Diabetic Cardiomyopathy (DbCM) is a form of heart failure (Stage B) characterized by a decrease in heart function and diagnosed by echocardiogram.

In the United States (U.S.), approximately 34 million people are living with diabetes – about one in ten people. The hallmark of diabetes is hyperglycemia, or high levels of glucose (sugar) in the blood. In people with diabetes, Aldose Reductase converts glucose to sorbitol, which can cause damage to tissues, including the heart. There are no approved therapies for DbCM, which affects ~17% of people with diabetes representing a prevalence of ~1 in 5 people with diabetes. Approximately 25% of patients with DbCM progress to overt heart failure or death within 18 months of diagnosis.

There are no approved therapies for DbCM, which affects 17% of people with diabetes representing a prevalence of ~1 in 5 people with diabetes

Total prevalence of DbCM is ~12.9M across the United States, France, Germany, Italy, Spain, United Kingdom and Japan, with 10.7M of this population meeting the criteria for Stage B Heart Failure

25% of patients with DbCM progress to overt heart failure or death within 1.5 years of diagnosis​

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DbCM can occur in both Type 1 and Type 2 diabetics, despite glucose control. When there is too much glucose in the body, it is broken down by the polyol pathway. The polyol pathway is a specific chemical reaction that converts glucose into other substances. The first enzyme in this pathway is Aldose Reductase, which converts glucose to a substance called sorbitol.

Sorbitol and fructose can damage the heart in many ways. One example is something called oxidative stress. As the name suggests, oxidative stress causes a lot of stress to the heart because of an increase in molecules, called free radicals, that are harmful to important structures in cells. When these structures are harmed, the cells in the heart cannot do their job properly. Aldose Reductase activation also detracts glucose from the energy efficient hexokinase/glycolytic pathway, resulting in less energy production for cardiomyocytes.

Sorbitol will eventually cause cell death if not controlled. The damage that occurs includes heart fibrosis, or “hardening” of the heart. When this happens, the heart becomes less effective at pumping blood to the rest of the body.

If DbCM is not treated, it can become worse, progressing to overt heart failure and potentially death. A specific treatment for DbCM is needed.

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DbCM patients present clinically with shortness of breath on exertion due to decreased functional capacity of the heart muscle. Fortunately, DbCM can be diagnosed early in the disease via echocardiogram, a simple non-invasive procedure performed in many physicians’ offices.

Our Commitment to DbCM Research

Applied Therapeutics is committed to advancing research in DbCM and potentially finding a new treatment option for this urgent unmet medical need. Our pipeline candidate AT-001 is an investigational, novel Aldose Reductase Inhibitor currently in a clinical trial for DbCM.

AT-001 was evaluated in a Phase 1/2 clinical trial of patients with type 2 diabetes (T2D). Results confirmed that AT-001 was well tolerated and significantly reduced levels of sorbitol, a key toxic biomarker of Aldose Reductase function, to the same levels as healthy volunteers, indicating complete Aldose Reductase inhibition. AT-001 rapid-release capsules provided sorbitol normalization effects through 10-12hrs post-dose at >10mg/kg. This included protection from food-related sorbitol spikes during times of post-prandial hyperglycemia. Additionally, approximately 50% of AT-001 treated patients demonstrated a clinically meaningful reduction in NT-proBNP, a biomarker of cardiac stress, over 28 days.

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