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.

graphic
View largeDownload slide
Disclosure

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.

Funding

Applied Therapeutics (NCT04083339)

© 2020 by the American Diabetes Association
2020
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.