The role of Aldose Reductase in diabetes complications, including DbCM is well established. Older generation ARIs were unsuccessful due to lack of selectivity, resulting in off-target toxicity, such as renal and hepatic toxicity, and hypersensitivity reactions.

AT-001 is a next generation ARI with improved selectivity and ∼1,000X higher potency. In preclinical studies, AT-001 demonstrated significant reduction of cardiac damage with no off-target inhibition. The safety, tolerability, PK, and PD of AT-001 were assessed in a phase 1/2, three-part, randomized, placebo controlled study (n=120) in adults with type 2 diabetes. AT-001 induced dose-dependent inhibition of sorbitol, the PD biomarker of AR activity. All doses and dosing regimens were well-tolerated. There were no treatment-related serious adverse events (AEs) and no AEs causing discontinuation of study treatment. No clinically relevant changes in liver and kidney function were reported [Table].

The study results support further clinical development to explore potential use of AT-001 as an emerging therapeutic strategy in preventing diabetes complications. A pivotal phase 2/3 study, ARISE-HF (NCT04083339) was initiated to evaluate the safety and efficacy of two doses of AT-001 vs. placebo to improve or prevent the decline of functional capacity in adults with DbCM.


R. Perfetti: Stock/Shareholder; Self; Applied Therapeutics. F.C. Lawson: Employee; Self; Applied Therapeutics. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. J. Januzzi: Consultant; Self; Roche Diagnostic USA. Research Support; Self; Janssen Pharmaceuticals, Inc. S. Shendelman: Employee; Self; Applied Therapeutics. Stock/Shareholder; Self; Applied Therapeutics. S. Wang: Employee; Self; Applied Therapeutics. A.F. Ghannam: Employee; Self; Applied Therapeutics Inc. Stock/Shareholder; Self; Sanofi US.


Applied Therapeutics (NCT04083339)

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