The most abundant protein in HDL is ApoA-I and it serves as the building block for high-density lipoprotein (HDL or the "good cholesterol") particles. Increased production of ApoA-I protein will result in the synthesis of new HDL particles. These newly synthesized HDL particles are more' functional' because of their ample capacity to remove cholesterol from atherosclerotic plaques. The efflux of cholesterol from the plaque to HDL is called reverse cholesterol transport (RCT). The goal of enhanced RCT with newly synthesized HDL is to remove cholesterol from plaque in the arteries, subsequently regressing atherosclerosis. ApoA-I production therapeutics are the only technologies to date to efficiently remove and regress atherosclerotic plaque in high risk CVD patients.
Reverse cholesterol transport (RCT) is the natural process within the body that describes how HDL removes cholesterol from atherosclerotic plaques found in the wall of arteries. Cholesterol removed from the plaque is transported on the HDL particle to the liver for excretion from the body in the bile. Newly synthesized HDL particles are flat and empty and thus have the most function in mediating RCT.
RVX-208 is a first-in-class, small molecule that inhibits BET bromodomains. It is currently being evaluated in a phase 2b clinical trial for its ability to reverse and/or stabilize atherosclerotic disease. RVX-208 acts to increase the production of ApoA-I protein which in turn is used to make new high-density lipoprotein (HDL) particles. These functional HDL particles are flat and empty and can efficiently remove plaque via reverse cholesterol transport (RCT), the natural process through which atherosclerotic plaque is transported out of the arteries and removed from the body by the liver.
RVX-208 acts via an epigenetic mechanism leading to enhanced activity of the ApoA-I gene resulting in increased production of the protein. RVX-208 works by binding to a target called a BET protein. Within the BET protein there are two specialized regions known as bromodomains. Each bromodomain can recognize and bind to an acetylated lysine. This modified amino acid is found in histones bound to DNA. When a BET protein, through the actions of a bromodomain, finds an acetylated lysine and binds to it, this epigenetic process is called 'reading'. When RVX-208 binds to the BET protein, it triggers a cascade of events leading to increased ApoA-I gene transcription and eventually production of the protein. RVX-208 is the first in this class of compounds to enter into clinical development. Clinical experience with RVX-208 demonstrates that BET inhibitors can be both safe and efficacious when given chronically.
RVX-208 has successfully completed a Phase 2b clinical trial 'SUSTAIN' and a second Phase 2b trial 'ASSURE' is ongoing.
In this Phase 2b clinical trial of 176 patients with established atherosclerotic CVD, RVX-208 significantly increased HDL-C, the primary endpoint. SUSTAIN also successfully met secondary endpoints, showed increases in levels of Apo-AI and large HDL particles, both believed to be important factors in enhancing reverse cholesterol transport activity. The SUSTAIN trial also showed that RVX-208 was safe when given daily for 6 months and increases in alanine aminotransferase (ALT) reported in previous trials were infrequent and transient with no new increases observed beyond week 12 of the 24-week trial.
ASSURE is a Phase 2b clinical trial that will evaluate the ability of RVX-208, to regress atherosclerotic disease versus placebo using intravascular ultrasound (IVUS) technology in patients with high-risk CVD. ASSURE is a 26-week, multi-center, double-blind, randomized, parallel group, placebo-controlled clinical trial. The primary trial endpoint will be the change in percent atheroma volume from baseline to 26 weeks measured by IVUS. Secondary objectives for ASSURE are evaluating the safety and tolerability of RVX-208 and effects of RVX-208 on HDL and non-HDL lipid parameters. IVUS technology will also be used to evaluate the changes in plaque stability, an important factor affecting risk of myocardial infarction. Over 310 patients have been enrolled of which 25% will receive placebo and 75% given 100 mg of RVX-208 twice daily.
ASSURE enrollment was completed September 2012. Data is expected in the first half of 2013.
All clinical trials are led by the Cleveland Clinic.
Following the phase 2b program, phase 3 clinical outcomes trials are planned. They will encompass high risk patients with coronary artery disease and with low baseline HDL. In addition, these patients will have at least one more risk factor such as diabetes, smoking or high blood pressure. These trials are often designed with a certain number of events to be observed such as cardiovascular death, non-fatal myocardial infarction, stroke or re-vascularization.
Apabetalone (RVX-208) is a first-in-class small molecule that inhibits BET bromodomain proteins. The Phase 3 clinical trial BETonMACE is advancing with a primary endpoint of time to first occurrence of Major Adverse Cardiac Events (MACE) in high-risk cardiovascular disease (CVD) patients with type 2 diabetes mellitus and low high-density lipoprotein (HDL).