Targeting Diabetes-Related Heart Disease

In 2004, oncologist Noah Berkowitz, M.D., Ph.D., founded HaptoGuard with a focus on developing therapies for select patients with diabetes, namely those at high risk for cardiovascular complications identified by a specialized laboratory test. He was inspired by the success of cancer drugs like Herceptin that target tumors expressing a specific gene.

Three years later, HaptoGuard merged with Alteon, a 15-year-old company with drug candidates that attack advanced glycation end-products (AGEs). AGEs’ contribute to complications of diabetes, such as cardiovascular disease (CVD) and renal failure.

Dr. Berkowitz is now president and CEO of the new company called Synvista Therapeutics. The company’s focus is on novel products to control the formation of oxidized lipids and AGEs in diabetes and its underlying complications.

Glutathione Peroxidase Mimic

Synvista has two compounds in clinical trials ALT-2074 and alagebrium. ALT-2074 is a selenium-containing, small molecule drug that mimics glutathione peroxidase, a powerful antioxidant that reduces oxidized lipids.

“By reducing oxidized lipids, we feel that we can interfere with the size of heart attacks if they occur or the development of atherosclerosis,” says Dr. Berkowitz.

Although other companies have organoselenium compounds in their pipelines, “to the best of my knowledge, I do not know of any others in clinical trials,” he adds. ALT-2074 is under investigation in two Phase II trials for diabetic patients with acute coronary syndrome and may eventually be used in acute coronary syndrome patients in general.

Glutathione peroxidase is a key enzyme in humans that uses selenium to reduce oxidized lipids, rendering them less toxic. “Our small molecule was designed rationally to use selenium like the enzyme does to reduce oxidized lipids,” continues Dr. Berkowitz.

Animal models show that when glutathione peroxidase is overexpressed, animals are protected from CVD, but when glutathione peroxidase is knocked out, the incidence of CVD increases. A few years ago, a European study found similar results in humans.

Haptoglobin Testing

Technology from the former HaptoGuard will be used to identify patients with diabetes who are at increased risk for CVD and who could benefit most from ALT-2074 or other treatments. The diagnostic test is based on haptoglobin, a protein that binds free hemoglobin in blood and acts as an antioxidant and antiatherosclerotic agent.

The general population has three genetic variations of haptoglobin, designated Hp 1-1, Hp 1-2, and Hp 2-2, which vary in their interaction with hemoglobin. Several multinational studies find that patients with diabetes who also carry the Hp 2-2 variant are up to five times more likely to develop CVD. “But, if you don’t have diabetes, Hp 2-2 is not a problem with respect to CVD,” assures Dr. Berkowitz. A strong antioxidant like ALT-2074 could lower the risk for CVD in this targeted group of high-risk patients with diabetes and Hp 2-2.

Patients with diabetes and Hp 2-2 are also at a higher risk for restenosis after angioplasty and heart attacks. A prospective clinical trial in Israel found that patients with diabetes and Hp 2-2 can reduce their risk for heart attack by taking vitamin E. In fact, vitamin E cut the rate for nonfatal heart attacks by 50% compared to a placebo, causing researchers to stop the study early.

A diagnostic tool to identify high-risk patients “gives us a wonderful opportunity to apply pharmacogenomics to diabetes,” Dr. Berkowitz says. Depending on a person's haptoglobin status, physicians can intervene with therapies like vitamin E or ALT-2074 to lower the CVD event rate.

“We have all the relevant intellectual property for haptoglobin testing in the diabetes population wrapped up,” Dr. Berkowitz continues. Synvista Therapeutics licensed key technology from Technion University in Israel and plans to release a commercial kit for physicians early in 2009.

The company is also evaluating biomarkers in Phase II trials to find ones that correlate with the ability of ALT-2074 to lower oxidized lipids in diabetic patients with Hp 2-2. “The goal is to develop ALT-2074 for this at-risk population as a therapy after heart attacks or as a possible drug to prevent heart attacks,” he says.

Breaking AGEs

The company’s other drug candidate, alagebrium, was originally developed by Alteon researchers. Alagebrium breaks down AGEs, which crosslink proteins in tissues, leading to structural changes and deterioration that cause diastolic heart failure (DHF) and kidney failure. When proteins in the heart or other organs become crosslinked, they stiffen and cannot function properly. By breaking down crosslinks, alagebrium restores function to affected organs. “Alagebrium was picked up in a screen for chemicals that can interfere with the crosslinking process,” says Dr. Berkowitz.

Researchers at Alteon had been studying alagebrium since 2002 as a treatment for systolic hypertension, which was postulated to be caused by elevated AGEs. Even though the drug failed to prove useful for controlling systolic hypertension, large Phase II trials generated a sizeable human safety database for alagebrium.

Recently, compelling animal models demonstrated that heart failure is linked to AGEs, and that breaking AGEs with alagebrium appears to prevent DHF. Late in 2007, Synvista launched a definitive clinical study called Beneficial to compare alagebrium to a placebo in 100 patients, many or whom have diabetes, to evaluate its effectiveness in improving symptoms of DHF as well as exercise tolerance. The results are expected in 2009.

“There’s a sizable market for a drug that targets patients with diabetes and Hp 2-2,” comments Dr. Berkowitz, “considering that 20 million people in the U.S. have diabetes and 40 percent of them also have Hp 2-2. On top of that, half of diabetic patients die of CVD, so millions could potentially benefit from drugs that reduce oxidized lipids and reduce AGEs to speed the healing process.”