ApoA-I Induction as a Potential Cardioprotective Strategy: Rationale for the SUSTAIN and ASSURE Studies

Nicholls, Stephen J.; Gordon, Allan; Johannson, Jan; Ballantyne, Christie M.; Barter, Philip J.; Brewer, H. Bryan; Kastelein, John J.P.; Wong, Norman C.W.; Borgman, Marilyn; Nissen, Steven E.

doi:10.1007/s10557-012-6373-5

Cited by 84 publications

(50 citation statements)

References 46 publications

(48 reference statements)

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“…1A) has been developed by Resverlogix Corporation for the treatment of cardiovascular diseases associated with atherosclerosis (27,28) and has more recently entered clinical studies on Alzheimer's disease (29). RVX-208 is a derivative of the plant polyphenol resveratrol (3,4',5-trihydroxy-transstilbene) that leads to an increase of plasma levels of the high-density lipid protein ApoA1.…”

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confidence: 99%

“…RVX-208 is a derivative of the plant polyphenol resveratrol (3,4',5-trihydroxy-transstilbene) that leads to an increase of plasma levels of the high-density lipid protein ApoA1. Increasing ApoA1 levels has emerged as a promising approach for the treatment of atherosclerosis (30), and recent phase IIb clinical trial data using RVX-208 as an ApoA1 modulator have been encouraging (28). ApoA1 expression is regulated by BET proteins, and chemical inhibition of BET bromodomains has been associated with ApoA1 up-regulation on transcriptional and protein levels (9,31,32).…”

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confidence: 99%

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RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain

Picaud

Wells

Felletar

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

404

406

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Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here, we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2s). Cocrystal structures revealed binding modes of RVX-208 and its synthetic precursor, and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene-expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation.small molecule inhibitor | epigenetics | microarray | ApoA1

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confidence: 99%

mentioning

confidence: 99%

RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain

Picaud

Wells

Felletar

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

404

406

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“…The ASSURE (ApoAI Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation) trial examined the effect of 26 weeks of treatment with RVX-208 on the progression of coronary atherosclerosis as assessed by intravascular ultrasound (IVUS) in 323 subjects with symptomatic CAD and low HDL-C levels. 44 No significant change in plaque regression was observed between placebo and the RVX-208 group. Furthermore, the drug did not increase apoAI or HDL-C levels, but it induced transaminase elevations.…”

Section: Hdl Therapiesmentioning

confidence: 90%

From Lipids to Inflammation

Shapiro

Fazio

2016

Circulation Research

177

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Abstract:The introduction of statins ≈30 years ago ushered in the era of lipid lowering as the most effective way to reduce risk of atherosclerotic cardiovascular disease. Nonetheless, residual risk remains high, and statin intolerance is frequently encountered in clinical practice. After a long dry period, the field of therapeutics targeted to lipids and atherosclerosis has entered a renaissance. Moreover, the demonstration of clinical benefits from the addition of ezetimibe to statin therapy in subjects with acute coronary syndromes has renewed the enthusiasm for the cholesterol hypothesis and the hope that additional agents that lower low-density lipoprotein will decrease risk of atherosclerotic cardiovascular disease. Drugs in the orphan disease category are now available for patients with the most extreme hypercholesterolemia. Furthermore, discovery and rapid translation of a novel biological pathway has given rise to a new class of cholesterol-lowering drugs, the proprotein convertase subtilisin kexin-9 inhibitors. Trials of niacin added to statin have failed to demonstrate cardiac benefits, and 3 cholesterol ester transfer protein inhibitors have also failed to reduce atherosclerotic cardiovascular disease risk, despite producing substantial increases in HDL levels.

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“…It is of note that the transaminase increase in the ASSERT trial was primarily observed in simvastatin-treated patients, and patients on simvastatin will therefore be excluded from the other phase IIb studies. 69 On June 27, 2013, Resverlogix reported that the ASSURE trial did not meet its primary end point of −0.6% atheroma volume regression. The RVX-208-treated group had −0.4% regression in atheroma volume (P=0.08).…”

Section: Apoa-1 Inductionmentioning

confidence: 99%

Novel Therapies Focused on the High-Density Lipoprotein Particle

Capelleveen

Brewer

Kastelein³

et al. 2014

Circulation Research

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Cardiovascular disease (CVD) remains a major burden for morbidity and mortality in the general population, despite current efficacious low-density lipoprotein-cholesterol–lowering therapies. Consequently, novel therapies are required to reduce this residual risk. Prospective epidemiological studies have shown that high-density lipoprotein-cholesterol (HDL-C) levels are inversely correlated with cardiovascular disease risk, and this initiated the quest for HDL-C–increasing therapies. Consequently, several different targets in HDL metabolism have been identified. Initial studies addressing the effect of cholesteryl ester transfer protein inhibition on cardiovascular disease outcome have been discontinued for reasons of futility or increased mortality. As of yet, 2 cholesteryl ester transfer protein inhibitors are still in phase III studies. Other HDL-based interventions, such as apolipoprotein A1–based compounds, ABC-transporter upregulators, selective peroxisome proliferator–activated receptor modulators and lecithin-cholesterol acyltransferase–based therapy, hold great promise for the future. The aim of this review is to provide a comprehensive overview of HDL-targeted pharmaceutical strategies in humans, both in early development as well as in late stage clinical trials.

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ApoA-I Induction as a Potential Cardioprotective Strategy: Rationale for the SUSTAIN and ASSURE Studies

Abstract: ApoA-I induction represents a potential novel strategy to reduce cardiovascular risk, by generating nascent HDL particles. These studies will provide early evaluation of the effects of RVX-208 on lipids and atherosclerotic plaque.

Cited by 84 publications

References 46 publications

RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain

RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain

From Lipids to Inflammation

Novel Therapies Focused on the High-Density Lipoprotein Particle

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