45-OR: The Role of the Angiopoietin-Tie2 Pathway in Microvascular Complications of Diabetes Mellitus

Abstract

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. AKB-9778 is a promising therapeutic for the prevention of end-organ damage in diabetic patients. Disclosure V.H. Gonzalez: Consultant; Self; AbbVie Inc., Alcon/Novartis, Alimera Sciences, Inc., Allegro Ophthalmics, LLC., Allergan, Bausch and Lomb, Bayer US, Clearside Biomedical, Genentech, Inc., PanOptica, Regeneron Pharmaceuticals, Santen Pharmaceutical Co., Ltd., Thrombogenics, Topcon, Valeant Pharmaceuticals International, Inc. Research Support; Self; 60 Pharmaceuticals, Alcon/Novartis, Allegro Ophthalmics, LLC., Allergan, Apellis Pharmaceuticals, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Chengdu Kanghong Biotechnology Co, LTD, Clearside Biomedical, DRCR NET, EyeGate Pharma, Genentech, Inc., Graybug Vision, Inc., ICON plc., Iconic Therapeutics, Insite Vision Inc, Mallinckrodt Pharmaceuticals, Opthea Ltd., Regeneron Pharmaceuticals, Santen Pharmaceutical Co., Ltd., Thrombogenics. Stock/Shareholder; Self; Alimera Sciences, Inc., PanOptica.