Today Dr. Norman Wong, Chief Scientific Officer of Resverlogix presented an oral abstract entitled ‘RVX-208 acts via an epigenetic mechanism to lower major adverse cardiovascular events (MACE) in patients with atherosclerosis and especially in those with diabetes mellitus’ at the annual meeting of the EASD held in Stockholm, Sweden.
The contents of the presentation detailed the continued efforts to understand the beneficial effects of RVX-208 (recently named apabetalone) on top of standard of care therapy in lowering MACE when given to patients with established cardiovascular disease (CVD). In previously completed Phase 2b clinical trials (SUSTAIN and ASSURE), post-hoc analyses showed that RVX-208 markedly reduced the combined MACE.
Our interest to understand the mechanisms by which RVX-208 reduces MACE in the trials comprised of patients with CVD and low levels of high-density lipoproteins (HDL) underlies the studies presented at the EASD. The data presented clearly showed the ability of RVX-208 to raise ApoA-I/HDL by enhancing production, but this effect of the compound was not sufficient to explain the observed reduction in MACE. Therefore, several studies were undertaken to further explore the actions of RVX-208 in lowering CVD risk. Results of new studies involving the use of micro-array technology to survey gene expression in both liver cells and whole blood showed a number of pathways were affected by exposing them in vitro to RVX-208. These studies revealed that the compound affected specific pathways known to be important contributors to CVD risks including; complement, coagulation, inflammation, diabetes pathways, cholesterol synthesis and fatty acid synthesis. These pathways were not only acted upon by RVX-208 in a beneficial fashion but they were amongst the pathways most affected by the actions of the compound. Of particular relevance to the EASD was the finding that in patients who had diabetes mellitus with established CVD and low HDL, RVX-208 use was associated with a serum glucose that was -0.3 mmol/L (n=76) lower while placebo was +0.9 mmol/L (n=43). The absolute difference between the two groups was 1.2 mmol/L and this was significant with a p<0.01.
The results arising from our findings opened our eyes to the benefits of RVX-208, the first selective bromodomain extra-terminal (BET) protein inhibitor being tested for CVD risk reduction. The significance of the data is that this selective BET inhibitor has effects beyond its ability to enhance HDL production. These unexpected actions of RVX-208 on several pathways that impact CVD risk provide potential biologic plausibility to why this compound may reduce MACE in the SUSTAIN and ASSURE trials.