A Novel Small Molecule for the Prevention and Treatment of Diabetic Retinopathy

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SUMMARY Diabetic retinopathy (DR) is a leading cause of blindness in the United States. Currently, most treatments for DR are only applicable at the late stage and are invasive. Anti-VEGF (vascular endothelial growth factor) agents have achieved impressive therapeutic effects against DR and neovascularization (NV). However, 40% of patients with DR have inadequate responses to the treatment. Given that DR is a multi-factorial disease, therapies that target one single pathogenic factor (such as VEGF) are clearly insufficient to achieve desired efficacy in all DR patients. Therefore, the development of novel, non-invasive, long-term and more effective pharmacological treatments for DR is urgently required, particularly at an early stage of the disease. The overall objective of this Phase II project is to develop a novel drug for the oral pharmacotherapy of DR. Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated nuclear receptor that regulates mitochondrial lipid β oxidation and peroxisome scavenge hydrogen peroxide in the cytoplasm. Two large and longitudinal clinical studies reported independently that oral administration of PPARα agonist fenofibrate has robust therapeutic effect on DR in type 2 diabetic patients. This is the first oral drug with proven effect in DR patients. In preclinical studies with animal models of DR, pharmacological activation of PPARα has been shown to decrease retinal pathologies typically observed in DR (e.g. pathogenic neovascularization, vascular leakage and inflammation in the retina), resulting in a profound therapeutic effect. Thus, PPARα represents a novel therapeutic target for the treatment of DR. However, there are currently no FDA-approved PPARα drugs for DR. Our medicinal chemistry team has synthesized and identified a non-fibrate, quinoline-derived small molecule A190, a novel PPARα agonist with more potent activity. In SBIR Phase I studies, we have completed Proof-of-Principle studies demonstrating that systemic administration of A190 is more effective than fenofibrate on two diabetic animal models. These studies established A190 as a promising drug candidate for further development. The proposed research in Phase II will focus on evaluating in vivo safety and toxicology of A190 in two species (rats and rabbits). In addition, the long- term efficacy of orally administered A190 will be tested in DR models. This Phase II program includes three specific Aims. Specific Aim 1: Evaluate and optimize the efficacy of A190 on retinal vascular leakage in DR models. Specific Aim 2: Determine the pharmacokinetics of A190 and its ocular tissue distribution. Specific Aim 3: Assess possible ocular and systemic toxicities of A190. These studies will provide essential information for IND-enabling studies and future clinical trials of A190 as an oral drug for DR.