Preclinical and Clinical Proof of Concept for Metabolic Intervention in Diabetic Cardiomyopathy

Introduction Hyperactivation of the polyol pathway (PP) contributes to development of diabetic complications such as diabetic cardiomyopathy (DbCM). Aldose reductase (AR), the rate-controlling enzyme in the PP, catalyzes NADPH-dependent reduction of glucose to sorbitol. Under hyperglycemic and ischemic conditions, PP activation causes intracellular sorbitol accumulation leading to osmotic stress, cell death and diabetic complications. Previous AR inhibitors (ARI) failed due to safety or lack of efficacy. AT-001 is a novel oral ARI with optimized specificity and affinity for AR. Objectives To assess cardioprotective activity of AT-001 in an animal model of DbCM and safety, tolerability and target engagement in a phase 1/2 clinical study. Preclinical Methods and Results The cardioprotective effect of AT-100 was studied in transgenic mice expressing human levels of AR (Tg hAR) and rendered diabetic with streptozotocin (55 mg/kg for 5d). Mice were treated with AT-001 40 mg/kg, n=6 or vehicle (V, n=6) for 3d prior to cardiac ischemia reperfusion (IR) injury induced by ligation and reperfusion of the left anterior descending (LAD) coronary artery. Control non-DM Tg hAR mice (non-DM, n=9) were also subjected to IR injury. After 48h recovery mice were euthanized and infarct area and fractional shortening (FS) assessed. Mean (±SD) infarct area (ratio of infarcted to total left ventricular area) was significantly lower in AT-001 (35.3±2.7) vs. non-DM (43±2) and V (59.1±0.8); P Clinical methods and Results The phase 1/2 study consisted of single and multiple oral ascending doses (SAD, n=8 per group) of 5, 10, 20 and 40 mg/kg once daily (QD) and multiple doses (MAD) of placebo (Pbo) or AT-001 5, 20, 40 mg/kg QD or 20 mg/kg twice daily for 7d. Subjects with type 2 diabetes (T2DM), age 18-75 and HbA1c 5.0-8.5% were allocated to AT-001 (n=8) or Pbo (n=2) in each dose cohort. AT-001 was well-tolerated with no drug-related AEs. AR inhibition and target engagement were demonstrated by dose-dependent decreases in sorbitol in AT-001 (up to -50 % change from baseline) vs. Pbo subjects (-3 % change). Maximum inhibition was between 2-4 h and lasted several hours. Conclusions AT-001 significantly attenuated or prevented cardiac damage in a relevant animal model and was safe, well-tolerated and reduced sorbitol levels in T2DM subjects. These findings support clinical development in DbCM.