The evolving therapeutic landscape of diabetic retinopathy

Abstract

Introduction: Diabetic retinopathy (DR) is a leading cause of blindness worldwide. Recent decades have seen rapid progress in the management of diabetic eye disease, evolving from pituitary ablation to photocoagulation and intravitreal pharmacotherapy. The advent of effective intravitreal drugs inhibiting vascular endothelial growth factor (VEGF) marked a new era in DR therapy. Sustained innovation has since produced several promising biologics targeting angiogenesis, inflammation, oxidative stress, and neurodegeneration.

Areas covered: This review surveys traditional, contemporary, and emerging therapeutics for DR, with an emphasis on anti-VEGF therapies, receptor tyrosine kinase inhibitors, angiopoietin-Tie2 pathway inhibitors, integrin pathway inhibitors, gene therapy 'biofactory' approaches, and novel systemic therapies. Some of these investigational therapies are being delivered intravitreally via sustained release technologies for extended durability. Other investigational agents are being delivered non-invasively via topical and systemic routes. These strategies hold promise for early and long-lasting treatment of DR.

Expert opinion: The evolving therapeutic landscape of DR is rapidly expanding our toolkit for the effective and durable treatment of blinding eye disease. However, further research is required to validate the efficacy of novel therapeutics and characterize real world outcomes.

Keywords: APX3330; Diabetic macular edema; EYP-1901; OTT166; OTX-TKI; RGX-314; VEGF; aflibercept; bevacizumab; diabetic retinopathy; faricimab; ranibizumab; vascular endothelial growth factor.

Figure 1.. Key angiogenic factors and receptors implicated in the pathogenesis of diabetic retinopathy and diabetic macular edema.

The vascular endothelial growth factor (VEGF) family consists of six major signaling proteins (VEGF-A through F). VEGF-A has been identified as the primary driver of angiogenesis in neovascular retinal disease. VEGF proteins interact with VEGF receptors (VEGFR) and neuropilin (Nrp) receptors on endothelial surfaces to promote neovascularization and vascular permeability. Placental growth factor (PIGF) has also been implicated in the pathogenesis of DR via its interactions with VEGFR-1. A second pathway involving interactions between angiopoietin (Ang) signaling proteins and endothelial tyrosine kinases (Tie) has also been implicated in angiogenesis. These signaling proteins and their receptors represent attractive targets for novel DR therapeutics. Image reproduced from [198], © 2017 mjeltsch, licensed for reuse under the Creative Commons BY-SA 4.0 license.

Figure 2.. Clinical features of diabetic retinopathy.

(a) The clinical appearance of severe non-proliferative diabetic retinopathy, with intraretinal hemorrhages, cotton wool spots, hard exudates, and venous beading visible in the photo. Reproduced from [199], © 2016 Besenczi et al., licensed for reuse under the Creative Commons BY 4.0 license. (b) Proliferative diabetic retinopathy involves neovascularization of the disc, seen here, or neovascularization elsewhere in the retina. Public domain image from National Eye Institute, National Institutes of Health.

Figure 3.. Pan-retinal (scatter) laser photocoagulation for proliferative diabetic retinopathy.

Pan-retinal photocoagulation (PRP) is currently the standard of care for the treatment of proliferative diabetic retinopathy (PDR) and has been demonstrated to be more effective than targeted laser therapy. In this patient with PDR, dense chorioretinal PRP scars are seen in the near periphery extending to the arcades and as close as three disc-diameters from the macular center temporally. Public domain image from National Eye Institute, National Institutes of Health.