Emerging drugs for hyperlipidaemia: an update.

Review

Emerging drugs for hyperlipidaemia: an update

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 11/09/14 For personal use only.

Matilda Florentin, Michael S Kostapanos, Anastazia Kei & Moses S Elisaf † †

Medical School, Department of Internal Medicine, Ioannina, Greece

1.

Background

2.

Medical need

3.

Existing treatment

4.

Current research goals

5.

Scientific rationale

6.

Competitive environment

7.

Potential development issues

8.

Conclusion

9.

Expert opinion

Introduction: Hypercholesterolaemia is a significant risk factor for cardiovascular disease (CVD), a major cause of morbidity and mortality. Up to now, the appropriate management has been aggressive hypolipidaemic therapy, particularly with statins, aiming at certain low-density lipoprotein cholesterol (LDL-C) levels for each patient population. This strategy has reduced CVDrelated morbidity and mortality. However, many cardiovascular events still occur, probably as a consequence of lipid disorders other than high LDL-C concentration or other risk factors. Because statins do not eliminate the residual CVD risk, there seems to be place for novel lipid modifying drugs with different mechanisms of action. Areas covered: This review is an update since 2010 regarding lipid-modifying drugs in development and their potent role in clinical practice. It focuses on cholesterol ester transfer protein inhibitors, mainly anacetrapib and evacetrapib, microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides, pre-protein convertase subtilisin kexin-9 inhibitors and high-density lipoprotein mimetics. Expert opinion: Several novel lipid-modifying drugs may be beneficial for certain patient populations. However, ongoing and future studies with clinical outcomes will clarify their actual role in clinical practice. Keywords: anacetrapib, evacetrapib, microsomal triglyceride transfer protein inhibitors, mipomersen, pre-protein convertase subtilisin kexin -9 inhibitors Expert Opin. Emerging Drugs [Early Online]

1.

Background

Lipid disorders, mainly hypercholesterolaemia, have been associated with increased risk for the development of cardiovascular disease (CVD) [1]. Low-density lipoprotein cholesterol (LDL-C) lowering with statins reduces the rate of cardiovascular events in primary and secondary prevention [2]. Yet a substantial risk persists, suggesting that additional lipid-modifying interventions may be needed [3]. Despite the supplementary improvement in lipid profile with other lipid-lowering drugs, their efficacy in reducing CVD outcomes has not been established [4]. Promising medications failed to demonstrate clinical benefit or were associated with deleterious outcomes [5,6]. Yet, several other agents are at various stages of development. This review focuses on these drugs and discusses the respective clinical trials and their potent role in CVD management. 2.

Medical need

CVD is the leading cause of death in the developed world. In the US, 2200 people die from CVD every day, which translates to nearly 800,000 deaths and > $312.6 billion in health care expenditures and lost productivity annually [7]. Similarly, CVD causes > 25% of deaths in the UK, accounting for > 161,000 deaths annually and approximately £19 billion due to premature death, lost productivity, hospital treatment and prescriptions [8]. LDL-C lowering has been associated with 10.1517/14728214.2014.976553 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

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of statin intolerance, novel lipid modifying agents may have a role.

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Statins are the mainstay of lipid lowering treatment. However, CVD risk is not eliminated even after intense LDL-C lowering with statins. ApoB-100 ASOs, MTP and PCSK-9 inhibitors have been associated with significant LDL-C reduction and may apply to certain patient populations, such as those with familial hypercholesterolaemia (FH). HDL-C elevation can be achieved with several drugs; however, the quality and properties of HDL seem to be more important than high HDL-C concentration. Furthermore, several drugs that raise HDL-C have failed. Thus, the role of agents aiming at HDL-C elevation is still obscure. Large long term clinical studies with cardiovascular endpoints are warranted to establish the role of novel lipid modifying drugs in CVD outcomes.

This box summarizes key points contained in the article.

