esverlogix Corp. today announced that the BET protein inhibitor RVX-208 significantly increased HDL-C (p=0.001), the primary endpoint of the SUSTAIN trial, a phase 2b clinical study. SUSTAIN also successfully met secondary endpoints, showed increases in levels of Apo-AI (p=0.002) and large HDL particles (p=0.02), both believed to be important factors in enhancing reverse cholesterol transport activity. The SUSTAIN trial also showed that 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. 

Epigenetics is the study of processes that enable information encoded in DNA to be expressed. Although DNA encodes the genes, by itself DNA cannot use this data. To use the data within DNA, it must work in concert with proteins. An essential aspect in this collaborative process is that both DNA and proteins are packaged together into chromosomes that reside within the cell's nucleus. There are thousands of different genes encoded within DNA, and, to enable expression of these genes when called upon by the cell requires epigenetic processes.

One of the key epigenetic processes involves modification of chromosomal proteins by acetylation, methylation or phosphorylation, each of which is regulated by specific enzymes. These modified entities serve as bait for other proteins, including BET proteins, to bind to, or "read," these modifications ("the epigenetic code"). As the BET proteins bind, they recruit additional proteins to regulate gene activity. When the gene becomes active, it leads to synthesis of messenger ribonucleic acid (mRNA) followed by translation of mRNA into a specific protein.

In the past decade, progress has been made in understanding the role of epigenetics in human disease. This in-depth understanding has led to the development of medicines directed toward cancer, such as DNA methylation inhibitors and HDAC inhibitors. The discovery that RVX-208 is a BET bromodomain inhibitor adds new momentum to the promise of epigenetic mechanisms as a rich source of new medicines.

The SUSTAIN trial was directed by a clinical steering committee chaired by Dr. Steven Nissen with Dr. Stephen Nicholls serving as Principal Investigator. The committee has approved release of topline findings pending submission of full trial results for publication in a peer-reviewed medical journal.

"Successful completion of the SUSTAIN trial provides Resverlogix with important data regarding improvement in the functionality of the HDL produced by RVX-208," stated Donald McCaffrey, president and chief executive officer of Resverlogix. "Safety data from SUSTAIN reconfirm our belief that early liver signals witnessed in this and previous trials were of a transient nature," Mr. McCaffrey added. "The data support that RVX-208 is suitable for chronic use. The value of this knowledge will benefit our entire epigenetic and bromodomain research program by showing safe versions of epigenetic regulating molecules are indeed achievable. We believe that based on the collective knowledge gained from our recent trials, our company is well positioned as we approach the key plaque regression data expected in our ongoing ASSURE trial."

The phase 2b SUSTAIN trial was conducted in South Africa and led by investigators at the Cleveland Clinic. The study enrolled 176 patients with established atherosclerotic cardiovascular disease (CVD) and low high-density cholesterol (HDL-C). The primary purpose of the SUSTAIN trial was to measure changes in HDL, Apo-AI and other lipid parameters compared with placebo, while also assessing safety over an extended treatment period in the patient population with the largest response to RVX-208 in the phase 2 ASSERT trial. The increase in HDL and Apo-AI observed in the 24-week SUSTAIN trial represents a notable increase over the respective HDL and Apo-AI values reported in the 12-week ASSERT trial.   

RVX-208 is a first-in-class, small molecule that inhibits BET bromodomains. It is currently in clinical study for the treatment of atherosclerosis. RVX-208 functions by removing atherosclerotic 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 increases production of ApoA-I, the key building block of functional high-density lipoprotein (HDL) particles and the type required for RCT. Because they are newly produced, these functional HDL particles are flat and empty and can efficiently remove plaque and stabilize or reverse atherosclerotic disease. RVX-208 is currently being evaluated in phase 2b studies for its ability to reverse and/or stabilize atherosclerotic disease. The drug candidate also has the potential to treat other indications, including neurodegenerative disorders.