Emerging clinical evidence of a dual role for Ang-2 and VEGF-A blockade with faricimab in retinal diseases

Abstract

Anti-vascular endothelial growth factor (VEGF) therapies have transformed the treatment of retinal diseases. However, VEGF signaling is only one component of the complex, multifactorial pathophysiology of retinal diseases, and many patients have residual disease activity despite ongoing anti-VEGF treatment. The angiopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor receptor-2 (Ang/Tie2) signaling pathway is critical to endothelial cell homeostasis, survival, integrity, and vascular stability. Ang-2 can interfere with Ang-1/Tie2 signaling and is increased in several retinal diseases. Lack of Tie2 signaling due to elevated Ang-2 levels drives vascular instability through pericyte dropout, neovascularization, vascular leakage, inflammation, and fibrosis. Although Ang-2 and VEGF can synergistically promote vascular instability and neovascularization, Ang-2 may also mediate vascular instability independently of VEGF. Faricimab is a bispecific antibody designed for intraocular use that inhibits two distinct pathways via Ang-2 and VEGF-A blockade. Clinical biomarkers of vascular instability are important for evaluating disease control and subsequent treatment decisions. These biomarkers include measurement/evaluation with optical coherence tomography (OCT) of intraretinal fluid, subretinal fluid, central subfield thickness, and pigment epithelial detachments (PEDs), and fluorescein angiography imaging of macular leakage and PEDs. Hyperreflective foci (HRF), thought to be representative of activated microglia, indicating an inflammatory microenvironment, and epiretinal membranes (ERMs), a marker for retinal fibrotic proliferation in diabetic macular edema (DME), are both also identified using OCT. Here we summarize data (secondary endpoint and prespecified exploratory analyses as well as post hoc analyses) from six Phase III trials suggest that dual therapy Ang-2/VEGF-A inhibition with faricimab (6 mg) has a greater effect on reducing/resolving biomarkers of vascular instability than aflibercept (2 mg), by both controlling neovascularization and vascular leakage (with resultant resolution of exudation associated with DME, neovascular age-related macular degeneration, and retinal vein occlusion), as well as by targeting inflammation (reduction of HRF in DME) and retinal fibrotic proliferation (reducing the risk of ERMs in eyes with DME). Modulation of both the Ang-2 and VEGF-A pathways with faricimab may therefore provide greater disease control than anti-VEGF monotherapy, potentially leading to extended treatment durability and improved long-term outcomes.

Keywords: Ang-2; Diabetic macular edema; Diabetic retinopathy; Neovascular age-related macular degeneration; Retinal vein occlusion; VEGF-A.

Fig. 1

Summary of potential factors involved in retinal diseases [–, , –12]. The roles of Ang-2 and VEGF-A are described in this manuscript. The complexity of retinal disease pathogenesis is further highlighted by the role of numerous other signaling pathways (indicated in grey). Ang-2, angiopoietin-2; CCL2, C–C motif ligand 2; EGF, epidermal growth factor; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IL, interleukin; PDGF, platelet-derived growth factor; PIGF, placental growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor; TRAF6, tumor necrosis factor receptor-associated factor 6; VEGF-A, vascular endothelial growth factor-A

Fig. 2

Role of VEGF and Ang-2 in the pathogenesis of retinal diseases and control of clinical biomarkers with dual VEGF/Ang-2 targeting [, –49]. DME: YOSEMITE/RHINE trials; nAMD: TENAYA/LUCERNE trials; RVO: BALATON/COMINO trials. * Post hoc analyses not adjusted for multiplicity; no formal statistical conclusion should be made based on nominal p values. Ang-2, angiopoietin-2; DME, diabetic macular oedema; ERM, epiretinal membrane; FA, fluorescein angiography; HRF, hyperreflective foci; IRF, intraretinal fluid; nAMD, neovascular age-related macular degeneration; OCT, optical coherence tomography; PED, pigment epithelial detachment; Q12W, every 12 weeks; RVO, retinal vein occlusion; VEGF-A, vascular endothelial growth factor-A