462-P: AT-001, a Next Generation Aldose Reductase Inhibitor with Improved Selectivity and Specificity, Protects from Cellular Damage Associated with Hyperglycemia

The generation of Reactive Oxygen Species (ROS) and Advanced Glycation Endproducts (AGE’s) resulting from chronic tissue exposure to elevated levels of glucose has been identified as a key modulator of diabetic complications including diabetic cardiomyopathy. Abnormal activation of the polyol pathway converts excess glucose to sorbitol, generating ROS and AGEs. This conversion is catalyzed by the enzyme Aldose Reductase. Inhibition of Aldose Reductase, the rate limiting enzyme in the polyol pathway, reduces the production of sorbitol, attenuates increases in NADH, and down-regulates the synthesis of ROS. Methods and Results: Cultured human adult cells (NHK) were exposed to elevated glucose [25mM] to simulate hyperglycemic conditions in diabetic tissue in the presence/absence of Aldose Reductase inhibitor AT-001 [0.18nM]. AT-001 dose selection was based on previous dose response studies. Cytosolic oxidative stress was evaluated and quantified using dihydroethidium (DHE) staining and quantitated via colorimetric assessment. Mitochondrial-specific oxidative stress ROS levels were quantitated using MitoSOX staining. AT-001 prevented the production and accumulation of ROS as assessed by both DHE quantitation and MitoSOX staining, demonstrating effective inhibition of polyol pathway associated damage to these cells. Conclusions: AT-001 effectively prevented cellular damage caused by oxidative stress under hyperglycemic conditions warranting further investigation of AT-001 in the treatment of diabetic complications. AT-001 is currently being evaluated in a pivotal phase 2/3 study (ARISE-HF NCT 04083339) to treat diabetic cardiomyopathy and prevent progression to overt heart failure and also includes sub-analyses for retinopathy and diabetic peripheral neuropathy. Disclosure R. Perfetti: Stock/Shareholder; Self; Applied Therapeutics. G. Yepuri: None. N.A. Quadri: None. R. Ramasamy: Consultant; Self; Applied Therapeutics. A.F. Ghannam: Employee; Self; Applied Therapeutics Inc. Stock/Shareholder; Self; Sanofi US. S. Shendelman: Employee; Self; Applied Therapeutics. Stock/Shareholder; Self; Applied Therapeutics. Funding Applied Therapeutics (NCT04083339)