Re: Resverlogix presenting at Vascular Discovery 2019 next week
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Top-Line Results for Phase 3 BETonMACE Cardio Outcomes Trial were Announced September 30, 2019
Second poster is now posted on the Resverlogix website. Click here for poster. The summary figure in the lower right portion of the poster provides a simple summary of how inflammatory mediators act on the liver, in a BET protein dependent mechanism, to increase hepatic CRP expression and circulating CRP levels. Apabetalone blocks this transcriptional activation of CRP.
Thursday May 16: 671 - Hepatic Expression of C-Reactive Protein is Epigenetically Regulated by BET Proteins and Inhibited by Apabetalone (RVX-208) in vitro and in CVD Patients. Abstract available here.
"Chronic inflammation contributes to cardiovascular disease (CVD) and is characterized by elevated plasma levels of interleukin (IL)-6, IL-1β and C-reactive protein (CRP). CRP serves as a CVD stratification marker as it correlates with major adverse cardiac events (MACE). Here we show that hepatic induction of CRP in response to chronic cytokine signaling is regulated by epigenetic mechanisms in vitro and in patients. Apabetalone is a small molecule inhibitor of epigenetic readers called bromodomain and extraterminal (BET) proteins that bind to acetylated DNA-associated proteins to regulate inflammatory gene transcription. In vitro, apabetalone attenuated CRP gene and protein expression under basal conditions in cultured primary human hepatocytes (PHH). Moreover, IL-6 and IL-1β mediated induction of CRP expression was also suppressed by apabetalone in both PHH and the HepaRG hepatic cell line (>50%). In HepaRG, PROTAC MZ-1 targeted degradation of BET proteins also reduced cytokine mediated CRP expression (93%), demonstrating that inflammatory expression of CRP is BET-dependent. Short-term cytokine treatment increased occupancy of the BET family member BRD4 on the CRP promoter, which was countered by either apabetalone or a structurally unrelated BET inhibitor JQ1. These data directly link BRD4 to CRP transcription. In a pooled analysis of phase 2 trials ASSERT, SUSTAIN and ASSURE, treatment with apabetalone resulted in a 62% relative risk reduction in MACE in CVD patients with elevated CRP (>2mg/L). In both ASSERT (12 weeks; n=55) and ASSURE (26 weeks; n=94), a comparison of baseline and end-of-study plasma proteome (SOMAscan 1.3K platform) detected a downregulation of inflammatory mediators, including CRP, in apabetalone treated patients versus placebo. Consequently, Ingenuity®-powered bioinformatics analysis of the proteomics data predicted an apabetalone-driven downregulation of inflammatory pathways. Based on this data, we predict that apabetalone reduces CVD associated chronic inflammation, contributing to the reduction in MACE in patients with high residual CVD risk. This is currently being explored in the phase 3 cardiovascular outcomes trial BETonMACE enrolling patients with CVD, type 2 diabetes mellitus and low HDL-c."