News | October 02, 2009

Resverlogix RVX-208 Clinical Trial Demonstrates Key Reverse Cholesterol Transport Markers

October 2, 2009 – Resverlogix Corp. said this week results from the company's second clinical trial for the drug RVX-208 showed it increases the production of plasma ApoA-I, the key cardioprotective protein in high-density lipoprotein (HDL). ApoA-I is generally endorsed as a key protective factor against atherosclerosis and cardiovascular disease with 40 percent of all first heart attack patients having low ApoA-I.

Resverlogix's phase 1b/2a study tested RVX-208 for 28 days in three different dosing arms, and met and exceeded expectations by successfully concluding the drug is safe and tolerable. The most pronounced results were demonstrated among those subjects with low HDL cholesterol levels. Low HDL is an important risk factor in coronary and cardiovascular disease patients. Resverlogix will continue to build upon its world leading position in development of novel small molecules that increase ApoA-l production and reverse cholesterol transport (RCT) markers in patients with high vascular risk profiles. RCT is a path by which cholesterol on the arterial wall is transported back to the liver by ApoA-I lipid complexes for excretion. Additional analysis was performed on other key RCT markers, which achieved high levels of statistical significance. The company has established a dosing range that it deems will be safe, well tolerated and effective for phase 2 intravascular ultrasound (IVUS) development trials.

The company said the range of increase in ApoA-l production of all subjects, but in particular low HDL subjects over placebo demonstrated in this study is one of the most significant pieces of data for RVX-208. The manufacturer said the drug exceeded its original expectation for enhancing ApoA-l production in humans.

The Phase 1b/2a trial was a double blind safety and tolerance study, which investigated the pharmacokinetics and also early pharmacodynamics effects of RVX-208. A total of 72 subjects enrolled in the trial. The study had three arms, a low dose arm with 24 subjects, a dose-escalation arm with 24 subjects, and a third high dose arm with 24 subjects. This trial also examined early markers for reverse cholesterol transport such as ApoA-l, HDL-c, pre-beta HDL and alpha HDL subparticles. Approximately half of the subjects had low levels of baseline HDL cholesterol.

Highlights from the study included:

• The primary endpoint, plasma ApoA-I increase compared to placebo, achieved a range in all subjects of 5.1–10.4 percent in all doses at days eight and 28 respectively.

• At the lowest dose of 1mg/kg b.i.d. in subjects with low levels of HDL-c, plasma ApoA-l increases reached statistical significance of 5.7 percent at day eight and 7.8 percent at day 28.

• A critical RCT functionality marker, alpha-1 HDL particles, illustrated highly statistical significance with an increase of 46.7 percent in all subjects and 57.2 percent in the low dose arm over placebo at day 28.

• Pharmacokinetic parameters of RVX-208 were dose dependant with oral administration.

• RVX-208 was shown to be compatible with simvastatin (40 mg). Seventy out of 72 subjects completed the trial. One subject did not complete the trial due to personal reasons and one other subject did not complete the trial due to a serious adverse event, cholecystitis (gall stones), which was judged not related to the study drug.

Based on these important findings, the company now plans to adjust its future dosing. Expanded phase 2 planning is moving forward to include phase 2 IVUS trials, a phase 2 dosing trial and a phase 2 combination statin trial. The IVUS Steering Committee is chaired by Steven Nissen, M.D., chairman of the Cleveland Clinic Department of Cardiovascular Medicine, and the principal investigator is Stephen Nicholls, M.D., medical director of intravascular ultrasound at Cleveland Clinic.

Developing small molecules that increase ApoA-I would satisfy a huge unmet medical need because CVD treatment with statins, the current standard of care, only stabilizes atherosclerosis and reduces cardiovascular risk by 30 percent, the company said. A recent cost-benefit pharmacoeconomic analysis of ApoA-I therapy for CVD estimated that a 1 and 5 percent regression of atherosclerosis would save the U.S. healthcare system and employers between $22.9 billion and $76.8 billion annually over and above statin therapy. The analysis assumes ApoA-I therapy will be given to CVD patients in combination with statins. ApoA-I therapy has the potential to reduce the overall cost of cardiovascular disease, which is estimated in the United States at $475 billion annually, by 5-16 percent.

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