RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease

AbstractHigh density lipoproteins (HDL), through activity of the main protein component apolipoprotein A-I (ApoA-I), can reduce the risk of cardiovascular disease (CVD) by removing excess cholesterol from atherosclerotic plaque. In this study, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor RVX-208 increases ApoA-I gene transcription and protein production in human and primate primary hepatocytes. Accordingly, RVX-208 also significantly increases levels of ApoA-I, HDL-associated cholesterol, and HDL particle number in patients who received the compound in recently completed phase 2b trials SUSTAIN and ASSURE. Moreover, a post-hoc analysis showed lower instances of major adverse cardiac events in patients receiving RVX-208. To understand the effects of RVX-208 on biological processes underlying cardiovascular risk, we performed microarray analyses of human primary hepatocytes and whole blood treated ex vivo. Overall, data showed that RVX-208 raises ApoA-I/HDL and represses pro-inflammatory, pro-atherosclerotic and pro-thrombotic pathways that can contribute to CVD risk

Data on gene and protein expression changes induced by apabetalone (RVX-208) in ex vivo treated human whole blood and primary hepatocytes

Apabetalone (RVX-208) inhibits the interaction between epigenetic regulators known as bromodomain and extraterminal (BET) proteins and acetyl-lysine marks on histone tails. Data presented here supports the manuscript published in Atherosclerosis “RVX-208, a BET-inhibitor for Treating Atherosclerotic Cardiovascular Disease, Raises ApoA-I/HDL and Represses Pathways that Contribute to Cardiovascular Disease” (Gilham et al., 2016) [1]. It shows that RVX-208 and a comparator BET inhibitor (BETi) JQ1 increase mRNA expression and production of apolipoprotein A-I (ApoA-I), the main protein component of high density lipoproteins, in primary human and African green monkey hepatocytes. In addition, reported here are gene expression changes from a microarray-based analysis of human whole blood and of primary human hepatocytes treated with RVX-208. Keywords: Bromodomain, BET proteins, BET inhibitor, RVX-208, JQ1, Vascular inflammation, ApoA-I, Apolipoprotein A-I, African green monkey, Primary human hepatocytes, Gene expression, Microarray

A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer

PurposeZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).Patients and methodsPatients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).ResultsSeventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post-ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6-12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0-7.8). Median duration of treatment was 3.5 months (range, 0-34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).ConclusionsZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity