An evaluation of RVX-208 for the treatment of atherosclerosis

Dragana Nikolic, Manfredi Rizzo, Dimitri P Mikhailidis, Norman C Wong &
Maciej Banach MD, PhD, FNLA, FAHA, FESC, FASA

To cite this article: Dragana Nikolic, Manfredi Rizzo, Dimitri P Mikhailidis, Norman C Wong
& Maciej Banach MD, PhD, FNLA, FAHA, FESC, FASA (2015) An evaluation of RVX-208 for the treatment of atherosclerosis, Expert Opinion on Investigational Drugs, 24:10, 1389-1398

An evaluation of RVX-208 for the treatment of atherosclerosis
Dragana Nikolic, Manfredi Rizzo, Dimitri P Mikhailidis, Norman C Wong
& Maciej Banach†
†University of Lodz, Medical University of Lodz, WAM University Hospital in Lodz, Department of Hypertension, Lodz, Poland
Introduction: RVX-208 is a first-in-class, orally active, novel small molecule in development by Resverlogix Corporation (Calgary, AB, Canada). It acts through an epigenetic mechanism by inhibiting the bromodomain and extra- terminal (BET) family of proteins, increasing apolipoprotein A-I (apoA-I) and targeting high-density lipoprotein (HDL) metabolism, including generating of nascent HDL and increased larger HDL particles, resulting in the stimulation of reverse cholesterol transport. RVX-208 also has a beneficial effect on inflammatory factors known to be involved in atherosclerosis and plaque stability. New therapeutic strategies are needed for patients with atherosclerosis.
Areas covered: In this review, the authors evaluate the use of RVX-208 as an agent for the treatment of atherosclerosis. The article is based on a literature search considering both animal and human studies available on PubMed as well as Media Releases from the Resverlogix Corporation.
Expert opinion: The current evidence suggests promising beneficial effects of this novel drug in the prevention and treatment of atherosclerosis and other metabolic disorders. Its unique mechanism of action is encouraging; it affects several pathways and has a modest effect on HDL levels. There is also a shift in particle size to larger HDL particles, which may have potent atheroprotective effects. Future clinical development is needed, including safety assessment.

Keywords: apolipoprotein A-I, atherosclerosis, high-density lipoprotein particles, high-density lipoprotein, RVX-208

Expert Opin. Investig. Drugs (2015) 24(10):1389-1398

1.Introduction

Numerous studies have demonstrated that statins reduce cardiovascular disease (CVD) risk; however, a substantial proportion of treated patients still remain at risk [1]. High-density lipoprotein (HDL) is believed to have a number of anti- atherogenic activities (e.g., reverse cholesterol transport, antioxidant, anti- inflammatory and anti-apoptotic properties) that contribute to reduced CVD risk [2]. Consequently, increasing HDL levels and activity have become potential therapeutic targets [3,4].
A novel approach to generate new HDL particles is upregulation of endogenous synthesis of the major protein of these particles, apolipoprotein A-I (apoA-I) and thereby inducing formation of pre-b particles [4]. Recently, bromodomain- containing proteins have emerged as attractive candidates for the development of inhibitors. The actions of these inhibitors on the bromodomain-containing proteins affect gene transcription. Specifically, the inhibitors of the bromodomain and extra- terminal (BET) family showed promising activity in different disease models [5]. However, safety concerns have been raised based on the pleiotropic nature of BET proteins regulating tissue-specific transcription suggesting that attempts should be made for domain-specific targeting [5]. A novel BET bromodomain
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1389

 

doses for 28 days [13] in early studies. Results from studies in

Box 1. Drug summary.
a Phase Ib/IIa (discussed in detail, below) demonstrate

Drug name Phase Indication Pharmacology description Route of administration
RVX-208 II
Atherosclerosis Bromodomain containing 4 inhibitor
Oral
RVX-208 to be safe and well tolerated [13].
RVX-208 upregulates apoA-I through epigenetic mecha- nisms resulting in increased transcription of the gene to augment production of the protein (Figure 1). The use of binding assays and X-ray crystallography showed that RVX-208 selectively binds to a target called a BET protein.

