CHICAGO – A novel oral drug designed to increase apolipoprotein A-I synthesis and thereby enhance HDL functionality showed mixed results in its first major clinical trial.
The 299-patient, 12-week, randomized, double-blind ApoA-I Synthesis Stimulation Evaluation in Patients Requiring Treatment for Coronary Artery Disease (ASSERT) trial showed that the investigational oral small-molecule RVX-208 achieved dose-dependent increases in apoA-I, HDL, and highly efficient and cardioprotective large-size HDL particles. The increases, however, were considerably more modest than anticipated based upon earlier animal studies, Dr. Stephen J. Nicholls, Ph.D., reported.
Moreover, a safety concern arose in the form of reversible transaminase elevations in 8% of patients treated with the first-in-class apoA-I booster, added Dr. Nicholls of Case Western Reserve University, Cleveland.
All ASSERT participants had stable CAD and were on statin therapy. The median increase in apoA-I from baseline, which was the primary study end point, was 0.1% with RVX-208 at 100 mg/day, 3.8% at 200 mg/day, 5.6% at 300 mg/day, and 0.9% with placebo.
HDL levels showed significant increases of 6.3% with RVX-208 at 200 mg/day and 8.3% with 300 mg/day. Large HDL particles increased by 20.2% over baseline with RVX-208 at 200 mg/day and 21.1% with 300 mg/day.
Most gains in HDL level and large HDL particles occurred in the last third of the trial, with no evidence of a plateau. This raises the possibility that longer-term therapy would result in further increases in the key lipid parameters, Dr. Nicholls noted.
“It's an interesting study. It's encouraging in some ways, discouraging in others,” commented discussant Dr. Eliot A. Brinton of the University of Utah, Salt Lake City.
Although he believes that advancing to a clinical trial of RVX-208 with atherosclerotic end points is “reasonable,” Dr. Brinton added that, in light of the modest efficacy and the safety signal seen in ASSERT, it's “imperative” to find and develop other new inducers of apoA-I synthesis.
“HDL raising is a great concept. HDL is perhaps our best antiatherogenic factor,” he said. “The concept that apoA-I probably knows how to prevent atherosclerosis, so make extra apoA-I and then get out of its way – that's a very attractive strategy for reducing heart disease.”
ASSERT coinvestigator Dr. Steven E. Nissen, chairman of cardiovascular medicine at the Cleveland Clinic Foundation, said in an interview that “there is no way we cannot go forward at this point” to test the hypothesis that boosting HDL functionality and/or quantity will prevent cardiovascular events.
Dr. Nicholls declared that he has received research support from Resverlogix, which sponsored the ASSERT trial, as well as consulting fees and honoraria from a handful of other pharmaceutical companies. Dr. Brinton disclosed that he has received consultation and speaking fees from a dozen pharmaceutical firms. Dr. Nissen has received research support from Resverlogix, AstraZeneca, Eli Lilly, Pfizer, Takeda, Sankyo, and Sanofi-Aventis and has consulted for a number of pharmaceutical companies without financial compensation; all honoraria, consulting fees, or any other payments from any for-profit entity are paid directly to charity, so that neither income nor any tax deduction is received.
HDL changes late in the trial suggest that longer-term therapy could yield further inreases.
Source DR. NICHOLLS