Oral Inducer of ApoA-1 Synthesis RVX-208 Misses End Point But Provides Reasons for Optimism

Reed Miller

November 17, 2010

November 17, 2010 (Chicago, Illinois) — Investigators in a phase 2 study of the first oral agent for raising high-density-lipoprotein cholesterol (HDL-C) through apolipoprotein A1 (apoA-1) synthesis are optimistic that the drug can increase the levels of large HDL particles, even though the trial missed its primary end point of apoA-1 increase.

Dr Stephen J Nicholls

Dr Stephen J Nicholls (Cleveland Clinic, OH), who presented results of ASSERT here at the American Heart Association 2010 Scientific Sessions today, said that there is consensus among the lipids research community that increasing the synthesis of the major protein in HDL-C, apoA-1, is a promising approach to raising HDL-C and thereby reversing cholesterol transport to prevent atherosclerosis. RVX-208 (Resverlogix, Calgary, AB) is the first oral agent that induces synthesis of apoA-1.

Although ASSERT missed its primary end point of percentage change in apoA-1 levels in patients treated with RVX-208 compared with the change in patients given placebo, Nicholls said, "Certainly, the results are encouraging [for] patients with coronary disease. There very well may be lipid mobilization in these patients." The investigators believe that activating production of apoA-1 creates nascent HDL particles that promote cholesterol influx that causes the particles to grow.

The trial was powered based on the estimate that 70 patients in each group would be enough to show patients taking RVX-208 had at least an 8% increase in apoA-1 compared with placebo. Other study objectives included characterizing the dose and time response relationships for apoA-1, measuring major lipid parameters and HDL subclasses, and assessing the safety and tolerability of RVX-208 over the 12-week treatment period.

ASSERT randomized 299 patients with stable coronary artery disease who had been on statin therapy for at least 30 days to take RVX-208--100 mg/daily, 200 mg/daily, or 300 mg/daily--or a placebo for 12 weeks.

The median increase in apoA-1 levels from baseline over the three months of the study was 0.9% in the placebo group, 0.1% for the patients on the 100-mg/daily dose of RVX-208 (p=0.09 compared with placebo), 3.8% for the 200-mg/daily-dose patients (p=0.10 compared with placebo), and 5.6% for the 300-mg/daily-dose group (p=0.06 compared with placebo).

Also, the 200-mg patients and the 300-mg patients showed a 6.3% and 8.3% increase in HDL-C levels, respectively, vs no change in the placebo group (p<0.05 and p<0.01). The 200-mg and 300-mg groups also showed a significant increase in large HDL particles, 20.2% and 21.1%, respectively (p<0.01 and p<0.001), and significant increases in the larger {:alpha:}1 HDL particles of 8.0% and 8.8%, respectively (p<0.05 and p<0.05).

In the safety biomarker analysis, eight patients in the 200-mg/daily-dose group and seven in the 300-mg/daily-dose groups had aspartate-transaminase/alanine-transaminase ratios that were at least at three times the upper level of normal, a possible marker of liver damage, vs none in the placebo group (p=0.009). These transaminase levels returned to the baseline level after the patient stopped taking the drug and were not associated with any observable liver-function impairments. None of the other safety biomarkers, including levels of bilirubin, creatinine, or creatine kinase, reached statistical significance.

Most of the increases in HDL-C and large HDL particles appeared in the last four weeks of the study without any plateau of the effect, "so we're left wondering whether, if we had treated patients for longer, we would in fact have seen a greater increase in terms of these lipid parameters," Nicholls asked.

Trending in the Right Direction, But . . . 

Dr Eliot Brinton

The expert assigned to respond to the ASSERT results, Dr Eliot Brinton (University of Utah, Salt Lake City) agreed that "HDL-raising is a great concept and is perhaps our best atherogenic factor, but it's a very complicated issue." Researchers have developed methods to observe how HDL removes cholesterol from the vessels, blocks oxidation, stops inflammation, and protects the endothelium, "but there are so many functions and there are so many potential ways of looking at this that there's a lot of confusion and no consensus on what to measure and how to measure it," he said. HDL is a very heterogeneous family of particles with a complex metabolic pathway, and the relative importance of its various functions is unknown, Brinton said.