Chemical structure
O

OH
All BET proteins have within them tandem ligand binding regions known as bromodomains. Each bromodomain

O N (of ~ 110 amino acids) can recognize and bind to an acety-

NH
lated lysine that can be found in histones bound to DNA [14]. When RVX-208 binds to the BET protein, it trig-
Pivotal trial(s)
O O
[19,21,23-27,32,33]
gers a cascade of events leading to increased apoA-I gene tran- scription and eventually production of this protein. Studies using silencing RNA suggest that induction of apoA-I gene

Pharmaprojects — copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
inhibitor, RVX-208, is a selective inhibitor for the second bromodomains (BD2s) within BET proteins and its activity displaces these proteins from chromatin [6]. RVX-208 is a first-in-class, novel small molecule, also known as RVX000222, in development by Resverlogix Corporation (Calgary, AB, Canada) for the treatment of acute coronary syndromes (ACS), atherosclerosis and Alzheimer’s disease (AD). This novel small molecule is currently in Phase II clin- ical trials and the evidence indicates that RVX-208 increases apoA-I and pre-b-HDL particles as potential therapeutic targets for reducing atherosclerotic disease, in non-human primates and humans [6,7].
There is a need for new drugs that influence lipids so as to treat but also prevent atherosclerosis because some drugs, like statins, may not be tolerated, especially at high doses [8,9]. In this review, we discuss the currently available data on the use of RVX-208 for increasing apoA levels as an agent for the treatment of atherosclerosis. The potential effects of RVX-208 in the treatment of ACS and AD were also briefly discussed.

2.Development milestones, pharmacokinetics and metabolism

Resverlogix established RVX Therapeutics in July 2005, a wholly owned subsidiary for business and strategic objec- tives [10]. In December 2007, the US FDA approved RVX-208 for a Phase I trial to determine its usefulness in the treatment of CVD [11]. This novel BET bromodomain inhibitor is related to the quinazolinones and its chemical name is 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)- 5,7-dimethoxyquinazolin-4(3H)-one [12]. RVX-208 is an orally administrated drug that was given at either low (2 mg/kg), dose-escalating (3 — 6 mg/kg) or high (6 mg/kg)
transcription is mediated by the BET family member BRD4 [15]. RVX-208 is the first human BET antagonist in clinical trials suggesting that BET inhibition may be a prom- ising new approach for the treatment of atherosclerosis and other diseases. Clinical experience with RVX-208 up to now demonstrates that BET inhibitors may be both safe and efficacious (Box 1) [15].
In order to understand the elimination of the compound from the body, as well as the safety profile for this drug, the structures of the two predominant metabolites of RVX-208 were determined to be involved in the metabolic pathways of RVX-208, and confirmed by comparison with a synthetic sample: i) a glucuronidated metabolite M4 (forma- tion of a glycosidic bond between the primary hydroxyl group of RVX-208 and glucuronic acid) and ii) an oxidized metab- olite M5 (a product of oxidation of primary hydroxyl group of RVX-208 to carboxylic acid), observed both in in vitro human and animal liver microsomal incubations, as well as in plasma from animal in vivo studies [12].

3.Pharmacodynamics of RVX-208

Pharmacodynamic data include significantly increased pre-b HDL, cholesterol efflux and serum apoA-I in healthy volun- teers; significantly increased average serum apoA-I and HDL-C levels in African Green monkeys and increased plasma levels of Apo-Al and HDL particles in humans. Affect- ing apoA-I, the key building block of functional HDL particles, and promoting reverse cholesterol transport are promising therapeutic options for atherosclerosis. These studies are described in detail below.
In addition, this drug can also be beneficial for the treat- ment of AD as supported by a double-blind, dose-escalation, placebo-controlled, Phase Ia trial conducted by Resverlogix (RVX-208 2, 3 and 8 mg/kg) in 24 AD subjects for a period of 7 days. Post hoc analysis revealed a 12 — 14% increase in plasma amyloid-b (Ab40) levels, an important marker of cognitive function and AD, at the highest dose of RVX-208 versus placebo [16]. RVX-208 has also shown

 
RVX -208
Liver The BET proteins

ApoA-1

Brd2

Brd3
1

1
74-185
BD1 34-145
BD1
345-457
BD2 307-419
BD2
632-710
ET 562-640
ET
801

726

pre-β HDL 1 58-159 349-461 600-678 1362

HDL synthesis
Brd4

1
BD1 27-138
BD2
268-380
ET 500-578

947

α1HDL BrdT
BD1 BD2 ET

Inhibition by RVX-208
Acetylated lysine (DNA)

