Novel BET-inhibitor affects several pathways that may reduce CVD risk via a single targetGilham D et al., Atherosclerosis. 2016
RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease
Gilham D, Wasiak S, Tsujikawa LM et al.,
Atherosclerosis. 2016 Jan 22;247:48-57.
BackgroundRecent studies have suggested that raising concentrations of HDL is not sufficient to reduce CVD risk . Attention has now shifted to increasing HDL functionality to augment reverse cholesterol transport (RCT). Cholesterol efflux capacity may better predict CV events than HDL-c levels [1,2].
RVX-208 is an orally active small molecule that increases ApoA-I transcription through an epigenetic mechanism, mediated by bromodomain and extra-terminal domain (BET) protein 4 (BRD4) [3-6]. In preclinical studies, it has been shown to increase plasma ApoA-I, HDL-c (pre-beta and alpha HDL) and to enhance the ability of serum to efflux cholesterol . After 12 weeks of treatment with RVX-208 on top of statins in patients with stable CAD, increases of HDL-c and large HDL was seen, suggesting elevated production of ApoA-I and efflux of cholesterol to nascent HDL particles .
RVX-208 prevents the interaction of the bromodomains on BET proteins with acetylated lysines on histone tails [6,7]. RVX-208 selectively binds to the second bromodomain (BD2), leading to differential effects on gene expression as compared to pan BET inhibition (BETi) .
This study examines the effects of RVX-208 on ApoA-I gene expression and protein synthesis, and on markers of CVD risk in various ways. It includes a retrospective analysis of two randomised, double-blind, placebo-controlled phase 2b studies (SUSTAIN and ASSURE)  in patients with CAD, which evaluated 6 months of treatment with RVX-208 on biomarkers and the incidence of major adverse cardiac events (MACE: death, nonfatal MI, coronary revascularisation and hospitalisation for unstable angina or HF).
- In different primary hepatocyte lines, exposure to RVX-208 increased ApoA-1 mRNA in a time- and dose-dependent manner.
Hepatocytes treated with pan-BETi also showed increased ApoA-1 transcription.
- Protein level analysis in spent media from hepatocyte cultures showed a modest increase of proApoA-1 (reflects recently synthesised and secreted protein) and total ApoA-1.
- In pooled data of the SUSTAIN and ASSURE trials, RVX-208 treatment led to significant average increases in HDL-c (7.69%), ApoA-I (10.3%), large HDL particles (30.7%) and average HDL particle size (1.16%), as compared with placebo.
No differences were seen in blood pressure, hsCRP and glucose between treatment groups.
- MACE was observed in 17/168 (10.1%) in the placebo group and in 18/331 (5.4%) RVX-208 treated patients, respectively.
- Microarray analyses of RVX-208-treated hepatocyte cultures revealed downregulation of several pathways linked to processes known to affect CVD risk. Affected pathways include the complement cascade, fibrin clotting, acute phase response, cholesterol synthesis, fatty acid synthesis and diabetes pathways.
- RVX-208-treated whole blood showed downregulated expression of factors that control immune cell migration and activation in atherosclerotic plaque.
8 out of 18 anti-atherogenic genes were upregulated in response to RVX-208.
- To confirm the microarray findings, selected protein levels were measured in plasma samples of RVX-208-treated patients, collected in the ASSURE trial, and compared with baseline pulmonary and activation-regulated cytokine (CCL18) was reduced by 22%, Il-18 by 10%, IL-12 subunit p40 by 6%, and ICAM-1 by 7%.
ConclusionVarious types of evidence suggest that the novel BETi RVX-208 yields increased production of ApoA-1 protein and HDL particles that are efflux-competent. The observed reduction in MACE was more pronounced than predicted based on the effects on ApoA-1 and HDL, suggesting that RVX-208 has other effects that could impact CVD risk. Indeed, microarray analysis revealed that several pathways underlying CVD were affected, among which reverse cholesterol transport, atherogenesis, thrombosis and vascular inflammation.
Find this article online at Atherosclerosis
1. A. Rohatgi, A. Khera, J.D. Berry, et al. HDL cholesterol efflux capacity and incident cardiovascular events, N. Engl. J. Med. 371 (2014) 2383e2393.
2. A.V. Khera, M. Cuchel, M. de la Llera-Moya, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis, N. Engl. J. Med. 364 (2011) 127e135.
3. S.J. Nicholls, A. Gordon, J. Johannson, C.M. et al. ApoA-I induction as a potential cardioprotective strategy: rationale for the SUSTAIN and ASSURE studies, Cardiovasc Drugs Ther. 26 (2012) 181e187.
4. S.J. Nicholls, A. Gordon, J. Johansson, et al., Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial, J. Am. Coll. Cardiol. 57 (2011) 1111e1119.
5. K.G. McLure, E.M. Gesner, L. Tsujikawa, O.A. et al. Young, RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain Antagonist, PloS One 8 (2013) e83190.
6. S. Picaud, C. Wells, I. Felletar, D. et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain, Proc. Natl. Acad. Sci. U. S. A. 110 (2013) 19754e19759.
7. P. Filippakopoulos, S. Picaud, M. Mangos, et al, Histone recognition and large-scale structural
analysis of the human bromodomain family, Cell 149 (2012) 214e231.