Ezetimibe Ezetimibe selectively inhibits cholesterol absorption in the intestine [22] and has been proven effective in cholesterol lowering, especially when co-administered with other lipidlowering drugs [23]. It also exhibits pleiotropic effects [23]; however, the exact role of this agent in cardiovascular risk reduction has not been elucidated as results are not consistent among various clinical trials [23]. The results of the ongoing IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [24] that compares the effect of ezetimibe plus simvastatin versus simvastatin monotherapy on CVD outcomes after acute coronary syndromes (ACS) may shed more light in this field. 3.2

Bile acid sequestrants Bile acid sequestrant (BAS) are positively charged indigestible resins that bind to negatively charged bile acids in the intestinal lumen forming a complex that is excreted in the faeces [25]. Previous BAS (cholestyramine and colestipol) were not well tolerated due to gastrointestinal side effects [26]. Colesevelam, a novel BAS, has a more favourable safety profile compared with other BAS [27] and achieves significant LDL-C lowering both as monotherapy (up to 19%) [28] and in combination with other hypolipidaemic agents. It also improves glucose homeostasis [29] and has been approved as an adjunct to other antidiabetic drugs, except dipeptidyl peptidase 4 inhibitors, in patients with inadequate glycaemic control [30]. 3.3

significant reduction in CVD-related morbidity and mortality [2]. However, numerous patients do not achieve the recommended levels of LDL-C with statins [9,10] Furthermore, residual risk remains even when optimal LDL-C levels are reached with statins [3], probably due to other lipid disorders, such as low high-density lipoprotein cholesterol (HDL-C) levels and/or high triglyceride, lipoprotein (a) [Lp(a)] and small dense LDL (sdLDL) particle levels [3,11-14], or nonlipid risk factors (e.g., defective glucose metabolism) [15,16]. Importantly, patients with familial hypercholesterolaemia (FH) frequently do not manage to reach target LDL-C levels [17]. Nonpharmacologic treatments for FH, such as portocaval shunting and LDL aphaeresis are not widely available, whereas treatment with statins (± other drugs) commonly leads to inadequate LDL-C reduction [18]. Therefore, novel therapeutic options are more than welcome for these patients. 3.

Existing treatment

Up to now, the main target of lipid-lowering treatment has been LDL-C concentration, with different goals for certain patient populations [19,20]. However, some agents are more potent in improving other lipid abnormalities, mainly atherogenic dyslipidaemia [3,11,14]. Statins Statins are the cornerstone of lipid-modifying therapy as they have been constantly associated with significant reductions in LDL-C levels and CVD-related morbidity and mortality [2]. Although statins are generally well tolerated, some patients cannot tolerate statins at all or only their high doses. For example, the incidence of myopathy and minor muscle pain was 195 cases per 100,000 patient-years and that of rhabdomyolysis 1.6 cases per 100,000 patient-years in a systematic review [21]. We should note that in real-world clinical practice, these percentages are much higher. In cases 3.1

2

Fibrates Fibrates bind to PPAR-a and activate them, resulting in enhanced gene transcription and protein synthesis [31]. Fibrates have been associated with triglyceride (20 -- 50%) and non-HDL-C reduction [32,33] and increases in HDL-C and apolipoprotein (apo) A-I levels [32], as well as LDL particle size [34]. Despite their longstanding use, considerable controversy regarding their clinical efficacy still remains. Two randomized, placebo-controlled trials demonstrated improvement in CVD outcomes with gemfibrozil [35,36], whereas bezafibrate and fenofibrate did not achieve significant CVD risk reduction in subsequent trials [33,37,38]. In the Action to Control Cardiovascular Risk in DiabetesLipid substudy, simvastatin plus fenofibrate did not significantly decrease the rate of major adverse cardiovascular events (MACE) compared with simvastatin monotherapy in diabetic patients. However, a 31% reduction in CVD outcomes occurred in patients with atherogenic dyslipidaemia (i.e., high triglyceride and low HDL-C levels) [38]. In agreement are subgroup and post hoc analyses from major fibrate trials that have overall demonstrated that fibrate treatment mainly reduces microvascular complications in diabetic patients [39] and nonfatal myocardial infarction in those with atherogenic 3.4

Expert Opin. Emerging Drugs (2014) 19(4)



dyslipidaemia [40,41]. Until sufficient evidence emerges, fibrates should selectively be used in high-risk patients after optimal control of LDL-C concentration with a statin. Aleglitazar, a dual PPAR a/g activator, failed to reduce the risk of cardiovascular outcomes in a large study (AleCardio) in patients with diabetes and recent ACS, despite achieving substantial reduction in triglycerides and elevation in HDL-C levels [42]. In fact, this study was prematurely terminated due to lack of efficacy and increased rates of serious adverse events, for example, heart failure, gastrointestinal haemorrhages and renal dysfunction [42]. In this context, Roche decided to terminate the AleCardio trial and all other trials involving aleglitazar.

lipid-lowering drugs are contraindicated or should be cautiously used [53] and in high-risk patients on maximal-dose statin with suboptimal triglyceride levels. Of course, their role is indispensable in patients with severe hypertriglyceridaemia at risk for acute pancreatitis. Interestingly, two large-scale, randomized, placebocontrolled trials with purified, concentrated w-3 fatty acids and cardiovascular outcomes are in progress. REDUCE-IT aims to enrol 8000 statin-treated patients with or at high risk of CVD and hypertriglyceridaemia [54]. STRENGTH aims to enrol 13,000 similar patients who also have low HDL cholesterol [55]. The estimated completion dates are 2016 and 2019, respectively.