•Increased RCT
•Increased cholesterol efflux potential
•Improved HDL quantity and quality

 
Functional HDL
particles
?
Beneficial effects on cardiovascular outcomes

 
Figure 1. RVX-208 properties and mechanism of action.
BET: Bromodomain and extraterminal; HDL: High-density lipoprotein.
positive effects on plasma Ab40 levels in 299 patients with coronary artery disease (the Phase II ASSERT trial popula- tion; 13.4% change compared with placebo), after 12 weeks of treatment (150 mg twice daily [b.i.d.]) [17].

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

A total of 126 preclinical studies with RVX-208 have been conducted comprising safety, toxicity, pharmacokinetics and pharmacology studies [18]. In vitro and in vivo studies were designed to determine whether this novel small molecule affected apoA-I and HDL-C levels.
In vitro HepG2 cells were treated with 0 — 60 µmol/l RVX-208, while for in vivo studies, African green monkeys (AGMs) received 7.5, 15 and 30 mg/kg b.i.d. and 60 mg/kg once-daily RVX-208. The serum from AGMs was analyzed for lipoprotein levels, HDL-subparticle distribution, choles- terol efflux and activity of lipid-modifying enzymes. RVX-208 induced apoA-I mRNA and protein synthesis in HepG2 cells, leading to increased levels of pre-b-migrating and a-lipoprotein particles containing apoA-I (LpA-I) in spent media. Similarly, in AGMs, RVX-208 treatment for
63 days increased serum apoA-I and HDL-C levels by 57 and 92%, respectively. In addition, the levels of pre-b 1-LpA-I and a1-LpA-I HDL-subparticles were increased as well as adenosine triphosphate binding cassette A1 (ABCA1), adenosine triphosphate binding cassette
G1 (ABCG1) and scavenger receptor class B type I-dependent cholesterol efflux. As expected, the lipid changes were not mediated by cholesteryl-ester-transfer protein (CETP) [19,20].
Safety, tolerability and pharmacokinetics of oral RVX-208 (1 — 20 mg/kg/day) were assessed in a Phase I clinical trial conducted in healthy volunteers. Treatment for 1 week increased apoA-I, pre-b-HDL and HDL functionality
pointing to its potential usefulness for treating atherosclero- sis [7]. RVX-208 in vitro in HepG2 cells increased apoA-I mRNA and protein levels in a dose– response manner that was associated with an increase in the larger nascent-LpA-I and lipid-poor pre-b-migrating particles. This observation was confirmed in vivo by these authors. The elevation of serum apoA-I and HDL-C was accompanied by changes in the HDL size distribution (more pre-b1-LpA-I and the larger a1-LpA-I particles but less a2-LpA-I) suggesting a possible direct effect of RVX-208 on the biogenesis of nascent apoA- I-containing particles in the liver and intestine or alterna- tively, an indirect effect of RVX-208 on plasma factors that

 

