OR14-6 The Role of the Angiopoietin-Tie2 Pathway in Microvascular Complications of Diabetes Mellitus

INTRODUCTION: The Tie2 pathway is a key regulator of vascular stability. Deactivation of this pathway, caused by hyperglycemia or ischemia, results in pathological vascular inflammation, permeability and neovascularization. AKB-9778 is a small molecule Tie2 activator. The TIME-2 study (NCT02050828) was performed to examine the efficacy of AKB-9778 for the treatment of diabetic retinopathy and nephropathy. METHODS: TIME-2 was a multicenter randomized trial in which 144 diabetic patients with center-involved diabetic macular edema (DME) were randomized (1:1:1) to 3 months of treatment with 15 mg AKB-9778 administered subcutaneously (SC) BID plus monthly intravitreal treatment (IVT) with 0.3 mg ranibizumab (RBZ), 15 mg AKB-9778 plus sham IVT, or RBZ plus placebo SC injections BID. DME was measured by optical coherence tomography (OCT), severity of diabetic retinopathy was measured by grading of 7-field color fundus photos (ETDRS DRSS scale), and kidney function was measured by UACR and eGFR. RESULTS: Reduction of DME was 50% greater after 3 months of combination AKB-9778 + RBZ treatment than with RBZ treatment alone (-164 µm vs -110 µm; P< 0.01). Diabetic retinopathy was improved by ≥ 2 steps in 11.4%, 8.8%, and 10% of patients in study eyes of the combination, RBZ, and AKB-9778 treatment groups, respectively. In fellow eyes (no RBZ) 11.4% showed ≥ 2-step improvement in retinopathy with systemic AKB-9778 compared to 4.2% of untreated eyes in the placebo group. UACR geometric mean was improved by 21% in patients with albuminuria at baseline (UACR ≥ 30 mg/g) in patients treated with AKB-9778 for 3 months. CONCLUSIONS: The TIME-2 study provides evidence that restoration of Tie2 activity by AKB-9778 has beneficial effects on retinal and kidney function in patients with diabetes mellitus. A one-year treatment trial is currently underway. AKB-9778 is a promising therapeutic for the prevention of end-organ damage in diabetic patients.