"We're left with an inability to accurately or confidently assess the effect of any intervention to raise HDL levels or to enhance one function or another in terms of its actual impact on atherosclerosis and cardiovascular disease risk," Brinton said. "We cannot assume that apoA-1 synthesis induction will necessarily be antiatherogenic, although it is an attractive target." Furthermore, it's not clear how big of a change in apoA-1 or HDL levels are needed to make a worthwhile impact on cardiovascular disease.

But regardless of exactly how HDL mitigates functions in the coronaries, the research has consistently shown that it can mitigate atherosclerosis, Nicholls said. "Fundamentally, we believe that whether you raise HDL a little bit or a lot--whether the primary biological activity of HDL is lipid mobilization, whether it's the anti-inflammatory effects or the nitrous-oxide effects--HDL will have a beneficial effect on the composition and size of plaque."

Nicholls said his group is currently planning a study of RVX-208 in acute coronary syndrome patients that will rely on intravascular ultrasound study to measure the effects of the agent in the vessel wall. That study is set to begin in 2011. "And, ultimately we'll need a clinical-end-point study. At that point, we'll know if this drug, which targets HDL functionality in a very different way from the [cholesteryl ester transfer protein] CETP inhibitors, will be beneficial."

Anacetrapib Steals Spotlight, But RVX-280 May Have Last Word

On the same day at the AHA meeting, Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA), presented results of the DEFINE trial, which showed that the new CETP inhibitor anacetrapib significantly decreased LDL-cholesterol levels by 36% and increased HDL-C levels by 138% vs placebo, with no increase in systolic blood pressure as was seen with torcetrapib.

Cannon told heartwire that RVX-208 is based on "a neat concept, but there was only a tiny effect, in comparison [with DEFINE] and with side effects."

"I wouldn't sign up for the trial [of RVX-208]," Cannon quipped.

Nicholls pointed out that, in some previous trials, statins and fibrates appeared to improve artery-wall composition or clinical outcomes while increasing HDL levels only modestly, 5% to 7%. "So relatively modest changes in HDL with different approaches may actually be quite beneficial."

And Brinton cautioned against assuming that just because DEFINE showed a large effect for anacetrapib and ASSERT showed a relatively small effect for RVX-208 that anacetrapib will ultimately prove more successful. "There's a lot we don't know about HDL, and there may be things happening that aren't visible with [just the HDL] level. So a drug that has a modest effect on levels could have very potent effects on atherosclerosis, and the way to learn that is to test it going forward because we just don't know," Brinton said. "We could see something very exciting with this drug because of its mechanism." ASSERT and DEFINE can't be directly compared because the drugs have completely different mechanisms of action. "It's possible that RVX-208 will ultimately work better," he said.

An advantage of RVX-208 over some of the previous HDL-raising approaches tried in the past is that it's a small-molecule oral drug as opposed to an infusion, which will be easier to manufacture and administer. "I'm very encouraged about that approach," Brinton said. "RVX-208 is right at the cut line where you say, 'Yeah, I think it's probably worthwhile going ahead.' It's just that the effect is so modest and there's potential toxicity and I'm worried about it, but I'm very excited about the mechanism. I guess I have muted enthusiasm for RVX-208. I think it's got potential and going forward with it is a good idea, but while they're going ahead, the door is wide open for other drugs in the same class and other drugs that address the same question."

ASSERT was sponsored by Resverlogix. Nicholls reported consulting agreements with AstraZeneca, Merck, Anthera, Omthera, Takeda, and Roche and research support from Resverlogiz, Anthera, AstraZeneca, Novartis, Karo Bio, Eli Lilly, and Roche. Brinton reported research grants from Abbott, Aurora Foundation, GlaxoSmithKline, Merck, and the National Institutes of Health and consulting deals with Abbott, Amarin, AstraZeneca, Atherotech, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Kaneka, Kowa, Kronos Longevity Research Institute, Merck, and Takeda. Cannon reports grants from AstraZeneca, Merck, and Roche and is also on the speakers' bureau for Abbott, Bristol-Myers Squibb, and Pfizer.

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