Caficrestat may prevent heart failure in diabetic cardiomyopathy patients: ARISE-HF trial

USA: Treatment with caficrestat (AT-001), an investigational oral aldose reductase inhibitor, stabilized cardiac functional capacity in patients with diabetic cardiomyopathy at high risk of progression to overt heart failure compared with placebo, findings from the phase 3 ARISE-HF trial have shown. 

The primary endpoint of the study was stabilization or improvement in cardiac functional capacity as measured by Peak VO2 in patients treated with AT-001 1500mg twice daily (BID) as compared to placebo. The placebo-treated group declined by a mean of -0.31 ml/kg/min over 15 months of treatment, while the AT-001 1500mg BID group remained primarily stable, with a mean change of -0.01 ml/kg/min over 15 months. While a trend favoured active treatment, the difference between active and placebo-treated groups (0.30 ml/kg/min) was not statistically significant (p=0.210).

The ARISE-HF study evaluated the treatment effect of AT-001 as an add-on to diabetes standard-of-care therapies. Approximately 38% of study subjects were on SGLT2 or GLP-1 therapies for the treatment of diabetes, while 62% were not. In a pre-specified subgroup analysis of the primary endpoint in patients not concomitantly treated with SGLT2 or GLP-1 therapies, the placebo group declined by a mean of -0.54 ml/kg/min, while the 1500mg BID AT-001 treated group improved by a mean of 0.08 ml/kg/min over 15 months of treatment, with a difference between groups of 0.62 ml/kg/min (p=0.040). Additionally, in this subgroup analysis, the number of patients who experienced a clinically significant worsening in cardiac functional capacity of 6% or more was substantially higher in the placebo group (46%) as compared to the 1500mg BID AT-001 treated group (32.7%), odds ratio 0.56 (p=0.035). A 6% change in cardiac functional capacity has been shown to predict long-term survival and hospitalization for heart failure. The effect of AT-001 was dose-dependent, with the low dose (1000mg BID) demonstrating an intermediate effect between the high dose and placebo.

AT-001 was generally safe and well tolerated, with no substantial differences in serious adverse events between AT-001 treated groups as compared to placebo (14.3% placebo; 12.3% AT-001 1000mg BID; 17.3% AT-001 1500mg BID), no substantial differences in treatment-emergent adverse events (79.1% placebo; 81.6% AT-001 1000mg BID; 81% AT-001 1500mg BID) and low incidence of treatment-related discontinuations (3.9% placebo; 9.6% AT-001 1000mg BID; 9.5% AT-001 1500mg BID).

Full study results will be presented at an upcoming medical conference, along with results of the Diabetic Peripheral Neuropathy sub-study, which are still being analyzed.

“AT-001 stabilized cardiac functional capacity as compared to placebo, and prevented clinically significant worsening of disease, an effect which was strengthened in patients not on concomitant treatment with an SGLT2 or GLP-1,” said Riccardo Perfetti, MD, PhD, Chief Medical Officer of Applied Therapeutics. “Given its favorable safety and tolerability profile and oral dosing, we believe that AT-001 represents an important potential tool for physicians in treatment of DbCM patients. We thank the patients and families who participated in the ARISE-HF study and made this important work possible.”

“There are currently no therapies approved for DbCM, and a high unmet need exists for a treatment that can prevent worsening of the condition and progression to overt heart failure,” said James Januzzi, M.D., Principal investigator of the ARISE-HF study and Hutton Family Professor of Cardiology at Massachusetts General Hospital. “Stabilization of cardiac functional capacity is an exciting finding, since declining functional capacity is a leading indicator of progression to overt heart failure.”

Given these encouraging results, the Company plans to focus on identifying an appropriate path forward through partnering in order to bring AT-001 to DbCM patients. Current resources are expected to be focused on the development, regulatory and commercial preparations for the govorestat rare disease program. The Company submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in December 2023 for govorestat for the treatment of Classic Galactosemia. The Marketing Authorization Application (MAA) was validated and accepted for review by the European Medicines Agency (EMA) in December 2023.

About AT-001 (Caficrestat)

AT-001 (caficrestat) is an investigational oral, novel, potent Aldose Reductase inhibitor in Phase 3 clinical development for the treatment of Diabetic Cardiomyopathy. The global ARISE-HF Phase 3 study evaluated the ability of AT-001 to improve or prevent worsening of disease, as measured by changes in cardiac functional capacity, in 675 patients with DbCM at high risk of progression to overt heart failure. The study demonstrated a positive impact of AT-001 treatment, which was statistically significant in a prespecified subgroup of patients not on concomitant treatment with an SGLT2 or GLP-1 inhibitor. AT-001 has been previously studied in a Phase 1/2 study in approximately 120 patients with type 2 diabetes, a subset of which had DbCM.