Hyperactivation of the polyol pathway (PP) contributes to development of diabetic complications. Aldose reductase (AR) is the rate-controlling enzyme in PP that catalyzes NADPH-dependent reduction of glucose to sorbitol. In hyperglycemic and ischemic conditions, PP activation causes intracellular sorbitol accumulation leading to osmotic stress, cell death and diabetic complications. We developed AT-001 based on further characterization of AR and structural changes within the active site of AR following enzymatic activation to design molecular AR inhibitors with enhanced specificity, affinity and selectivity compared with previous AR inhibitors that failed to inhibit redox-activated AR and were associated with off-target effects and/or lack of efficacy. AT-001 safety, pharmacokinetics (PK) and efficacy were assessed in a phase 1/2 study comprised of single 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 (BID) for 7 d. Subjects with type 2 diabetes, age 18-75 and HbA1c 5.0-8.5% were allocated to each dose cohort (n=8 AT-001, n=2 Pbo). AT-001 was well-tolerated with no drug-related AEs or changes in liver or renal function up to the highest dose tested. Mean half-life (T1/2) and time of maximum concentration (Tmax) ranged from 1.7-3h and 1.75-3h, respectively in both SAD and day 1 MAD with no accumulation at day 7. AR inhibition was confirmed by significant dose-dependent reductions in whole blood sorbitol in SAD and MAD up to approximately -50% change from baseline in SAD and days 1 and 7 of MAD vs. a -3% change in Pbo (p<0.05 for all doses vs. Pbo). Maximum inhibition occurred between 2-4 h. Conclusions: greater selectivity and affinity of AT-001 for AR may endow acceptable safety. These findings support further investigation of the therapeutic potential of AT-001 in subjects with diabetes complications.


S. Shendelman: Stock/Shareholder; Self; Applied Therapeutics Inc. Other Relationship; Self; Applied Therapeutics Inc. R. Perfetti: Employee; Self; Applied Therapeutics Inc., Sanofi. Stock/Shareholder; Self; Applied Therapeutics Inc., Sanofi.

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