AT-001 Fails to Achieve Significance for Primary Endpoint in ARISE-HF


Applied Therapeutics announced topline results from ARISE-HF on January 04, 2023 and plans to present full results at an upcoming medical conference.

James Januzzi, MD | Credit: BAIM Institute

James Januzzi, MD
Credit: BAIM Institute

AT-001 (Caficrestat) failed to achieve statistical significance for its primary endpoint of stabilization or improvement in cardiac functional capacity among patients with diabetic cardiomyopathy, according to a press release from Applied Therapeutics.

Announced on January 04, 2023, topline results of the ARISE-HF trial indicate use of AT-001 was associated with a favorable, but nonsignificant trend toward benefit for Peak VO2 relative to placebo therapy, with additional analysis suggesting a greater degree of benefit among patients not concomitantly treated with SGLT2 inhibitors or GLP-1 receptor agonists.

“There are currently no therapies approved for [diabetic cardiomyopathy], 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, MD, principal investigator of the ARISE-HF study and Hutton Family Professor of Cardiology at Massachusetts General Hospital.1 “Stabilization of cardiac functional capacity is an exciting finding, since declining functional capacity is a leading indicator of progression to overt heart failure.”

According to the release from Applied Therapeutics, the full trial results will be presented at an upcoming medical conference. A disease with no approved therapies, the ARISE-HF trial was launched in 2019 following positive data within a subset of patients with diabetic cardiomyopathy from a phase 1/2 trial examining use of the novel, potent, highly selective aldose reductase inhibitor in patients with type 2 diabetes.1,2

A randomized double-blind placebo-controlled Phase 3 registrational trial, ARISE-HF enrolled 675 patients from North America and Europe with diabetic cardiomyopathy considered to be at high risk for progression to overt heart failure. Patients included in the trial randomized this population in a 1:1:1 ratio to either placebo, low dose AT-001 (1000 mg), or high dose AT-001 (1500 mg), taken twice daily.1

The trial’s primary outcome of interest was as difference in cardiac functional capacity, as measured by Peak VO2, at 15 months of treatment. Per trial protocol, patients in the trial continued in blinded format for an additional 12 months of treatment to produce secondary endpoint data on progression to overt heart failure, hospitalization, morbidity and mortality.

Topline results announced by Applied Therapeutics indicated Peak VO2 declined by a mean of -0.31 ml/kg/min and -0.01 ml/kg/min over 15 months of treatment in the placebo and AT-001 1500 mg groups, respectively (difference, 0.30 ml/kg/min; P =.210). Additional data from the release suggested a pre-specified subgroup analysis of the primary endpoint in patients not concomitantly treated with SGLT2 inhibitor or GLP-1 receptor agonist therapies, which represented approximately 62% of the trial, Peak VO2 declined by a mean of -0.54 ml/kg/min among the placebo cohort and improved by a mean of 0.08 ml/kg/min in the AT-001 1500 mg group (difference, 0.62 ml/kg/min; P=.040).1

Further analysis of the aforementioned subgroup revealed the number of patients who experienced a clinically significant worsening in cardiac functional capacity of 6% or more was substantially greater among the placebo group than the AT-001 1500 mg group (46% vs 32.7%; odds ratio, 0.56; P=.035).1

According to Applied Therapeutics, the trial’s safety analysis demonstrated no substantial difference in serious adverse events (14.3% placebo; 12.3% AT-001 1000 mg; 17.3% AT-001 1500 mg) or treatment emergent adverse events (79.1% placebo; 81.6% AT-001 1000 mg BID; 81% AT-001 1500 mg). The release also indicated there was a low incidence of treatment-related discontinuations (3.9% placebo; 9.6% AT-001 1000 mg; 9.5% AT-001 1500 mg).1

“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.1 “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 [diabetic cardiomyopathy] patients.”


  1. Applied Therapeutics. Applied Therapeutics announces topline results from the ARISE-HF phase 3 study of AT-001 in diabetic cardiomyopathy. Applied Therapeutics. January 4, 2024. Accessed January 7, 2024.
  2. Applied Therapeutics. Applied Therapeutics announces initiation of phase 3 registrational trial of AT-001 in diabetic cardiomyopathy (arise-HF). Applied Therapeutics. September 4, 2019. Accessed January 7, 2024.

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