caficrestat (AT-001) / Applied Therap - LARVOL DELTA

Sex Differences in Diabetic Cardiomyopathy and Treatment Response to AT-001: Insights From the ARISE-HF Study. (PubMed, JACC Heart Fail) - P3 | "Despite baseline differences between women and men with DbCM, the efficacy and safety of high-dose AT-001 are comparable across sexes. These findings highlight the presence of sex-specific characteristics in DbCM and underscore the importance of further research to understand potential sex-specific mechanisms. (Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial [ARISE-HF]; NCT04083339)."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • Type 2 Diabetes Mellitus • AKR1B1

"Emerging clinical approaches in diabetic cardiomyopathy: insights from clinical trials and future directions". (PubMed, Acta Diabetol) - "Pharmacological treatments like GLP-1 agonists, SGLT-2 inhibitors, NHE-1, NHE-3, and PPAR-γ agonists show promise for treating DCM. These treatments improve myocardial glucose absorption, address dysregulated glucose and lipid metabolism, and lower heart failure and cardiovascular events. Further research is needed to confirm effectiveness and safety."

Journal • Review • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • AKR1B1

Relationship between NT-proBNP, echocardiographic abnormalities and functional status in patients with subclinical diabetic cardiomyopathy (ESC 2024) - "Purpose: This study aimed to evaluate associations between NT-proBNP concentrations, clinical characteristics, echocardiographic findings, health status and activity, and outcomes from cardiopulmonary exercise testing The Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial (ARISE-HF) trial is evaluating the effects of AT-001, a novel aldose-reductase inhibitor in participants with DbCM without a prior history of heart failure (1)... Among highly selected patients with subclinical DbCM, elevated NT-proBNP concentrations are associated with worse health status, lower activity levels, and reduced functional capacity, but not with cardiac structural abnormalities. These findings suggest that regardless of cardiac structural abnormalities, biomarker concentrations reflect important deterioration in functional capacity in affected individuals."

Clinical • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • AKR1B1

Racial Differences in Diabetic Cardiomyopathy: The ARISE-HF Trial. (PubMed, J Am Coll Cardiol) - P3 | "Racial and ethnic differences exist in baseline characteristics of persons affected by DbCM, with Black and Hispanic study participants demonstrating higher risk features. These insights inform the need to address differences in the population with DbCM. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339)."

Clinical • Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • Type 2 Diabetes Mellitus • AKR1B1

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2024 American College of Cardiology Conference. (PubMed, Curr Atheroscler Rep) - "The LIBerate-HR trial showed the efficacy and safety of lerodalcibep, a subcutaneous injection that prevents binding of Pro-Protein Convertase Subtilisin/Kexin (PCSK) 9 to low-density lipoprotein (LDL)-receptors resulting in LDL-cholesterol (LDL-C) lowering in patients at very high risk or high risk of atherosclerotic CV disease (ASCVD). The AEGIS-II randomized patients with type 1 myocardial infarction (MI) with multivessel coronary artery disease and additional CV risk factors and found no benefit in major adverse CV events (MACE) with CSL112, an apolipoprotein A1 infusion shown to increase cholesterol efflux capacity. The Bridge-TIMI 73a trial showed a significant reduction in triglyceride (TG) levels with olezarsen, an antisense mRNA, in patients with moderate hyperTG with elevated CV risk...The VICTORIAN-INITIATE trial showed efficacy and safety in early use of inclisiran in patients with ASCVD who did not reach target LDL-C < 70 mg/dL despite maximally..."

Journal • Review • Atherosclerosis • Cardiomyopathy • Cardiovascular • Coronary Artery Disease • Diabetes • Dyslipidemia • Metabolic Disorders • Myocardial Infarction • Type 2 Diabetes Mellitus • AKR1B1 • APOA1

Randomized Trial of a Selective Aldose Reductase Inhibitor in Patients With Diabetic Cardiomyopathy. (PubMed, J Am Coll Cardiol) - P3 | "Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339)."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • Type 2 Diabetes Mellitus • AKR1B1

Physical Activity Levels And Cardiac Functional Capacity In Patients With Diabetic Cardiomyopathy: Baseline Analysis From The Arise-hf Trial (HFSA 2023) - "Lower PASE score was not associated with duration of diabetes or presence of albuminuria.Conclusion Among those with DbCM substantial impairment in cardiac functional capacity is frequently present, indicating a significant reduction in physical activity. The ARISE-HF trial is evaluating the effect of aldose reductase inhibition with AT-001 on functional capacity in DbCM."