Omega 3 fatty acids Omega 3 (w-3) fatty acids are polyunsaturated fatty acids. Fish oil supplementation as well as eicosapentaenoic (EPA)/ docosahexaenoic acid (DHA) fixed combinations are currently used for the management of hypertriglyceridaemia, particularly in patients with atherogenic dyslipidaemia and diabetes [43]. w-3 fatty acids seem to exhibit pleiotropic actions (e.g., anti-thrombotic [44], anti-inflammatory), while they decrease the concentration of atherogenic sdLDL particles [44] and blood pressure [45]. However, evidence from clinical trials cannot support an indisputable role of w-3 fatty acids in reducing cardiovascular morbidity and mortality [46-49]. For example, in the Gruppo Italiano per lo Studio della Sopravvivenza nell’ Infarto Miocardico (GISSI)-Prevenzione study that included 11,232 patients with a recent myocardial infarction, w-3 fatty acid supplementation (1 g/day) for 3.5 years significantly reduced the risk of death, nonfatal myocardial infarction and stroke compared with controls [46]. Similar benefits were relevant among 6975 participants in the GISSI-Heart Failure study [47]. In contrast, in a study including 4837 patients with a history of myocardial infarction on ‘state-of-the-art’ treatment, low-dose (400 mg/day) EPA--DHA supplementation was not associated with reduction in vascular morbidity and mortality compared with placebo [49]. Likewise, in 12,536 high-risk patients with dysglycaemia, w-3 fatty acids (1 g/day) did not reduce vascular morbidity and mortality compared with placebo after a median of 6.2 years [50]. We performed a systematic review and meta-analysis of 20 randomized clinical trials including 68,680 patients [51]. Treatment with w-3 fatty acids was not associated with significant reductions in all-cause mortality [51], sudden death and cardiac death, myocardial infarction or stroke [51]; this result was relevant for supplementation both with diet and fixed supplements [51]. Our findings were consistent with the results of another meta-analysis, including 20,485 participants in randomized trials [52]. Most authorities recommend the use of w-3 fatty acids as an adjunct to diet for the management of hypertriglyceridaemia [53]. These agents may also be a relevant treatment option in patients with stage 5 chronic kidney disease where most

Nicotinic acid (niacin) Nicotinic acid has a history of >50 years in the management of lipid disorders and was the first widely used lipid-lowering agent [56]. Although it improves almost all lipid parameters [57], it failed to demonstrate cardiovascular benefit in large recent studies [58]. Specifically, the addition of nicotinic acid/ laropiprant to simvastatin (± ezetimibe) not only did not reduce cardiovascular outcomes in patients with established CVD, but was associated with excess adverse events [59,60]. Apart from the expected skin-related side effects, gastrointestinal, musculoskeletal, infectious and bleeding complications also occurred [61,62]. The loss of glycaemic control among diabetic patients and new-onset diabetes among persons without diabetes at baseline were also concerning. Whereas some debate the role of laropiprant in the unfavourable safety profile, the consistency of the overall findings with earlier trials of niacin monotherapy suggests that niacin is the major culprit [61]. Therefore, Merck went on to suspend the drug worldwide.

3.5

3.6

4.

Current research goals

The classical primary end points of the studies with lipidmodifying agents have so far been LDL-C reduction [19] and CVD outcomes [2]. Changes in lipid parameters other than LDL-C were usually included in the secondary end points of clinical trials [20]. 5.

