Clinical trial summary
Tried to post this before but failed. Was long but gave up.
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.
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