New data in a mouse model of spontaneous choroidal neovascularisation support the role of angiopoietin‐2 inhibition in driving sustained vascular stabilisation and reduced fibrosis progression

Abstract

PurposeTo explore the vessel stabilisation potential of dual angiopoietin‐2 (Ang‐2)/vascular endothelial growth factor‐A (VEGF‐A) inhibition in a mouse model of spontaneous choroidal neovascularisation (sCNV) in the context of phase 2 clinical data on faricimab, a bispecific antibody that binds to and neutralises both Ang‐2 and VEGF‐A.MethodsSeven‐week‐old JR5558 mice, developing sCNV in both eyes, were treated intraperitoneally with mouse cross‐reactive tool antibodies against Ang‐2, VEGF‐A, or both (bispecific antibody VA2); n = 7–15 mice per group. Fluorescein angiography (FA)‐evaluated CNV leakage and fibronectin (fibrosis marker) deposition on the retinal pigment epithelium (RPE)/choroid and around CNV lesions were assessed at baseline and 1 (PT1), 3 (PT2) and 5 weeks (PT3) post treatment to assess the effects on CNV lesion activity relative to untreated/IgG‐exposed mice.ResultsAnti‐Ang‐2‐, anti‐VEGF‐A‐ and VA2‐treated mice showed a significant reduction in CNV leakage (p < 0.05 to p < 0.001) versus controls at PT1, maintained only in anti‐Ang‐2‐ and VA2‐treated mice at PT2/3 (p < 0.05 to p < 0.0001). Lesions treated with anti‐VEGF alone showed reactivation on FA at PT2. The area of fibronectin staining on RPE/choroid and around lesions was significantly reduced with VA2 (38%; p < 0.01) and anti‐Ang‐2 (41%; p < 0.001) versus IgG control at PT1; the effect of VEGF‐A inhibition alone was not significant. At PT2 and PT3, only VA2 inhibition showed significant reduction in fibronectin staining over both control groups (by 47%; p < 0.01 and 54%; p < 0.05, respectively).ConclusionsFaricimab's potential for extended durability observed in phase 2 clinical trials was further explored in a mouse model of sCNV. CNV leakage and fibronectin staining around CNV lesions were suppressed for longer with dual Ang‐2/VEGF‐A inhibition versus VEGF‐A alone. These findings support the hypothesis that the sustained efficacy of faricimab observed in phase 2 trials is due to vessel‐stabilising effects driven by Ang‐2 inhibition.