were assessed such as lecithin:cholesterol acyl transferase, CETP and phospholipid transfer protein activity, which are known to affect HDL concentration, composition and sub- population distribution. Importantly, such a shift to larger HDL particles could have important therapeutic implications for atherosclerotic CVD. In this context, a recent animal study investigated the effect of RVX-208 (150 mg/kg b.i.d.) on aortic lesion formation in hyperlipidemic apoE-/- mice. After 12 weeks of the treatment aortic lesion formation signif- icantly reduced, the levels of HDL-C increased by twofold, while low-density lipoprotein cholesterol (LDL-C) decreased by ~ 50%.However,nosignificantchanges wereseeninplasma- apoA-I level. Additionally, circulating adhesion molecules as well as cytokines levels were significantly reduced. Of interest, haptoglobin, a pro-inflammatory protein, known to bind with HDL/apoA-I, decreased more than 2.5-fold after RVX-208 treatment. Similarly, with a therapeutic dosing regimen in which mice were fed Western diet for 10 weeks to develop lesions followed by switching to a low fat diet and concurrent treatment with RVX-208 for 14 weeks, RVX-208 reduced lesion formation by 39% in the whole aorta but without significant changes in plasma lipid, while pro-inflammatory cytokines IFN-g -inducible protein 10, macrophage inflammatory protein 1 and macrophage-derived chemokine were significantly reduced. Such results indicate
that this BET inhibitor exerts its anti-atherogenic activity through a combination of lipid changes and anti-inflammatory activities [6].
A double-blind, placebo-controlled, US-based, Phase Ib/IIa study (RVX222-CS-003; NCT00768274) [21] investigating the safety, pharmacokinetics and pharmacodynamics of three dosages of RVX-208 (low-dose, dose-escalation and high- dose) in 72 patients with normal or low HDL-C levels was completed in August 2009. The primary end point, an increase in apoA-I levels, achieved a range of 5.1 — 10.4% in all patients at all doses at days 8 and 28, respectively, when compared with placebo. At the lowest dose of 1 mg/kg b.i.d. in patients with low levels of HDL-C, RVX-208 significantly increased plasma apoA-I levels by 5.7 and 7.8% at days 8 and 28, respectively (p < 0.05). Also, a-1 HDL particles, a critical marker of reverse
cholesterol transport functionality, showed an increase of 46.7% (p < 0.004) in all patients and 57.2% (p < 0.02) in the low-dose arm over placebo at day 28. Thereafter, RVX-208 was shown to be compatible with simvastatin (40 mg) and well tolerated showing good oral absorption [13].
An interim analysis of 24 healthy volunteers who participated in a 7-day Phase I trial of RVX-208 (at 2, 3 or 8 mg/kg/day) compared with placebo showed statistically significant increases in pre-b HDL of 42% (p = 0.007), correlated with ABCA1-dependent cholesterol efflux change of 11% (p = 0.03) and a serum apoA-I level increase of 11% (p = 0.03). However, HDL-C level increased by 10% but not significantly, although a rapid onset of action was observed [20,22].
In October 2010, Resverlogix and the Cleveland Clinic in the USA completed a Phase II, randomized, placebo- controlled, dose-ranging trial (ASSERT; NCT01058018) [23] that was initiated in December 2009 with the aim to assess the safety, tolerability and efficacy of RVX-208 after 3 months of dosing. Statin-treated patients (n = 299) with coronary artery disease received RVX-208 (50, 100 or 150 mg b.i.d.) or placebo for 12 weeks. For each dose of RVX-208, compar- isons of apoA-I changes with placebo, the primary end point, did not achieve statistical significance. However, treatment with RVX-208 led to a dose-dependent increase in apoA-I levels by 0.1 — 5.6% (p = 0.035 for trend). Also, HDL-C significantly increased ranging from 3.2 to 8.3% (p = 0.02), including a1 particles or functional HDL with increased large
HDL particles by 11.1 — 21.1% (p = 0.003) [24]. Interestingly, the peak pharmacological effect had not been achieved by the end of the 12-week study, but apoA-I levels increased rapidly from 8 to 12 weeks. Increases in liver transaminases > 3 times upper limit of normal, but the rises were transient, rapidly reversible and were observed in 18 patients on RVX-208 treatment, without associated increase in bilirubin levels. The mechanism underlying the liver enzyme elevation remains unknown, although it was observed more frequently in patients treated with simvastatin, high-dose statin therapy and those with liver enzyme elevations at baseline [4]. Finally, the authors suggested that maximal increases in apoA-I may require longer exposure [24]. In addition, a non- significant dose-dependent reduction in C-reactive protein (CRP; by 13.0 — 22.0%) was observed that was inversely related with changes in HDL-C (r = -0.19, p = 0.004). Further, when RVX-208-treated subjects were stratified according to tertiles of percent change in CRP, those with the greatest reduction in levels demonstrated the greatest elevation in apoA-I (+5.6 vs +0.1%, p = 0.004), HDL-C (+7.7 vs +2.8%, p = 0.02) and concentration of large HDL particles (+27.5 vs +3.9%, p = 0.003). The greatest reduction in CRP was observed in subjects with greatest increases in quantitative measures of HDL that may reflect an anti- inflammatory effect of RVX-208 arising from newly generated functional HDL particles with apoA-I induction or other explanations. However, the impact of these changes on atherosclerotic plaque remains to be established [25].
There were two studies (Phase IIb) that provided early eval- uation of the effects of RVX-208 on lipids and atherosclerotic plaque: i) The Study of Quantitative Serial Trends in Lipids with apoA-I Stimulation (SUSTAIN, NCT01423188) [26]
study aimed to assess the lipid efficacy, safety and tolerability of RVX-208 and ii) the ApoA-I Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation (RVX222-CS-007; ASSURE, NCT01067820) [27]
study aimed to evaluate the effect of this apoA-I inducer on plaque burden. In SUSTAIN, 176 patients with low levels of HDL-C were randomized (1:1) to receive RVX-208 100 mg b.i.d. (n = 88) or placebo (n = 88) for 24 weeks. The primary efficacy parameter was the percentage change in

