ASSURE study of experimental agent to raise HDL yields 'disappointing and surprising' results

The search continues for an agent that increases high-density lipoprotein (HDL) and reduces arterial plaque, after the experimental apolipoprotein A1 (apoA1) inducer, RVX-208 failed to do so in the ApoA1 Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation (ASSURE) study.

The lack of efficacy of RVX-208 is "disappointing and surprising, given promising earlier findings," noted lead investigator Stephen Nicholls MBBS, PhD, Deputy Director at the South Australian Health and Medical Research Institute, Professor of Cardiology at the University of Adelaide and Consultant Cardiologist at the Royal Adelaide Hospital in Adelaide, Australia.

However, the failure of RVX-208 to incrementally impact atherosclerotic plaque should not be interpreted as a failure of the hypothesis that increasing the level and activity of HDL could result in this benefit, he said.

"RVX-208 represents the first epigenetic foray into the metabolic treatment of cardiovascular disease, and ongoing clinical trials will evaluate the potential cardiovascular efficacy of other agents that target HDL."

ASSURE was a prospective, randomized, double-blind clinical trial carried out at 60 centers.

It randomized 323 patients with low HDL and who had a target blood vessel for imaging with less than 50% stenosis.

All patients received treatment with either 10-40 mg daily or 5-20 mg daily during the study and were also randomized to receive either RVX-208 100 mg (n=244) or placebo (n=80) twice daily for 26 weeks.

The primary and secondary outcomes of the study were change from baseline in percent atheroma volume (PAV) and normalized total atheroma (TAV), both measures of the amount of plaque present in the coronary artery.

Intravascular ultrasonography was used at baseline and the end of the study to measure these outcomes.

Of the 281 patients that remained in the study and had this imaging, while a trend towards plaque regression was observed with RVX-208 compared with baseline, there was no significant difference in efficacy outcomes between the groups, said Dr. Nicholls.

However, there were more discontinuations due to adverse events in the RVX-280 group (3.7% vs. 2.5%) as well as significantly more elevations of liver enzymes at triple the normal limit or more (7.0% vs. 0%, P=0.009).

In terms of efficacy, PAV decreased by 0.40% in the RVX-208 group compared to 0.30% in the placebo group ( P=0.81) and TAV decreased by 4.2 mm3 vs 3.8 mm3 respectively (P=0.86).

HDL cholesterol increased by 10.9% in the RVX-280 group compared to 7.7% in the placebo group (P=0.32), and LDL cholesterol decreased by 16.0% vs 17.6% with placebo (P=0.72).

There were no significant differences in cardiovascular events between the groups (13.8% in the RVX-2008 group vs 7.4% in the placebo; P=0.09), and all liver enzyme elevations occurred within the first 2 months of treatment with spontaneous resolution when the study drug was discontinued.

Additionally, the impact of RVX-208 on apoA1 levels from baseline was not significantly different from placebo (P=0.18). The levels increased by 10.6% (P<0.001 compared with baseline) in the group and 12.8% (P<0.001 compared with baseline) in the RVX-208 group.

"We anticipated that RVX-208 might promote regression of atherosclerotic plaque, however it did not demonstrate this benefit," said Dr. Nicholls. "This is an intriguing therapeutic agent from a small company, and many in the HDL field found it exciting. The preliminary data made them wonder if it would be as good as infusional HDL agents and they elected to test this in a highly provocative fashion, over only 6 months. That is quite a change from the traditional studies of oral agents, which typically take 18-24 months," he explained.

ASSURE's lack of positive findings suggests that oral therapies may need longer to show an effect, he added. "We can't make any extrapolations about what might happen with the drug over a longer period because we did not test this, but if you look at longer trials of established therapies, there is a suggestion that, while there may be some early impact on plaque, significant change does not occur quickly and appears take a longer period of time."

He suggested the negative finding might either reflect lack of efficacy of RVX-208 "or the inability to improve on benefits produced by statins and other background therapies in the study".

"In the quarter century following the introduction of statins to clinical practice there has been an intensive, yet unsuccessful, search to identify new strategies to achieve greater cardiovascular risk reductions," he added. "The search to identify a strategy that promotes HDL functionality, and improve cardiovascular outcomes continues."

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