Physicians' Academy for Cardiovascular Education

A novel epigenetic approach to reduce atherosclerosis

Literature - Nikolic D et al., Expert Opin Investig Drugs. 2015

An evaluation of RVX-208 for the treatment of atherosclerosis.

Nikolic D, Rizzo M, Mikhailidis DP, et al.
Expert Opin Investig Drugs. 2015 Oct;24(10):1389-98.


Due to its supposed antiatherogenic activities, a number of strategies to increase HDL levels and activity are explored for their potential therapeutic value. Upregulation of endogenous synthesis of the major protein of new HDL particles, apolipoprotein A-I (apoA-I) is a novel approach to induce formation of pre-β HDL particles. Moreover, bromodomain-containing proteins are considered attractive candidates for the development of inhibitors to alter gene transcription. Bromodomains are tandem ligand binding regions in the bromodomain and extraterminal (BET) protein family, that can recognise and bind to acetylated lysines in histones, which are bound to DNA.

Promising activity of inhibitors of the BET family has been shown in disease models, but safety concerns have been raised based on the pleiotropic nature of BET proteins. Domain-specific targeting may overcome this challenge.

RVX-208 is a novel BET bromodomain inhibitor that acts on the second bromodomains (BD2s) within BET proteins, with the result that these proteins are displaced from chromatin. RVX-208 is in development for the treatment of acute coronary syndromes (ACS), atherosclerosis and Alzheimer’s Disease (AD), as evidence indicates that it increases apoA-1 and pre-β-HDL particles.
This review outlines the currently available data on the use of this novel small molecule to increase apoA levels.
Development milestones, pharmacokinetics and metabolism
RVX-208 is an orally administered drug that has been tested in several doses, ad was found to be safe and well-tolerated in phase Ib/IIa studies.
RVX-208 selectively binds to a BET protein, and via epigenetic mechanisms it results in upregulation of apoA-I gene transcription and production of the protein. RNA silencing studies suggest that induction of apoA-I gene transcription is mediated by BET family member BRD4.
The two predominant metabolites of RVX-208 are a glucuronidated metabolite M4 and an oxidised metabolite M5.

Pharmacodynamics of RVX-208

Increased pre-β-HDL, cholesterol efflux and serum apoA-I have been observed in response to administration of RVX-208 in healthy volunteers, as well as increased serum apoA-I and HDL-c in African Green monkeys (AGMs) and increased plasma Apo-Ai and HDL particles in humans.
In addition to atherosclerosis, RVX-208 may also be interesting in light of AD, as it increased plasma amyloid-β (Aβ40) levels, an important marker of cognitive function and AD, in 7 days by 12-14% in a phase Ia trial in AD subjects. Also in the phase II ASSERT trial population, 12 weeks of treatment with RVX-208 positively affected Aβ40 levels.

The potential anti-atherogenic role of RVX-208 in different preclinical and clinical models and against individual targets

Both in vitro studies in HepG2 cells and in vivo studies in AGMs indicated increased apoA-I mRNA and protein synthesis, and increased levels of pre-β-migrating and α-lipoprotein particles containing apoA-I (LpA-I).

In healthy volunteers, the increase of serum apoA-I and HDL-c was accompanied by changes in HDL size distribution, towards more pre-β1-LpA-I and the larger LpA-I particles but less α2-LpA-I). This may suggest that RVX-208 directly affects biogenesis of nascent apoA-I-containing particles in the liver and intestine.
In hyperlipidaemic apoE-/- mice, 12 weeks of treatment of RVX-208 significantly reduced aortic lesion formation, doubled HDL-c levels and halved LDL-c levels. Plasma apoA-I levels were, however, not altered. In another mouse model in which mice were fed a Western diet for 10 weeks to develop lesions, followed by switching to a low fat diet and concomitant treatment with RVX-208, reduced lesion formation was seen but without significant changes in plasma lipids. In both models, a decrease in pro-inflammatory proteins was seen. This may suggest that the BET-inhibitor exerts it anti-atherogenic effect through a combination of lipid changes and anti-inflammatory effects.

The first study in human patients with normal or low HDL-c levels showed increases of apoA-I by 5.1-10.4% at day 8 and 28 as compared with placebo. Α-1 HDL particles, a marker of reverse cholesterol transport functionality, were increased by almost 50%.
A phase II randomised, placebo-controlled, dose-ranging ASSERT trial in statin-treated patients with coronary artery disease showed that the effect of 12 weeks of RVX-208 (50, 100 or 150 mg BID) on apoA-I did not significantly differ from placebo. Dose-dependent increases in apoA-I levels by 0.1-5.6% (significant trend) were, however, seen. HDL-c was also significantly increased, including α1 particles or functional HDL with increased large HDL particles. While the maximum pharmacological effect had not yet been achieved after 12 weeks, apoA-I levels increased rapidly in week 8-12. Non-significant dose-dependent reductions of C-reactive protein were observed, which appeared correlated to changes in HDL-c, apoA-I and concentration of large HDL.
Two phase IIb studies provided preliminary evidence on the effects of RVX-208 on lipids and atherosclerotic plaque (SUSTAIN and ASSURE). In SUSTAIN, patients with low HDL-c randomised to RVX-208 showed an increase in HDL-c as compared with placebo (Primary endpoint met). apoA-I and the proportion of total and large HDL particles were also increased, and hsCRP levels reduced. In ASSURE, patients with angiographic CAD and low HDL-c randomised to RVX-208 did not show a significant nominal decrease in percent atheroma volume after 26 weeks of treatment (primary endpoint not met), nor a significant change in plaque regression in comparison to placebo. Increases of apoA-I and HDL-c also did not differ from placebo, but the trial was not powered for comparison with placebo.
In these studies, some patients showed transiently increased liver transaminases were >3 times ULN.

While individual studies did not always show clinical benefit, combining data of SUSTAIN and ASSURE suggests significant lipid changes and even a reduction of major adverse cardiac events with RVX-208 in CVD patients, especially in those with diabetes mellitus.
Data have also been presented on the reducing effect of short duration treatment RVX-208 on glucose absorption and endogenous glucose production. These effects on glucose metabolism may be beneficial in patients with prediabetes. The ability of RVX-208 to change lipid profile towards HDL favouring normalisation of the composition has been reported.


In summary, RVX-208 increases apoA-I and HDL-c levels in vitro, in vivo and in humans, which increases cholesterol efflux and raises the levels of large HDL particles. These characteristics of RVX-208 may be useful for treating atherosclerosis and apoA-I induction may represent a potential novel strategy to lower CV risk. Larger trials are needed to confirm the atheroprotective potential seen in earlier studies, including the reduction of MACE. Additional studies should also shed further light on HDL functionality and effect of different HDL particles on arterial structure and function.

Expert opinion

It is possible that achieving maximal increases in apoA-I may require longer exposure to RVX-208 than the durations tested to date. Larger studies should also examine safety regarding the observed increases in liver enzymes.
More understanding is also needed on the relative importance of different types of HDL particles in the complex metabolic pathway. Various studies that modified HDL metabolism through different approaches have shown different results, and changes in HDL parameters are not always directly related to clinical measures. A clinical endpoint study will need to establish whether RVX-208 has clinical benefit for patients.
Overall, pharmacological manipulation of HDL-c appears to be less efficient than lowering LDL-c to reduce CV risk. The mechanism of RVX-208 may have an advantage over other small molecules that are currently being tested to modulate HDL-c levels and HDL functionality.
Future, well-designed studies will have to evaluate the benefits of RVX-208 in improving glucose and lipid abnormalities and ultimately in reducing atherosclerosis and CV events.
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