 

HDL-C levels that has been met successfully (p < 0.0001). Also, the secondary end points, increased apoA-I (p < 0.0004), total and large HDL particles (p < 0.004 for both) as well as reduced high-sensitivity CRP levels at 12 weeks (p < 0.003) were observed. In ASSURE, 324 patients with angiographic coronary artery disease and low HDL-C levels were randomized (3:1) to receive RVX-208 100 mg b.i.d. (n = 243) or placebo (n = 81) for 26 weeks. The primary effi- cacy parameter was the nominal change in percent atheroma volume (PAV), determined by analysis of intravascular ultra- sound (IVUS) images of matched coronary artery segments acquired at baseline and at 26-week follow-up. Also, the effect of RVX-208 on inflammatory markers, safety and tolerability was assessed in both studies [4]. The primary end point, change in PAV was not met (-0.4%; p = 0.08) and no significant change in plaque regression was observed when the RVX-208 group was compared with the placebo group. The question is whether this lack of beneficial effect on plaque regression is due to the weak efficacy of RVX-208 or the impos- sibility to confer beneficial effects on top of statins, since 84% of subjects were on statin therapy (atorvastatin [10/20/40 mg]
or rosuvastatin [5/10/20 mg]) [28]. However, the increases of apoA-I and HDL-C levels also did not differ from placebo but the trial was not powered for comparison with placebo. As seen previously, a small number of patients had transient elevations in the transaminases. Based on the ASSURE data, no clinical benefit has been demonstrated for RVX-208 up to now [29]. On the other hand, summarizing effects of RVX-208 in all subjects from both studies SUSTAIN and ASSURE (n = 331), all changes in lipids (HDL-C, apoA-I lev- els, large HDL particles, HDL particle size and total HDL par- ticles) were increased significantly, while alkaline phosphatase decreased versus baseline. Furthermore, all these changes were significant compared with placebo (n = 166) excluding increases in total HDL particles [30]. In both SUSTAIN and ASSURE, there were a significant number of CVD events. Both trials had similar patient populations with CVD, standard of care including statins, duration of 24 — 26 weeks and identi- cal treatment with RVX-208 (200 mg/day). The combined events from both trials showed that RVX-208 lowered major adverse cardiac events (MACE) by 55% in CVD patients (p = 0.02) with accentuated effect in patients with diabetes mel- litus. Furthermore, RVX-208 treatment lowered glucose by
-0.3 mmol/l (p = 0.008) in patients with diabetes mellitus and low HDL (< 40 mg/dl) versus +0.9 mmol/l in similar patients given placebo [30,31].
A Phase II Multiple-Dose Study to Characterize the Pharmacokinetics of RVX000222 Capsule Formulation in Combination With Either Atorvastatin or Rosuvastatin in 13 Patients With Dyslipidemia (NCT01863225) has been conducted for 14 days and completed in June 2013 [32]. There were four arms: i) 200 mg daily + atorvastatin 40 mg, ii) 200 mg daily + rosuvastatin 20 mg, iii) 200 mg daily + atorvastatin 80 mg and iv) 200 mg daily + rosuvastatin 40 mg.
A randomized, Phase II, double-blind study (NCT01728467) with the primary objective to determine the effects of RVX-208 on postprandial plasma glucose in 20 men with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), during a frequently sampled oral glucose tolerance test (OGTT) (pre-diabetes) have been com- pleted in March last year after 29 — 33 days of treatment with RVX-208 (200 mg daily) versus placebo [33]. The results have been presented at the 2015 American Diabetes Association Scientific Sessions in Boston, MA [34]. Treatment led to not only a reduction in glucose absorption, but also suppression of endogenous glucose production highlighting the findings that short duration of RVX-208 treatment had effects on glu- cose metabolism, and that both the reduction in glucose absorption and production are expected to be of benefit in patients with prediabetes. Also, at the recent International Atherosclerosis Society meeting (23 — 26 May 2015 in Amsterdam, The Netherlands), the ability of RVX-208 to change lipid profile within the HDL favoring normalization of the composition towards that observed in healthy individ- uals has been reported [35]. These data together indicate on the ability of RVX-208 to affect glucose and lipid metabolism in ways that will be of benefit to patients with high CVD risks.
The main clinical trial findings are summarized in Table 1.