Scientific rationale

Most of the lipid-modifying drugs in development aim at LDL-C reduction, whereas others are more potent in improving other lipid parameters. 5.1

Drugs aiming at LDL-C reduction Cholesterol absorption inhibition

5.1.1

Apart from ezetimibe and BAS, other compounds may inhibit cholesterol absorption, such as acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors [63]. ACAT catalyzes the esterification of free cholesterol with fatty acids. There are two isoforms of this enzyme, ACAT1 and ACAT2. The latter


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regulates hepatic lipoprotein and cholesterol absorption, whereas ACAT1 maintains cholesterol homeostasis in the brain, adrenal glands and macrophages [63]. In theory, inhibition of ACAT-1 could slow the progression of atherosclerosis and prevent the development of vulnerable plaque. Although the results of preclinical studies with ACAT inhibitors were encouraging [64,65], they had neutral or even deleterious effects in clinical studies [66-68]. Therefore, these drugs are no longer under development, with the exception of ACAT-1 selective K-604 (Kowa Pharmaceuticals; Nagoya, Japan) that was tested in an interventional study for atherosclerosis; the results are pending [69]. Microsomal triglyceride transfer protein inhibition

5.1.2

Microsomal triglyceride transfer protein (MTP) is a key enzyme for the assembly and secretion of apo B-containing lipoproteins [70,71]. These include chylomicrons, very LDLs (VLDL) and their remnants. MTP is active in both the liver and intestine, where VLDL and chylomicron assembly takes place [70,71]. It facilitates the transfer of lipids through various compartments during apo B lipidation [70,71]. This process prevents from apo B degradation, resulting in apo B-rich lipoprotein secretion. MTP inhibition induces poor apo B lipidation and, thus, reduced lipoprotein production [70,71]. Several MTP inhibitors have been used in preliminary studies [72]. These are active at the liver, intestine or both sites. Liver-specific MTP inhibitors primarily inhibit the synthesis of apo B-100-rich VLDL [72], whereas intestine-specific MTP inhibitors reduce the synthesis of apo B-48-rich chylomicrons [72]. The clinical studies and data regarding the current role of MTP inhibitors are discussed in the next section. Apo B-100 antisense oligonucleotides Antisense oligonucleotides (ASOs) are short synthetic analogues of natural nucleic acids designed to specifically bind to a target mRNA and selectively degrade it or prohibit the translation of the target mRNA into the encoded protein [73]. ASOs targeting apo B-100 are probably the most promising ones, as VLDL and LDL cannot be produced without apo B-100, whereas the latter is the main ligand of hepatic LDL receptors (LDL-R). Mipomersen (previously ISIS-301012) is the most advanced apo B-100 ASO and will be presented in the next section. 5.1.3

Thyroid hormone analogues Thyroid hormones are important in the regulation and maintenance of lipid and energy homeostasis. Although selective thyroid receptor modulators demonstrated promising results in cholesterol lowering in preclinical animal models and human clinical trials [74], they failed to progress beyond early Phase III human trials. No clinical trial with these drugs is ongoing [74]. 5.1.4

4

Squalene synthase inhibitors Squalene synthase inhibitors upregulate hepatic LDL-R by restraining cholesterol synthesis [75]. Despite the favourable effects of these agents in experimental studies, their development has been halted for safety reasons. 5.1.5

Pre-protein convertase subtilisin kexin-9 inhibitors

5.1.6

Pre-protein convertase subtilisin kexin (PCSK)-9 serine protease, a protein primarily synthesized and secreted by hepatocytes [76], regulates cholesterol homeostasis via accelerating the degradation of LDL-R [77], leading to the accumulation of LDL particles in plasma [78]. The pharmacologic inhibition of PCSK9 may be achieved with mAbs, ASOs, small interfering RNAs and small molecule inhibitors. Drugs aiming at HDL-C elevation Robust epidemiologic evidence supports a strong inverse relationship between HDL-C concentration and coronary heart disease (CHD) regardless of LDL-C concentration [79]. However, several therapeutic attempts at raising HDL-C levels did not reduce hard clinical end points [80]. Furthermore, Mendelian randomization does not support HDL-C as a causal cardiovascular risk factor [14]. Therefore, some HDLtargeted therapies mainly focus on promoting reverse cholesterol transport rather than on raising HDL-C. 5.2

Apo A-I stimulation The sole agent under development in this category is RVX-208 (Resverlogix, Alberta, Canada). It acts via an epigenetic mechanism by binding to BET protein [81], triggering a cascade of events that lead to increased apo A-I and HDL-C production. Two Phase IIb studies with RVX-208, namely the Study of Quantitative Serial Trends in Lipids with Apo A-I Stimulation (SUSTAIN) and the Apo A-I Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation (ASSURE) are discussed next [82]. 5.2.1

HDL or apo A-I administration (reconstituted HDL or apo A-I)

