AMSTERDAM – A novel oral drug that raises HDL cholesterol levels by upregulating hepatic synthesis of apolipoprotein A1 failed to significantly reduce coronary atheroma volume in a large phase II study.
The lack of efficacy for the drug known as RVX-208 in the ASSURE trial (ApoA1 Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation) was "disappointing and surprising, given promising earlier findings," Dr. Stephen J. Nicholls observed in presenting the trial results at the annual congress of the European Society of Cardiology.
The study involved 323 patients with symptomatic coronary artery disease and low HDL cholesterol who were randomized 3:1 to 26 weeks of RVX-208 at 100 mg twice daily or placebo. All subjects were on atorvastatin or rosuvastatin. The RVX-208 group experienced a mean 10.9% increase in HDL over baseline, a 12.8% rise in ApoA-1, and a 16% drop in LDL. But these beneficial lipid changes weren’t significantly different than in the placebo group, which showed a 7.7% increase in HDL, a 10.6% bump in ApoA-1, and a 17.6% fall in LDL.
The primary study endpoint was change from baseline in atheroma volume. The median drop was 40% in the RVX-208 group and not statistically different from the 30% decrease in placebo-treated controls. Nor was there a significant difference between the two study arms in reduction in atheroma volume within the most-diseased 10-mm coronary segment, reported Dr. Nicholls, professor of medicine at the University of Adelaide and deputy director of the South Australian Health and Medical Research Institute.
Moreover, RVX-208 was associated with liver enzyme elevations in the great majority of treated patients, exceeding three times the upper limit of normal in 7.1% of them.
"This drug had been developed with the thought that it would be a potent oral compound from the perspective of an HDL therapeutic and would be comparable to the HDL infusional approaches that were previously seen to regress plaque. That’s clearly not the case. We saw no biochemical or plaque improvement whatsoever above and beyond the placebo group. So RVX-208 does not appear to be a potent approach to HDL therapeutics," Dr. Nicholls concluded.
Nonetheless, he expressed some regret that the trial hadn’t been designed to be lengthier. It’s possible that with another 6 months or more of treatment the trends favoring the investigational agent might have achieved statistical significance.
Asked if the negative result in ASSURE, coming on top of a steady flow of consistently negative clinical trials for niacin, torcetrapib, and other HDL-raising agents, means that the HDL-raising hypothesis of cardiovascular prevention is dead, Dr. Deepak L. Bhatt replied, "I think that’s a good question. The hypothesis has always been a good one, but I believe that in patients who are statin treated, no one has really shown an incremental benefit of HDL-raising. Of course, there are older data in patients not on statins to show that drugs like niacin are useful, but these drugs also have an effect on other lipid parameters, like LDL.
"It does appear that low HDL is a risk marker. But it may not be a modifiable risk factor. I think for the time being, the HDL hypothesis remains a hypothesis with a lot of holes in it. Moving forward, we’ll probably have more to gain by reducing LDL incrementally beyond the levels obtained with statins than with solely trying to raise HDL, unless those HDL-raising compounds we study in the future also have LDL-reduction or other properties," added Dr. Bhatt, professor of medicine at Harvard Medical School, Boston, and chief of cardiology at Veterans Affairs Boston Healthcare System.
Dr. Nicholls conceded that "this continues to be a field with a lot of uncertainty." But he asserted "there continues to be immense interest in the development of therapies targeting HDL."
Noting that, in ASSURE, RVX-208 wasn’t significantly better at raising HDL than was state-of-the-art background medical therapy including statins in the placebo arm, he said, "I think we haven’t really tested the HDL hypothesis yet." Advancing an investigational agent to phase III testing with clinical outcomes will require that the drug first demonstrate atheroma regression in a solid phase II study, he added.
The ASSURE trial was sponsored by Resverlogix. Dr. Nicholls has received research support from, and serves as a consultant to, Resverlogix and more than half a dozen other pharmaceutical companies.