September 02, 2013

AMSTERDAM — A novel drug that induces production of the HDL precursor protein apolipoprotein A1 (apoA1) failed to show significant regression of atherosclerosis vs placebo in the ASSUREstudy.

Dr Stephen Nicholls

Presenting the results at the European Society of Cardiology (ESC) 2013 Congress today, Dr Stephen Nicholls (Royal Adelaide Hospital, Australia) said the results with RVX-208 (Resverlogix) were "disappointing and surprising, given promising earlier findings."

However, he stressed that because of an unusually large placebo effect, no significant difference in lipoprotein changes were seen with the new drug, meaning that the study had not tested the HDL hypothesis.

"With just a 26-week treatment period, this was a short study for an oral agent. As HDL infusions have shown impressive atherosclerosis regression in just a few weeks, we were hoping to see similar effects with this first oral agent to induce hepatic synthesis of apoA1, the precursor to new HDL particles. But this was not to be the case."

The primary end point of the study--change from baseline in percent atheroma volume--just failed to meet significance (p=0.08) in the RVX-208 group, as did the secondary end point (normalized total atheroma). There were numerically fewer cardiovascular events, but the study was not powered for this end point, so this was also not statistically significant. And RVX-208 was also associated with increases in liver enzymes.

Nicholls said he had three take-home messages:

This agent was developed as a potent oral compound comparable to HDL infusion but has not turned out not be so.

The placebo group did very well --this highlights the importance of treating patients well. These patients were seen regularly throughout the study and risk factors treated.

There is trend toward regression at six months, but longer treatment is probably needed to show an effect.

ASSURE randomized 323 patients with low HDL and coronary disease who had a target blood vessel for imaging with less than 50% stenosis. All patients received treatment with either atorvastatin 10-40 mg daily or rosuvastatin (Crestor, AstraZeneca) 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. Atherosclerosis was assessed by intravascular ultrasound (IVUS) at baseline and the end of the study.

Both groups showed increases in HDL and reductions in LDL, as well as trends toward a regression of atherosclerosis.

ASSURE: Main Results

Outcome RVX-208 Placebo p between groups
HDL (%) +10.9 +7.7 0.32
LDL (%) -16.0 -17.6 0.56
Change in percent atheroma volume (%) -0.40 -0.30 0.81
Change in atheroma volume (mm3) -4.2 -3.8 0.86
Cardiovascular events (%) 7.4 13.8 0.09

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). All liver enzyme elevations occurred within the first two months of treatment and resolved spontaneously when the drug was discontinued.

Nicholls would not be drawn out on whether future studies would be conducted with RVX-208. He commented to heartwire : "We will have to look at the data more closely to see if there were any groups where HDL and apoA1 did go up more than placebo. But even without the placebo effect, the comparison vs baseline still didn't reach the primary end point. At the end of the day it does not seem to be as potent as we hoped. This is a highly controversial area. Are we ever going to develop an HDL drug that works? We really need a home run in this field. To achieve that we need the right drug acting on the right target. It is tough to see how this drug will be the answer."

Another Blow for the HDL Field

The ASSURE trial is the latest in a long line of disappointing clinical results with drugs aiming to raise HDL. Answering a question as to whether the HDL hypothesis was now dead, Dr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA) said: "It is a good hypothesis, but so far no one has shown any incremental benefit of raising HDL in patients already well treated with statins. And Mendelian studies have not shown an association of HDL with outcomes, suggesting it may be a marker rather than a causal risk factor. So it is a hypothesis with lots of holes in it."

But Nicholls responded that the HDL hypothesis has not been tested properly yet. "The only agents that have addressed the hypothesis directly are the HDL infusions, which have shown a rapid regression of atherosclerosis. So I would not say the HDL hypothesis is dead. But these products haven't progressed to large-scale clinical trials yet, largely because of formulation issues. HDL is not as simple as LDL. Unlike LDL, it appears that the functionality of HDL is more important than actual levels of HDL. The strategy of how we alter HDL is important, and we don't know which strategies are the best ones yet."

The study was sponsored by Resverlogix. Nicholls reports research support from AstraZeneca, Amgen, Anthera, Eli Lilly, Novartis, Resverlogix, InfraReDx, Roche, and LipoScience and consulting for/honoraria from AstraZeneca, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi, CSL Behring, Esperion, and Boehringer Ingelheim.

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