5.2.2

Apo A-I Milano is a mutant form of apo A-I whose carriers have very low HDL-C levels, but also reduced CVD risk [83]. Thus, the development of reconstituted apo A-I mimetic peptides was considered promising. Infusion of apo A-I containing recombinant HDL particles or of lipid-poor HDL particles is currently progressing. Recombinant apo A-I or apo A-I isolated from human plasma is recombined with phospholipids to form a particle that prevents apo A-I from being rapidly catabolised. Two Phase II trials using coronary intravascular ultrasound (IVUS) demonstrated encouraging data for recombinant mutant apo A-I Milano and apo A-I isolated from human plasma [84,85]. Another approach is delipidation of autologous HDL and re-infusion of the lipid-poor HDL; a small study showed plaque regression [86].




5.2.3

Cholesterol ester transfer protein inhibitors

Cholesterol ester transfer protein (CETP) is an enzyme crucial for reverse cholesterol transport, a key action of HDL [87]. Although CETP inhibition leads to significant HDL-C elevation, studies with the first CETP inhibitor, torcetrapib, demonstrated increased mortality [5]. The ‘off-target’ effects of torcetrapib, that is, increases in blood pressure and aldosterone and cortisol production may have been the culprits for its failure. The other agents of this class lack the ‘off-target’ actions of torcetrapib. Dalcetrapib (Roche, Basel, Switzerland) demonstrated beneficial effects in lipid profile and atherosclerosis in some of its first clinical trials [88,89]. The optimism for dalcetrapib led to the Dalcetrapib HDL Evaluation, Atherosclerosis and Reverse cholesterol Transport (dal-HEART) program, which included five principal studies, namely dal-PLAQUE, dal-VESSEL, dal-PLAQUE2, dal-ACUTE and dal-OUTCOMES. In dal-PLAQUE (n = 130) dalcetrapib was associated with a significant difference in plaque progression (i.e., lower increase in total vessel area) as assessed by MRI compared with placebo (p < 0.04) in high-risk subjects [90]. In the dal-VESSEL trial (n = 476), no significant differences in brachial flow mediated dilatation occurred with dalcetrapib in patients with established CVD or CVD equivalent and low HDL-C levels, despite a 50% reduction in CETP activity and a 31% increase in HDL-C concentration [73]. The Phase III trial dal-OUTCOMES in patients with ACS was ended prematurely for futility; there was no trend for benefit despite a >25% increase in HDL-C [91]. Consequently, Roche terminated the entire dalcetrapib program. The Phase III clinical trials regarding anacetrapib and evacetrapib will be discussed in the next section. Drugs aiming at triglyceride reduction Although triglyceride reduction is not the first-line treatment target, hypertriglyceridaemia is regarded an independent risk factor for the development of CHD and has been associated with increased risk of disease recurrence in patients with stable CHD [92]. Some of the drugs in development (e.g., PCSK9, MTP and CETP inhibitors, mipomersen) acquire triglyceride-lowering capacity; however, their role in hypertriglyceridaemia is obscure. Apart from fibrates and w-3 fatty acids, drugs aiming at triglyceride reduction include apo C-III ASOs and lipoprotein lipase gene replacement therapy. Apo C-III ASOs are in the first stages of development. Apo C-III inhibits the lipolysis of triglyceride-rich lipoproteins by antagonizing apo C-II-mediated activation of lipoprotein and hepatic lipase [93]. It also promotes intrahepatic VLDL assembly and secretion [93], reducing triglyceride-rich lipoprotein clearance and increasing the formation of atherogenic sdLDL. Furthermore, the enrichment of HDL with apo C-III renders this molecule atherogenic, whereas apo C-III seems to promote inflammation and endothelial cell dysfunction [94]. In 5.3

this context, effort has been made to pharmacologically decrease apo C-III levels. ASO-mediated suppression of apo C-III has demonstrated robust triglyceride and VLDL lowering along with HDL-C elevation in experimental models and healthy humans with no adverse effects on LDL [95]. Based on the favourable preclinical and Phase I clinical pharmacodynamics and tolerability profile, apo C-III ASOs have advanced to Phase II trials. Initial patient populations include individuals with triglycerides >500 mg/dl (5.7 mmol/l) on maximally tolerated firstline agents. Future clinical studies will evaluate the role of apo C-III in metabolic syndrome, diabetes mellitus and HDL homeostasis to further broaden the potential therapeutic benefit of this agent [95]. Diacylglycerol acyl transferases (DGATs) are involved in triglyceride synthesis in adipose tissue, gut and liver [96]. DGAT-2 seems involved in hepatic triglyceride and subsequently VLDL production [97], whereas DGAT-1 is implicated in triglyceride formation, hepatic steatosis, obesity and insulin resistance. Several studies with the DGAT-1 inhibitor LCQ-908, in patients with hypertriglyceridaemia, chylomicronaemia, diabetes and nonalcoholic fatty liver disease (NAFLD) are ongoing, whereas the results of others are pending [98]. 6.

