Apo A1 Synthese: nieuwe aanpak HDL verhoging en CV risico modificatie

Nieuws - 17 nov. 2010

New drug aimed at apoA-1 did not have significant effect, more research needed

November 17, 2011

CHICAGO, Nov. 17, 2010 — A new drug designed to raise levels of apolipoprotein A-1 (apoA-1), the primary cholesterol transport protein associated with high-density lipoprotein cholesterol, and thus possibly clear plaque from arteries, didn’t cause a significant difference in apoA-1 levels compared to placebo according to a late-breaking clinical trial reported at the American Heart Association’s Scientific Sessions 2010.

The drug did cause a statistically significant increase in blood levels of both high density lipoprotein (HDL) cholesterol, known as the “good” cholesterol, and the largest HDL particles. High levels of both are linked with good heart health.

In the randomized, double-blind ApoA-I Synthesis Stimulation Evaluation in Patients Requiring Treatment for Coronary Artery Disease (ASSERT) trial, researchers tested the safety and effectiveness of the new drug, RVX-208, on blood levels of apoA-1. The drug is the first oral agent to induce production of apoA-1 in basic studies.

The researchers note that apoA-1 levels increased as the dose of RVX-208 increased. However, the study’s primary endpoint, which compared each individual dose of RVX-208 to a placebo, did not achieve statistical significance. The HDL-raising effect was a secondary finding.

“The study may not have had enough patients to answer its primary question about apoA-1,” said Stephen J. Nicholls, Ph.D., lead author of the trial and assistant professor of molecular medicine in the Lerner College of Medicine at Case Western Reserve University in Cleveland, Ohio.

“Nevertheless,” he said, “there does appear to be a dose-dependent effect. In addition, the secondary findings suggest there is a benefit in terms of moving cholesterol on to the good particles.”

The 12-week trial included 299 coronary artery disease patients treated at 35 medical centers in the United States who were already taking a cholesterol-lowering statin drug. Twenty-five percent of patients were female and 93 percent were Caucasian. Researchers divided patients into four treatment groups, three receiving different doses of RVX-208 — 100 milligrams (mg) per day, 200 mg/day, 300 mg/day — and the fourth receiving placebo.

The researchers saw a significant 8.3 percent increase in HDL levels in the 300 mg RVX-208 group compared to placebo. HDL’s designation as the “good” cholesterol carrier stems from a process known scientifically as reverse cholesterol transport. In terms of adverse effects, some patients treated with RVX-208 had significant, but reversible, increases in liver enzymes, but no evidence of liver damage.

“There’s a lot of interest in developing new ways to raise HDL, but we don’t know the best way to do it,” Nicholls said. “One avenue that has been of particular interest for decades is to ask if we could just turn on apoA-1. We think these findings suggest that the drug is turning on apoA-1 production, resulting in lipid changes that are consistent with more cholesterol transport out of the vessel wall.”

Low HDL levels are defined as below 40 milligrams per deciliter (mg/dL) of blood in men and below 50 mg/dL in women. Cholesterol-lowering treatment with statin drugs focuses on reducing low-density lipoprotein (LDL, or “bad” cholesterol). “This could be the first oral therapy that acts by inducing apoA1 production,” said Nicholls, who is also cardiovascular director of the Cleveland Clinic Coordinating Center for Clinical Research. “If that is true, it should be possible to measure arterial plaque shrinkage in response to therapy.”

In a new trial, the group is using intravascular ultrasound to measure changes in plaque volume in coronary artery disease patients treated with the drug.

Co-authors are: Christie M. Ballantyne, M.D.; John J. Kastelein, M.D.; Allen J. Taylor, M.D.; Allan Gordon, M.D., Ph.D.; Jan Johansson, M.D., Ph.D. and Steven E. Nissen, M.D. Author disclosures are on the abstract. Resverlogix Pharmaceuticals funded the study.

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