American Heart Association abstract to be presented 11/15 in New Orleans

T1221 / 1221 - Apabetalone (RVX-208) Reduces Expression of Acute Phase Response Markers in vitro and in Patients With Cardiovascular Disease

Authors

Ewelina Kulikowski, Sylwia Wasiak, Dean Gilham, Cyrus Calosing, Laura Tsujikawa, Christopher Halliday, Resverlogix Corp., Calgary, AB, Canada; Mike Sweeney, Jan Johansson, Resverlogix Corp., San Francisco, CA; Norm C. W. Wong, Resverlogix Corp., Calgary, AB, Canada

Abstract

Introduction: Apabetalone (RVX-208) is an inhibitor of the epigenetic regulators bromodomain and extraterminal (BET) proteins, currently in a phase 3 outcomes trial in patients with cardiovascular disease (CVD) and diabetes mellitus. A post-hoc analysis of phase 2b trials demonstrated a 55% relative risk reduction in major adverse cardiac events (MACE) in CVD patients. In vitro, apabetalone modulates expression of genes that underlie CVD, including those in the acute phase response pathway (APR).
Hypothesis: Since APR proteins are inflammatory biomarkers known to correlate with CVD outcomes, apabetalone treatment may downregulate their expression levels in vitro and in patients.
Methods: Microarrays, real-time PCR and ELISA were performed on primary human hepatocytes (PHH). SOMAscan™ proteomic analysis was performed on plasma from the phase 2b ASSERT (12 weeks; n=25) and ASSURE (26 weeks; n=47) clinical trials.
Results: Microarrays of apabetalone treated PHH showed downregulation of the APR pathway. APR genes that correlate with CVD and MACE were suppressed by 20 to 95%, including C-reactive protein (CRP), ceruloplasmin (CP), serum amyloid P (SAP), PAI-1, alpha 2-macroglobulin (A2M), complement C2, C3 and C5, MBL2, serum amyloid A and interleukin 18. Apabetalone decreased the IL-6-induced expression of CP, SAP and A2M, with most striking effects on CRP (-75%). Interestingly, in PHH, CRP mRNA was upregulated two-fold by the pro-inflammatory metabolite trimethylamine N-oxide (TMAO). Apabetalone not only countered this increase, but also decreased the expression of the TMAO producing enzyme FMO3 by 40%. Consistent with these findings, plasma proteomic analysis identified APR as the top downregulated pathway by apabetalone in both clinical trials. Circulating levels of C2, C3, C5, and SAP were significantly decreased, and CRP was downregulated by 43% (p=0.01) and 21% (p=0.02) versus placebo in ASSERT and ASSURE, respectively.
Conclusions: BET inhibition by apabetalone decreases basal and inflammatory transcription of APR biomarkers, which correlate with CVD. Clinical studies demonstrate that apabetalone reduces circulating levels of APR proteins, which may partly contribute to the reduction in MACE in patients with high residual CVD risk.