5.Conclusions

The novel small molecule, RVX-208, increases apoA-I and HDL-C levels in vitro, in vivo and in humans, enhancing cholesterol efflux, but also raising large HDL particle levels. Such beneficial features of RVX-208 might be useful for treating atherosclerosis and apoA-I induction represents a potential novel strategy to reduce CV risk, by generating nascent HDL particles. Furthermore, the evidence suggests the potential of RVX-208 to lower MACE in CVD patients, especially in those with diabetes mellitus. Larger trials are needed to confirm such atheroprotective potential of novel HDL-targeted therapy with RVX-208, including further assessment of safety (including activity of liver enzymes). It should be highlighted that additional studies are required also in terms of HDL functionality, and effect of different HDL particles on arterial structure and function.

6.Expert opinion

The data obtained in vitro, and in vivo in monkeys as well as in clinical Phase I and II trials of RVX-208 support increased synthesis of apoA-I and HDL-C and, consequently, stimula- tion of reverse cholesterol transport as a new approach for treating atherosclerosis [15]. Also, administration of this novel molecule was associated with raising the concentration of large HDL particles, however, it is possible that maximal increases in apoA-I may require longer exposure than the

 
duration tested in the clinical trials to date [24]. It is obvious that larger trials are needed to confirm findings reported to date, as well as the study regarding safety given that an increase in liver enzymes was observed with the active treat- ment group. In addition, stabilization of atheroma and increasing HDL-C levels are likely to be useful objectives in familial hypercholesterolemia [36]; thus, future studies may show if this molecule might be beneficial in this population.
On the other hand, we should bear in mind that HDL is a heterogeneous family of particles with a complex metabolic pathway, and the relative importance of its various functions is unknown [37]. It remains unclear how big of a change in apoA-I or HDL levels are needed to make a worthwhile impact on CVD [38]. The ASSURE 1 study did not meet the primary end point. In addition, we should not forget that we know little about HDL, beyond just the HDL level, especially about role of different subparticles and dysfunc- tional HDL [3,37,39]. Thus, even if a drug has a modest effect on HDL levels it might have potent effects on atherosclerosis that remain to be elucidated by future studies. Similarly, a clinical end point study will show if such a drug, which targets HDL functionality in a very different way from the CETP inhibitors, is really beneficial [38]. In the DEFINE (Determin- ing the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) trial [40], encouraging data were reported regarding CETP inhibitor — anacetrapib: significantly decreased LDL-C levels (by 36%) and increased HDL-C lev- els (by 138%) versus placebo; while the ASSERT study showed a relatively small effect for RVX-208 (modest increases in HDL-C and apoA-I; 8.3 and 5.6%, respec- tively). However, a different approach in affecting HDL metabolism (decreasing HDL catabolism through CETP inhibition) may not affect reverse cholesterol transport to the same magnitude as RVX-208 (enhancing apoA-I pro- duction). Also, these two studies cannot be directly com- pared because the drugs have different mechanisms of action [38]. Approximately 20% increase in large HDL par- ticles at the highest dose of RVX-208 suggests an improve- ment in reverse cholesterol transport. Also, it has been noted that these modest changes in large HDL particles with RVX-208 are less than can be achieved with niacin therapy [41,42]. However, it has been pointed out that rela- tively modest changes in HDL with different approaches may actually be quite beneficial and have very potent effects on atherosclerosis, as seen in some previous trials where statins and fibrates appeared to improve artery-wall compo- sition or clinical outcomes while increasing HDL levels only modestly (5 — 7%) [38]. In addition, the mechanism involved in anti-atherosclerotic effects may be happening without visible changes in the HDL level.
Among apoA-I mimetic peptides, 4F showed promising results in several animal models and in a Phase I/II human study [43] indicating potential benefits in the prevention of atherosclerosis, but further studies are needed. An advantage of RVX-208 compared with other HDL-raising approaches
(especially apoA-I-based infusion therapies) is that it is an oral drug that will be easier to manufacture and administer. Recently, it was reported that recombinant HDL containing apoA-IMilano exerts greater anti-inflammatory and plaque stabilizing properties rather than anti-atherosclerotic proper- ties in an animal model [44], while infusion with other drugs from the same class failed to meet its primary end point [45].
We have discussed above the potential beneficial effects of this novel agent that need to be confirmed by future, large, randomized, placebo-controlled studies to reduce residual CVD risk on top of statin therapy. However, it should be highlighted that based on the current evidence the utility of increasing HDL-C is not yet established, and pharmaceutical manipulation of HDL-C appears to be less efficient than low- ering LDL-C to reduce CV risk. This raises doubts about the relevance of the ‘HDL-C hypothesis’ and highlights the com- plexity of HDL metabolism in contrast to that of LDL. In favor of LDL-C-lowering agent in CV risk reduction are very recent results achieved by another novel orally adminis- tered agent [46].
The biological activities of HDL mediated by different HDL subclasses may not be reflected by raising HDL-C lev- els. Actually, the mechanism of action of RVX-208 may be an advantage over other small molecules currently being developed and tested in clinical trials to pharmacologically modulate not only HDL-C levels and HDL functionality. Furthermore, heterogeneous particle subpopulations of HDL, whose composition, metabolism and functionality dif- fer depending on the metabolic status [47], needs to be further investigated, with the aim to assess any improvement in HDL function [28]. Additional data on functionality would be valuable, especially since it remains uncertain whether changes in HDL-particle size alone can provide confident estimates of the functionality and atheroprotective effects of the HDL [48]. In clinical trials with other lipid-modifying agents, large a-1 particle concentrations have been associated with favorable changes in coronary atherosclerosis and reduction in CV events [49].
Finally, future, well-designed studies will evaluate the benefits of this lipid-modifying agent, especially changes of HDL particles, on atherosclerosis and CV events. Such studies may confirm that RVX-208 has a potential to lower MACE in CVD patients with particular benefit in those with diabetes mellitus [31]. The latest data [34] support ben- efits of RVX-208 in patients at high CVD risk improving glucose and lipids abnormalities and indicating the idea of exploring the use of a BET inhibitor to treat metabolic abnormalities including renal parameters [50]. Also, it may become useful as part of the clinical management of patients with AD to improve not only cognitive functions, but also potentially reduce the risk for atherosclerosis development.