Clinical • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Diabetes • Heart Failure • Metabolic Disorders • Renal Disease • AKR1B1

Applied Therapeutics to Present Baseline Data from Phase 3 ARISE-HF Study Evaluating AT-001 at the 2023 EASD Annual Meeting (GlobeNewswire) - "Applied Therapeutics...today announced it will participate in a Symposium presentation, entitled Diabetic Cardiomyopathy (DbCM): a severe complication of diabetes, at the 59th European Association for the Study of Diabetes (EASD) Annual Meeting to take place October 2-6, 2023 in Hamburg, Germany and online....'The Phase 3 ARISE-HF study is investigating the potential benefit of AT-001 in treating DbCM, and we look forward to the data readout later this year.'"

P3 data • Cardiomyopathy • Cardiovascular • Diabetes • Heart Failure

Diabetic Cardiomyopathy is Associated With Worsening of Quality of Life Long Before the Development of Overt Heart Failure: Lessons From the Baseline Analysis of the Arise-Hf Study (AHA 2022) - "The ARISE-HF study is designed to investigate the efficacy of AT-001, a novel aldose reductase inhibitor, in preventing the worsening of functional capacity in patients with DbCM.Hypothesis: The impact of DbCM on quality of life is greater than previously recognized, as patients with DbCM often adopt lifestyle changes to mitigate the impact of early symptoms... DbCM is a form of HF leading to decreased cardiac functional capacity. Many patients with DbCM have reduced their daily physical activities to mitigate the presentation of symptoms of fatigue; however, their quality of life is significantly affected by the disease even before the progression to overt HF."

HEOR • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Fatigue • Heart Failure • Hypertension • Type 2 Diabetes Mellitus • AKR1B1

N-Terminal Pro-B Type Natriuretic Peptide Concentrations in Diabetic Cardiomyopathy—Baseline Data from the ARISE-HF Trial (ADA 2023) - P3 | "The ARISE-HF study (NCT04083339) is evaluating efficacy of AT-001, a highly selective aldose reductase inhibitor (AT-001) to improve exercise tolerance in affected patients... Among patients with DbCM, elevated NT-proBNP is associated with echocardiographic abnormalities and worse cardiac functional capacity and inversely associated with activity."

Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • AKR1B1

The Face of Diabetic Cardiomyopathy—Baseline Characteristics from the ARISE-HF Trial (ADA 2023) - P3 | "Background: Diabetic Cardiomyopathy (DbCM) is a severe complication of diabetes and a cause of heart failure (HF) occurring in the absence of other causes of cardiac dysfunction.Methods and ARISE-HF (NCT04083339) is a global Phase 3 randomized study evaluating the safety and efficacy of a novel highly selective aldose reductase inhibitor (AT-001) versus placebo to improve exercise capacity in individuals with DbCM (defined by elevated cardiac biomarkers or structural/functional cardiac abnormalities along with impaired exercise capacity)... The ARISE-HF trial is an ongoing phase 3 clinical trial evaluating the safety and efficacy of aldose reductase inhibition on exercise capacity in patients with DbCM. The baseline analysis of the study cohort provides a unique characterization of individuals with DbCM."

Diabetes • Metabolic Disorders • AKR1B1

Diabetic Cardiomyopathy: baseline Characteristics of patients enrolled into the ARISE-HF trial (HEART FAILURE 2023) - " ARISE-HF trial is a global phase 3 randomized study evaluating the safety and efficacy of two doses a novel aldose reductase inhibitor (AT-001) versus placebo to improve or prevent decline in cardiac functional capacity in individuals with DbCM... 684 study participants with DbCM are described in Table 1. 50% of patients were female, with a mean age 67.5years. Patients enrolled had a duration of diabetes of 14 years, with excellent glycemic control at baseline (HbA1c of 6.99%)."

Clinical • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Coronary Artery Disease • Heart Failure • AKR1B1

Phenotypic characterization of echocardiographic abnormalities in patients with diabetic cardiomyopathy (HEART FAILURE 2023) - P3 | "Baseline characteristics of individuals with DbCM across the four groups are shown in Table 1. Patients with solely diastolic abnormalities were most commonly female, treated with beta blockers, and less commonly treated with GLPRA. Patients with diastolic and mixed abnormalities had higher NT-proBNP and lower cardiac functional capacity."

Clinical • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Coronary Artery Disease • Heart Failure • AKR1B1

NT-proBNP levels in diabetic cardiomyopathy: results from the ARISE-HF trial (HEART FAILURE 2023) - "Median NT-proBNP in the overall study population was 71 ng/L (IQR 35-133). Main baseline characteristics were similar across baseline NT-proBNP concentrations, however participants with higher NT-proBNP levels had a greater left atrial volume (LAVI) (p<0.001) and higher right ventricular systolic pressure (p=0.04) on baseline echocardiogram. Higher NT-proBNP concentrations were associated with reduced physical activity reflected in lower Physical Activity Scale for the Elderly (PASE) Score (p<0.001) and a worse quality of life defined by a lower mKCCQ score (p=0.02)."

