal efdamrofusp alfa demonstrated favorable safety profiles and exhibited antiangiogenetic efficacy in a nonhuman primate laser-induced CNV model. A phase 1 dose-escalating clinical trial (NCT03814291) was thus conducted on the basis of the preclinical data. Preliminary results showed that efdamrofusp alfa was well tolerated in patients with nAMD. These data suggest that efdamrofusp alfa might be effective for treating nAMD and possibly other complement-related ocular conditions.
Targeting both C3b/C4b and VEGF exerted antiangiogenic effects in CNV models and was well tolerated in patients with nAMD.
Neovascular age-related macular degeneration (nAMD) is characterized by pathological angiogenesis that contributes to vision loss. Anti–vascular endothelial growth factor (VEGF) treatments are not completely effective, and more than 30% of patients progress to more severe disease. Here, Yang et al. developed a bispecific fusion protein, called efdamrofusp alfa, able to target simultaneously VEGF and the complement system and tested it in preclinical models and in a phase 1 clinical trial. Efdamrofusp was more effective than anti-VEGF treatment alone in a mouse model of choroidal neovascularization (CNV) and exerted antiangiogenic activity without inducing side effects in a CNV model in nonhuman primates. In patients with nAMD, efdamrofusp alfa was well tolerated, suggesting strong potential for clinical use.