 

Declaration of interest

M Banach has received lecture fees from Amgen Inc, Abbott Laboratories, Merck Sharp and Dohme and Sanofi Aventis. He is also a member of the advisory boards for Amgen Inc., Sanofi Aventis and Abbott Vascular and has worked on trials for Amgen Inc., Sanofi Aventis, Daiichi Sankyo and Resverlo- gix Corporation. DP Mikhailidis has held talks and been
involved with conferences sponsored by Merck Sharp and Dohme, AstraZeneca and Libytec S.A. Finally, NC Wong receives both his salary from and holds stock and options in Resverlogix Corp. The authors have no other relevant affilia- tions or financial involvement with any organization or entity with a financial interest in or financial conflict with the sub- ject matter or materials discussed in the manuscript apart from those disclosed.
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Affiliation
Dragana Nikolic1, Manfredi Rizzo1,2,
Dimitri P Mikhailidis3, Norman C Wong4 &

†5
Maciej Banach
MD, PhD, FNLA, FAHA,

FESC, FASA
†Author for correspondence
1University of Palermo, Biomedical Department of Internal Medicine and Medical Specialties, Palermo, Italy
2Euro-Mediterranean Institute of Science and Technology, Italy
3University College London (UCL), University College London Medical School, Department of Clinical Biochemistry, Royal Free Campus, London, UK
4University of Calgary, Department of Medicine, Biochemistry and Molecular Biology, Calgary, Alberta, Canada
5Professor, Chair of Nephrology and Hypertension, Head,
University of Lodz, Medical University of Lodz, WAM University Hospital in Lodz, Department of Hypertension, Zeromskiego 113; 90-549 Lodz, Poland
Tel: +48 4 2639 3771; Fax: +48 4 2639 3771;
E-mail: [email protected]