The Resverlogix rollercoaster ride continues. Cholesterol drug RVX-208 failed to raise levels of a protein believed to help clear plaque from clogged heart arteries in a mid-stage trial, although the company expects to move ahead with more research into the compound’s biological effects.
Despite the Canadian company’s attempts to put a positive spin on the news – the study did see a significant rise in HDL, or "good cholesterol" – investors were wholly underwhelmed; shares have lost more than half their value in the last two days. Resverlogix see signals positive enough to justify continued mid-stage testing on the compound, but a partner or more funding is sorely needed.
RVX-208 signals the body to produce increased levels of apolipoprotein A1 (apoA-1), the chief protein found in high-density lipoprotein (HDL) molecules, the so-called “good cholesterol”. These molecules carry atherosclerotic plaque from the arteries to the liver, a process called reverse cholesterol transport. Thus, increasing HDL levels by boosting levels of the precursor molecule ApoA-1 is one strategy being pursued to fight cardiovascular disease.
The Assert trial measured increases in ApoA-1 at three different dosage levels against placebo in 300 statin-treated patients with stable coronary artery disease. Whilst RVX-208 resulted in numerical increases in the protein, statistical significance was not met. At the two highest dosages, RVX-208 did result in statistically significant increases in HDL, said chief investigator Dr Stephen Nicholls, clinical director of the Cleveland Clinic Center for Cardiovascular Diagnostics and Prevention.
“We think that is consistent with mobilisation of lipids.” Dr Nicholls said
The trial also found an increase in the number of subjects experiencing elevated liver enzymes, although this was reversed when patients were taken off the medication. This signal will be a worry for investigators, although Resverlogix chief executive, Donald McCaffrey, was keen to stress the positive, pointing out that the liver plays in key role cholesterol metabolism.
“We really did want to see liver enzyme (elvatation),” Mr McCaffrey said in an investor call. “If you don’t see elevation in liver enzymes your drug is not working.”
Other researchers gave a more muted review.
“It’s an interesting study,” Dr Elliot Brinton, associate professor at the University of Utah medical school, said of the study. “It’s encouraging in some ways and discouraging in other ways. I think it is imperative to look for other drugs in this class and other ways of increasing ApoA-1 synthesis.”
Based on the results, Dr Brinton said, “I think it’s reasonable to do an atherosclerosis endpoint trial.”
This is exactly what Resverlogix has in store for the candidate. In the first quarter of 2011, a trial in patients with acute coronary syndrome measuring plaque regression via ultrasound will start enrolling. Called Assure-1, the study will be of a similar size to Assert and run for about 12 weeks
That the study is a phase II trial indicates Resverlogix does not yet have the confirmation necessary to move RVX-208 into the pivotal stage of development. And even after two equity offerings amounting to C$19.2m in June, the Calgary company finished July with only C$15.5m in cash, which will not last long while a phase II trial is being funded.
In the context of the unexpected win by Merck & Co candidate anacetramib, which showed efficacy at both raising HDL and lowering low-density lipoproteins (LDL), the so-called “bad cholesterol,” the mixed results for RVX-208 was clearly a let down for Resverlogix investors (AHA 2010 – A defining moment for CETP inhibitors, November 17, 2010). Company executives, however, were putting a positive light on the results.
“We are thrilled to be moving forward with this trial and can show that we are removing plaque from the arterial wall,” Mr McCaffrey said.
Investors seem less thrilled, and appear to be reading events as an exit sign. Indeed, if Resverlogix cannot find the big pharma partner it aims to secure within the next year, investors will end up footing the clinical bill.
|Trial ID||NCT01058018 (Assert)|