AHA Abstracts!

November 11, from 10:30 AM to 11:45 AM CST: "Cardiovascular Evaluation of the Selective BET Inhibitor, Apabetalone, in ACS Patients With Diabetes: Baseline Characteristics of the BETonMACE CV Outcomes Study." 

Abstract

Introduction: Vascular perturbation in acute coronary syndrome (ACS) is linked to inflammation. Bromodomain and extraterminal (BET) proteins coordinate gene transcription following inflammatory insult. Apabetalone (ABL) selectively inhibits binding between BET proteins and acetyl-lysine marks on histone tails reducing the effects of inflammation. Post-hoc analysis of phase IIb trials with ABL demonstrated a 55% RRR in major adverse cardiac events (MACE) in patients with coronary heart disease , with more pronounced benefit among patients with diabetes (DM) and low HDL cholesterol (HDL-C).
Hypothesis: BETonMACE is the first Phase III cardiovascular (CV) outcome study with a BET inhibitor. It tests the hypothesis that ABL reduces MACE in patients with T2D, recent ACS, and low HDL-C.
Methods: At 195 centers in 13 countries, BETonMACE includes patients with ACS during the preceding 7-90 days, DM, HDL-C <40 mg/dL (males) or <45 mg/dL (females), and treatment with atorvastatin 40-80 mg, rosuvastatin 20-40 mg daily, or the maximum tolerated dose of these agents. Qualifying patients were randomized 1:1 to treatment with ABL 100 mg orally twice daily or placebo. The primary endpoint is time to first occurrence of CV death, non-fatal myocardial infarction or stroke. The trial will continue until at least 250 patients have a primary endpoint. With an assumed event rate of 10.5% in the placebo group over 1.5 years, 2400 patients provide 80% power to detect a 30% reduction in MACE with ABL.
Results: Enrollment of 2418 patients was completed on Mar 6, 2018. Baseline characteristics include: male sex 74.5%; mean age 61 (SD 9.5) years; median (interquartile range) LDL-C 65.0 (36) mg/dL, HDL-C 33.0 (7) mg/dL, HbA1c 7.3 (2.3) %, and blood pressure 129/76 mmHg; eGFR<60 ml/min 11%; treatment with atorvastatin (40/80mg) or rosuvastatin (20/40mg) 91.6%; dual anti-platelet therapy 85%; index ACS event MI 75% ; coronary revascularization for index ACS 78%; and median time from index ACS to randomization 34 days.
Conclusions: BETonMACE is a unique proof-of-concept trial that will determine if selective BET inhibition with ABL, added to evidence-based treatments, reduces MACE in high-risk patients with DM, recent ACS, and low HDL-C. Results are expected early 2019.

November 12, from 1:00 PM – 2:15 PM CST: "Apabetalone (RVX-208) Suppresses Expression of Key Vascular Inflammation Markers in Monocytes, Endothelial Cells and LPS-Challenged Mouse Liver and Monocyte Adhesiveness to Activated Endothelial Cells."

Abstract

Apabetalone (RVX-208), a small molecule bromodomain & extraterminal (BET) protein inhibitor that selectively targets the second bromodomain (BD2), ameliorates vascular perturbation including vascular inflammation (VI). A phase 3 trial (BETonMACE) is being conducted to evaluate apabetalone’s ability to prevent major adverse cardiac events in post-acute coronary syndrome patients with type 2 diabetes mellitus (DM) and low-HDL-C. Cardiovascular disease (CVD) patients enrolled in phase 2b trials demonstrated a 44% relative risk reduction in CVD events with apabetalone treatment (Nicholls 2017). In CVD and DM, elevated cytokines drive VI. TNFα activation of NF-κB is linked to the induction of inflammatory and adhesion marker expression (Pierce 1988, Baltimore 2011). Apabetalone treatment did not prevent TNFα-induced translocation of NF-κB subunit p65 to the nucleus in endothelial cells (HUVECs) but did inhibit the transcription of genes regulated by p65. These include cell adhesion molecules (CD44, E-selectin, VCAM-1 and MCP-1) and inflammatory cytokines (IL-6, IL-8, IL-1β, and CSF2). At the protein level VCAM1, CCL2, and E-selectin expression was also suppressed. In TNFα-stimulated monocytes (THP-1 cells), apabetalone also reduced the upregulation of inflammatory and adhesion molecule expression (CCR1, CCR2, IL-1β, MCP-1, MYD88, TLR4, TNFα, and VLA-4). In vivo, leukocytes adhere to an inflamed endothelium where they extravasate into arterial walls and initiate atherosclerotic plaque formation. In our in vitro assays, apabetalone suppressed monocytic THP-1 cell adhesion to inflamed endothelial cells under both static (HUVEC) and flow (HAEC) conditions. Acute endotoxemia is associated with activation of liver macrophages and endothelial cells and infiltration of immune cells. In mice exposed to 50 ug of LPS for 24h, apabetalone reduced liver mRNA marker expression for infiltrating monocytes, activated macrophages, and cellular adhesion (CCR2, ICAM and P-selectin). Our data indicate that apabetalone attenuates VI through the regulation of transcription. Downregulation of VI by apabetalone may contribute to the reduction in CVD events observed in phase 2 studies. This hypothesis is being tested in the ongoing BETonMACE phase 3 trial.