Encouraging Top Line Results from ARISE-HF Phase III Study of AT-001 in Diabetic Cardiomyopathy
SOURCE: Radcliffe Cardiology, Jordan Rance; Special Editor: Greg Guillory
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Applied Therapeutics, Inc. has shared the promising results from its Phase III ARISE-HF study (NCT04083339), exploring the potential of AT-001, an investigational aldose reductase inhibitor (ARI), also known as caficrestat, to enhance cardiac function in patients with diabetic cardiomyopathy (DbCM). 

By inhibiting aldose reductase, AT-001 disrupts this detrimental pathway and helps to alleviate the damaging effects of sorbitol accumulation in DbCM.

Methodology

  • The ARISE-HF study was a phase III randomized, double-blind, placebo-controlled clinical trial. This study is conducted at 62 global sites across Australia, Canada, Czech Republic, France, Germany, Hong Kong, Poland, Spain, United Kingdom and United States.  
  • The study enrolled 675 patients with diabetic cardiomyopathy (DbCM) who were at high risk of progressing to overt heart failure (HF). To be eligible, patients had to be at least 40 years old, have type 2 diabetes, diabetic cardiomyopathy and a peak oxygen consumption (VO2) value of less than 75% of the predicted normal value based on their age and gender.
  • Patients were randomly assigned in a 1:1:1 ratio to receive either high-dose AT-001 (1,500 mg twice daily), low-dose AT-001 (1,000 mg twice daily) or placebo. 
  • The primary endpoint of ARISE-HF was the change in cardiopulmonary exercise test (CPET) performance (peak VO2) from baseline to month 15, with a second assessment at month 27 if no statistically significant changes were observed at month 15.
  • Secondary endpoints include progression to overt heart failure, changes in NT-proBNP and changes in the modified Kansas City Cardiomyopathy Questionnaire (KCCQ) score at 27 months. 

Top Line Results

  • The placebo-treated group exhibited a mean decline in cardiopulmonary exercise test (CPET) performance (peak VO2) of -0.31 ml/kg/min over a 15-month treatment period, while the AT-001 1500mg BID group demonstrated a relatively stable condition, with a mean change of -0.01 ml/kg/min over the same period. While a trend favored active treatment, the difference between the groups (0.30 ml/kg/min) did not reach statistical significance (p=0.210). The effect of AT-001 was dose-dependent, with the low dose (1000mg BID) demonstrating an intermediate effect between the high dose and placebo.
  • ARISE-HF study assessed the effectiveness of AT-001 added to standard diabetes treatments. About 38% were on SGLT2 or GLP-1 therapies. In a subgroup of patients not taking SGLT2 or GLP-1 therapies, AT-001 1500mg BID demonstrated a stabilization in cardiopulmonary exercise test (CPET) performance (peak VO2) over 15 months compared to a decline in the placebo group. The difference was 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).
  • 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).

Principal Investigator James Januzzi emphasised the significance of these findings, stating, "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. The stabilisation of cardiac functional capacity observed in this study is an exciting finding, since declining functional capacity is a leading indicator of progression to overt heart failure."

Full results, in addition to the findings from the ongoing analysis of the Diabetic Peripheral Neuropathy sub-study, are set to be unveiled at an upcoming medical conference.

The study is sponsored by Applied Therapeutics, Inc. 

References

Applied Therapeutics announces topline results from the ARISE-HF phase 3 study of AT-001 in diabetic cardiomyopathy. News release. Applied Therapeutics. January 4, 2024. Accessed January 4, 2024. https://www.globenewswire.com/news-release/2024/01/04/2804317/0/en/Applied-Therapeutics-Announces-Topline-Results-from-the-ARISE-HF-Phase-3-Study-of-AT-001-in-Diabetic-Cardiomyopathy.html.

Januzzi JL, Butler J, Del Prato S, et al. Rationale and design of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial (ARISE-HF) in patients with high-risk diabetic cardiomyopathy. Am Heart J. 2023 Feb:256:25-36. Accessed January 4, 2024. https://doi.org/10.1016/j.ahj.2022.11.003 

Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy. ClinicalTrials.gov. Accessed January 4, 2024. https://clinicaltrials.gov/study/NCT04083339

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