Cardiomyopathy • Cardiovascular • Coronary Artery Disease • AKR1B1

Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation. (PubMed, Cardiovasc Diabetol) - "Inhibiting aldose reductase activity ameliorates diastolic dysfunction in mice with experimental type 2 diabetes, which may be due to the decline in myocardial fatty acid oxidation, indicating that treatment with AT-001 may be a novel approach to alleviate diabetic cardiomyopathy in patients with diabetes."

Journal • Cardiomyopathy • Cardiovascular • Diabetes • Fibrosis • Immunology • Metabolic Disorders • Type 2 Diabetes Mellitus • AKR1B1

ARISE-HF: Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy (clinicaltrials.gov) - P3 | N=675 | Active, not recruiting | Sponsor: Applied Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

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. (PubMed, Am Heart J) - P3 | "AT-001 is a novel investigational highly specific ARI with higher binding affinity and greater selectivity than previously studied ARIs...Additional endpoints include percentage of patients progressing to overt HF, health status metrics, echocardiographic measurements, and changes in cardiac biomarkers. This report describes the rationale and study design of ARISE-HF."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • Type 2 Diabetes Mellitus • AKR1B1

CADD Studies in the Discovery of Potential ARI (Aldose Reductase Inhibitors) Agents for the Treatment of Diabetic Complications. (PubMed, Curr Diabetes Rev) - "AR inhibitors (ARI) have been widely discussed in the literature, for example, Epalrestat is currently the only ARI used to treat patients with diabetic neuropathy in Japan, India, and China...AT-001, an AR inhibitor, is now being tested in COVID-19 to see how safe and effective it is at reducing inflammation and cardiac damage...New data shows that diabetes and obesity are among the strongest predictors of COVID-19 hospitalization. Patients and risk factors for severe morbidity and mortality of COVID- 19."

Journal • Cardiovascular • Diabetes • Diabetic Neuropathy • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Metabolic Disorders • Novel Coronavirus Disease • Obesity • Pain • Respiratory Diseases • AKR1B1

Applied Therapeutics Reports First Quarter 2022 Financial Results (BioSpace) - "Applied Therapeutics, Inc...today reported financial results for the first quarter ended March 31, 2022....Decrease in drug manufacturing and formulation costs of $5.6 million primarily related to the completion and release of AT-001...drug product batches in the three months ended March 31, 2021." "

Commercial • CNS Disorders • Pain • Peripheral Neuropathic Pain

ARISE-HF: Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy (clinicaltrials.gov) - P3 | N=675 | Recruiting | Sponsor: Applied Therapeutics, Inc. | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2022 ➔ Dec 2023

Trial completion date • Trial primary completion date • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

A pilot open-label study of aldose reductase inhibition with AT-001 (caficrestat) in patients hospitalized for COVID-19 infection: Results from a registry-based matched-control analysis. (PubMed, Diabetes Metab Syndr) - "In hospitalized patients with COVID-19 and co-morbid diabetes mellitus and heart disease, treatment with AT-001 was safe and well tolerated. Exposure to AT-001 was associated with a trend of reduced mortality and shortened LOS. While the observed trend did not reach statistical significance, the present study provides the rationale for investigating potential benefit of AT-001 in COVID 19 affected patients in future studies."

Clinical • Journal • Cardiomyopathy • Cardiovascular • Diabetes • Heart Failure • Immunology • Infectious Disease • Inflammation • Metabolic Disorders • Novel Coronavirus Disease • Type 2 Diabetes Mellitus • AKR1B1

Cardiovascular Effects of COVID-19 (clinicaltrials.gov) - P2; N=81; Completed; Sponsor: NYU Langone Health; N=10 ➔ 81

Clinical • Enrollment change • Cardiovascular • Infectious Disease • Novel Coronavirus Disease

[VIRTUAL] Diabetic Cardiomyopathy: An Opportunity for Clinical Intervention (ADA 2021) - "There are currently no approved treatments for DbCM. The ARISE-HF clinical trial is currently enrolling patients and studying the ability of AT-001, a novel, potent, selective Aldose Reductase Inhibitor, to halt or prevent progression of Diabetic Cardiomyopathy."

Clinical • Diabetes • Metabolic Disorders • AKR1B1

ARISE-HF: Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy (clinicaltrials.gov) - P3; N=675; Recruiting; Sponsor: Applied Therapeutics, Inc.; Trial completion date: Sep 2023 ➔ Dec 2024; Trial primary completion date: Sep 2021 ➔ Dec 2022

Clinical • Trial completion date • Trial primary completion date • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

Cardiovascular Effects of COVID-19 (clinicaltrials.gov) - P2; N=10; Completed; Sponsor: NYU Langone Health; Recruiting ➔ Completed; N=500 ➔ 10

Clinical • Enrollment change • Trial completion • Cardiovascular • Infectious Disease • Novel Coronavirus Disease