ACC 2019 abstract are out now.
March 16 Poster: Session 1135 - Vascular Medicine: Basic 1
1135-454 / 454 - Apabetalone, an Epigenetic BET Inhibitor in a Phase 3 Trial, Inhibits Vascular Inflammation and Cellular Adhesion Leading to Beneficial Outcomes in CVD Patients
Abstract
Background: Apabetalone (RVX-208) is a small molecule bromodomain & extraterminal (BET) protein inhibitor, targeting the second bromodomain (BD2) of BET proteins. In cardiovascular disease (CVD) patients enrolled in phase 2 trials apabetalone treatment reduced the relative risk of a CV event by 44% (Nicholls 2017). Elevated cytokines, such as TNFα, promote vascular inflammation (VI) and monocyte adhesion in CVD and Diabetes Mellitus, driving atherosclerosis. Here we test the impact of apabetalone on cell types that contribute to atherosclerosis.
Methods: Human endothelial cells (HUVECs) and THP-1 monocytes were stimulated with TNFα and treated with apabetalone or MZ-1 PROTAC. mRNA (qPCR, Nanostring) and protein levels (FACS, western blot) were compared. HUVEC-THP-1 adhesion assays assessed the functional consequences of TNFα stimulation and apabetalone treatment. The phase 2 ASSURE CVD patient plasma proteome (SomaScan®) was analyzed using Ingenuity® Pathway Analysis (IPA®) to predict canonical and upstream regulator pathways impacted by apabetalone.
Results: Apabetalone repressed transcription of inflammatory and adhesion genes in TNFα-stimulated HUVEC and THP-1 cells. Corresponding HUVEC protein abundance was also reduced. MZ-1 BET protein degradation blocked TNFα responses, indicating BET-dependency. Functionally, apabetalone suppressed monocytic THP-1 cell adhesion to inflamed endothelial cells. CVD patient plasma proteome analysis revealed that apabetalone reduced key players in adhesion (VCAM-1, ICAM-1) and plaque stability (MMP-3, MMP12). IPA® analysis of the clinical proteome data predicted that apabetalone inhibits pro-atherogenic mediators and inflammatory pathways.
Conclusion: Apabetalone attenuates VI through the epigenetic regulation of inflammatory and adhesion gene transcription. Downregulation of VI by apabetalone may contribute to the reduction in CVD events observed in phase 2 studies. The ability of apabetalone to prevent major adverse cardiac events in post-acute coronary syndrome patients with type 2 diabetes mellitus (DM) and low HDL-C is being assessed in phase 3 trial (BETonMACE).
March 18 Poster: Session 1331 - Prevention: Clinical 5
1331-413 / 413 - BET Protein Inhibition and Cognition: A Pre-Specified Substudy of the BETonMACE Phase 3 Trial Evaluating Apabetalone in Patients With Diabetes and Acute Coronary Syndrome
AbstractBackground: Type 2 diabetes (T2D) and cardiovascular disease (CVD) are associated with impaired cognition. Epigenetic dysregulation by bromodomain and extraterminal domain (BET) proteins is implicated in CVD, as well as T2D and dementia. Apabetalone (ABL) is a selective BET inhibitor which in phase 2 trials was associated with a significant 55% reduction in major adverse CV events. Effects of ABL on cognition are unknown.
Methods: The ongoing phase 3 cardiovascular outcomes trial BETonMACE compares ABL (100 mg orally twice daily) with placebo in 2425 patients with recent acute coronary syndrome (ACS), T2D, and low HDL cholesterol, enrolled at 195 sites in 13 countries. The primary outcome is time to first occurrence of CV death, myocardial infarction, or stroke. Cognition, a pre-specified secondary outcome, is assessed at baseline and annually in patients 70 years and older by the Montreal Cognition Assessment (MoCA). MoCA covers several cognitive domains including attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. A score of <25 of 30(31) indicates cognitive impairment. MoCA score change from preliminary blinded data shows a standard deviation of 3.2 points and a sample size of 54 subjects per arm to provide a 90% power to detect a mean between-group difference of 2 points at p<0.05.
Results: Baseline MoCA (versions 7.1, 7.2, and 7.3) was performed in 19% of BETonMACE participants (n=460, mean age 74). Compared with the entire BETonMACE cohort, the MoCA subset is older, comprises more women (35 vs. 25%), has lower eGFR (70 vs. 99 ml/min), and higher neutrophil/lymphocyte ratio (2.80 vs. 2.33) (all p<0.0001). At baseline 53% (n=243) show a MoCA score <25, indicating cognitive impairment. Demographics and basic serum chemistry in the MoCA score <25 population does not differ significantly from the whole MoCA population.
Conclusion: Cognitive impairment, as assessed by MoCA, is common among elderly patients with diabetes and ACS. BETonMACE will determine whether the first-in-class BET-inhibitor ABL affects the time course of cognitive function in these patients, as well as macrovascular CV events.
