American Society for Nephrology abstract to be presented 11/18 in Chicago

FR-PO1033

Apabetalone Reduces Levels of Key Markers Involved in Vascular Calcification

Ewelina Kulikowski, Dean Gilham, Laura Tsujikawa, Sylwia Wasiak, Kamyar Kalantar-Zadeh, Christopher Halliday, Jan O. Johansson, Michael Sweeney, Norman C.W. Wong.

Background: Apabetalone (RVX-208) treatment lowered alkaline phosphatase (ALP) in CVD patients in phase II studies. Apabetalone inhibits the interaction of BET (bromodomain extra terminal) proteins & acetyl-lysine marks on histone tails. BET proteins control recruitment of transcriptional machinery to coordinate gene transcription of sensitive genes, including factors that contribute to vascular calcification. Vascular calcification is an underlying process in CKD pathogenesis. We examined the effect of apabetalone on markers known to contribute to vascular calcification in vitro & in the clinic.

Methods: Microarrays of human whole blood (WB) & primary human hepatocytes (PHH) treated with apabetalone were analyzed. Expression of vascular calcification markers was evaluated using real-time PCR in PHH & U937 macrophages. Proteomic analysis of plasma samples (n=47 apabetalone; n=47 placebo) from phase II CVD trials was performed using SOMAscan™. SOMAscan™ uses aptamers which are highly specific for their cognate protein, to assess levels of ~1300 proteins.

Results: In WB treated with apabetalone, microarrays showed suppression of a variety of vascular inflammation & calcification factors. Expression of osteopontin (SPP1), a proinflammatory molecule, is reduced in LPS stimulated U937 macrophages (-94%) as well as in PHH (-82%). Expression of additional calcification related genes was also reduced in PHH including ALP, RANKL, CCL2, IL8, OPG & BMP2. In the 26 week ASSURE trial, circulating levels of OPG (associated with higher incidence of arterial calcification) & IBSP (major component of bone matrix) were reduced by 14% & 18% (p<0.05) versus placebo.

Conclusions: BET inhibition by apabetalone decreases expression & circulating levels of markers known to contribute to vascular calcification, which may decrease pathology & mortality in CKD. The potential of apabetalone to treat high-risk diabetes & CKD patients is being explored in the phase III BETonMACE trial. Further, a PK study in severe renal impaired patients is underway.