Angiopoietins as Targets for Diabetic Retinopathy Treatment

*Lauren M. Ciulla, Nimesh A. Patel, Nicolas A. Yannuzzi and Rehan M. Hussain*

## **Abstract**

Diabetic eye diseases, such as diabetic retinopathy (DR) and diabetic macular edema (DME) are among the leading causes of blindness in developed countries. Anti-VEGF therapies such as, ranibizumab, aflibercept and off-label bevacizumab have become first-line treatment for DME. While randomized controlled trials show significant improvement in vision, these anti-VEGF agents have limited durability leading to a significant treatment burden, as reflected in real-world studies, which generally demonstrate under-treatment and less favorable visual acuity outcomes than observed in prospective trials. Alternative pathways, such as the Tie-2 angiopoietin pathway may address unmet needs, with potential for greater efficacy or durability when compared to anti-VEGF monotherapy. While some Tie-2 angiopoietin therapeutic agents, such as nesvacumab, ARP-1536 or AKB-9778, did not meet primary endpoints in clinical trials, other agents have shown promise. One such agent is faricimab, a bispecific antibody inhibiting both VEGF-A and Ang-2. The phase 3 DME trials (YOSEMITE and RHINE) demonstrated favorable safety, visual, and durability outcomes; patients receiving faricimab injection every 4 months achieved similar visual gains as those receiving aflibercept injection every 2 months. Another agent, AXT107 is a peptide that inhibits VEGFR2 and modifies Ang-2 to behave more similarly to Ang-1, promoting vascular stability. This drug is currently undergoing phase 1/2a trials for safety and bioactivity to be completed in May 2022.

**Keywords:** diabetic retinopathy, diabetic macular edema, angiopoietins, Ang-2, Ang-1, Tie2 receptor, faricimab, AXT107, nesvacumab, AKB-9778, ARP-1536

### **1. Introduction**

The global prevalence of diabetes and its comorbidities has rapidly increased, likely due to an aging population and a high prevalence of obesity [1]. As such, DR has become one of the leading causes of blindness within the Western World [2]. Several pooled analyses have disclosed the prevalence of DR within diabetic populations is greater than 30% [3]. Previously, diabetic macular edema (DME) resulted in approximately half of affected patients losing two or more lines of visual acuity within two years [4]. Historically, laser photocoagulation was validated in clinical trials to slow visual loss in patients with DME and proliferative diabetic retinopathy (PDR), an advanced form of DR involving neovascularization, potentially complicated by vitreous hemorrhage, tractional retinal detachment, and neovascular

glaucoma. However, recent and continuing medical advancements in intravitreal corticosteroids and anti-vascular endothelial growth factor (VEGF) agents have led to improvements in clinical outcomes. This chapter reviews the current treatment options and those under development for diabetic eye disease specifically in the Tie-2/Angiopoietin vascular stability pathway.
