ASSERT: Novel drug raised apoA-1 levels but failed to meet primary endpoint

Issue: February 2011

American Heart Association Scientific Sessions 2010

CHICAGO — New data from ASSERT has shown that RVX-208, an investigational drug designed to raise apolipoprotein A-1 levels, was unable to meet its primary endpoint in patients with coronary artery disease when compared with placebo. However, the observed increase in apolipoprotein A-1 afforded by the drug may have important implications for increasing HDL levels in patients with this disease, suggested study investigators.

The ApoA1 Synthesis Stimulation Evaluation in Patients Requiring Treatment for Coronary Artery Disease (ASSERT) trial was a double blind, randomized study conducted at 35 US medical centers. All patients (n=299) had CAD and were already taking a cholesterol-lowering statin drug at baseline. They were divided into four groups: three given different doses (100 mg, 200 mg or 300 mg) of RVX-208 (Resverlogix) and one given placebo. All groups were treated for 12 weeks.

Researchers reported that the primary endpoint of percentage change in apolipoprotein A-1 (apoA-1) levels in patients treated with RVX-208 vs. placebo did not reach statistical significance. However, they did note that as the dose of RVX-208 increased so did apoA-1 levels, culminating with an increase of 8.3% in HDL levels in the 300-mg group compared with placebo (P<.01).

According to Stephen J. Nicholls, PhD, who presented the results of the ASSERT trial at a press conference, a 2-D gel analysis demonstrated that the highest dose of RVX-208 was associated with a statistically significant increase in the amount of alpha-1 HDL compared with placebo (P<.05). Nicholls also noted that the majority of increases in HDL occurred in the latter part of the study with no plateau in effects.

“We think that these results are encouraging for patients with CAD. And they importantly suggest from a lipid perspective that there very well may be lipid mobilization for these patients,” said Nicholls, who is assistant professor of molecular medicine, Lerner College of Medicine, Case Western Reserve University, Cleveland.

While the induction of apoA-1 synthesis remains a novel approach to HDL functionality rather than necessarily quantitative changes in terms of primary impact, he added, the impact ultimately on plaque in the artery wall and CV outcomes remains to be determined in future studies. – by Brian Ellis and Stacey Fisher

Nicholls reports receiving research support from Resverlogix. The ASSERT study was funded by Resverlogix.

This is an interesting study; it is encouraging in some points and it’s discouraging in others. RVX-208 might reduce atherosclerosis and CV events, and it is reasonable to do an atherosclerosis endpoint trial. I think it is imperative that we look for other drugs in this class and for other methods of raising A-1 synthesis.

– Eliot Brinton, MD
Department of Internal Medicine, Division of Cardiovascular Genetics
University of Utah School of Medicine, Salt Lake City

For more information:

Nicholls SJ. LBCT IV, Abstract 21774. Presented at: American Heart Association Scientific Sessions 2010; Nov. 13-17, 2010; Chicago.

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