The evolving therapeutic landscape of diabetic retinopathy

ABSTRACTIntroduction 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: Diabetic macular edemadiabetic retinopathyvascular endothelial growth factorVEGFranibizumabafliberceptbevacizumabEYP-1901OTX-TKIfaricimabOTT166RGX-314APX3330 Article highlights The management of diabetic retinopathy and its complications consists of four major strategies: modification of systemic risk factors, retinal photocoagulation, targeted pharmacotherapy, and vitrectomy.In recent years, intravitreal anti-VEGF therapies such as bevacizumab, ranibizumab, and aflibercept have largely replaced destructive macular photocoagulation as first-line therapy for diabetic macular edema (DME).Despite the great success of intravitreal anti-VEGF therapies for DME, these agents broadly suffer from limited therapeutic durability and require strict, long-term adherence to serial treatment sessions in order to achieve disease remission.While pan-retinal photocoagulation (PRP) remains first-line standard of care for treatment of proliferative diabetic retinopathy (PDR), there is increasing use of intravitreal anti-VEGF agents for DR, often in combination with PRP.Treatment of non-proliferative diabetic retinopathy, prior to the development of PDR or even DME, remains a high priority.Therapies to potentially improve the safety, efficacy, and/or durability of targeted treatment for NPDR and PDR are in clinical trials and include receptor tyrosine kinase inhibitors (EYP-1901, OTX-TKI), angiopoietin-Tie2 pathway inhibitors (faricimab), integrin pathway inhibitors (topical OTT166), gene therapy ‘biofactory’ approaches (RGX-314), and novel systemic therapies (oral APX3330).Declaration of interestT Ciulla reports prior employment by, and holds stock options in, Clearside Biomedical, and consults for Ocuphire. He also reports employment by, and holds stock options in, Viridian Therapeutics. A Bhatwadekar is an ad hoc pharmacist at CVS Health/Aetna and the manuscript contents do not reflect that of CVS Health/Aetna. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresA reviewer on this manuscript has disclosed that they are involved in the management of and hold equity in Ojai Retinal Technologies, LLC, Retinal Protection Sciences, LLC and Vision Protection Institutes, LLC. They also hold equity in Replenish, Inc. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.Additional informationFundingThis work is supported by funding from National Eye Institute grant numbers [R01 EY027779] and R01 EY032080 to AB and an unrestricted grant from Research to Prevent Blindness (RPB) to the Department of Ophthalmology, Indiana University.