Competitive environment

In this section, we will present the drug classes and respective agents for lipid disorders that are in advanced stages of development (Table 1). MTP inhibitors Liver-active MTP inhibitors have been associated with significant reductions in apo B-containing lipoprotein secretion both in vitro [99] and in vivo, as well as in experimental models of homozygous FH [100]. To date, lomitapide is the most studied MTP inhibitor in the clinical setting, thus being the sole agent of this class with an FDA approval. In an open-label study with 6 homozygous FH patients, lomitapide significantly decreased total cholesterol, LDL-C, apo B and triglyceride levels by 58, 51, 56 and 65.5%, respectively [101]. In another Phase II study in patients with hypercholesterolaemia (n = 84) who were randomized to ezetimibe (10 mg/day), lomitapide or their combination, LDL-C levels were dose-dependently reduced by up to 30% with lomitapide monotherapy and up to 46% with combination treatment [102]. Therefore, MTP inhibitors might be useful for the management of homozygous FH. To date, the latter is the sole FDA-approved indication for the use of lomitapide [103]. Similarly, in July 2013, the European Commission approved lomitapide as an adjunct to low-fat diet and other lipid-lowering drugs, with or without LDL aphaeresis, in adult patients with homozygous FH [104]. 6.1


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Table 1. Emerging lipid-modifying drugs that are in Phase II and III clinical trials.


Drug

Drug class

Mechanism of action

Mipomersen (ISIS 301012)

Apo B-100 antisense oligonucleotide

Inhibition of apoB-100 production

SLx-4090

MTP inhibitor

Lomitapide (AEGR-733 BMS-201038)

MTP inhibitor

Inhibition of the intracellular assembly of chylomicrons in the small intestine and VLDL particles Inhibition of the intracellular assembly of chylomicrons in the small intestine and VLDL particles

JTT-130

MTP inhibitor

Evolocumab (AMG145)

PCSK-9 inhibitor

Alirocumab (REGN727)

PCSK-9 inhibitor

RVX-208

CSL-112

Apo A-I synthesis activator Recombinant human Apo-A-1 based HDL mimetic Reconstituted HDL

Anacetrapib

Stage of development Marketed as Kynamro. Indicated for the management of homozygous FH Phase III Phase II Marketed as Juxtapid in the USA and Lojuxta in the EU. Indicated for the management of homozygous FH Phase III Phase II

Inhibition of the intracellular assembly of chylomicrons in the small intestine and VLDL particles Inhibition of LDL receptor degradation. Increase in liver’s ability to remove LDL-C from the circulation Inhibition of LDL receptor degradation. Increase in liver’s ability to remove LDL-C from the circulation Regulation of apo A-I and HDL synthesis in the liver and intestine Apo A-I and HDL-C elevation

Phase II

HDL-C elevation

Phase IIb

CETP inhibitor

CETP inhibition

Phase III

Evacetrapib (LY2484595)

CETP inhibitor

CETP inhibition

Phase I

DEZ-001

CETP inhibitor

CETP inhibition

Phase IIb

ISIS 308401

Apo C-III antisense oligonucleotide DGAT inhibitor

Apo C-III inhibition

Phase II

DGAT inhibition

Phase III

CER-001

LCQ-908

Company Isis Pharmaceuticals, Genzyme (Massachusetts, USA)

Surface Logix, Massachusetts, USA Aegerion Pharmaceuticals, New Jersey, USA

Japan Tobacco, Tokyo, Japan

Phase III

Amgen, Thousand Oaks, USA

Phase III

Sanofi/Regeneron Pharmaceuticals, Inc., Paris, France

Phase II

Resverlogix, Alberta, Canada Cerenis Therapeutics, SA, France CSL Behring, King of Prussia, Pennsylvania, USA Merck & Co, New Jersey, USA Eli Lilly& Co, Indianapolis, Indiana, USA Dezima Pharma, Amsterdam, the Netherlands Isis Pharmaceuticals, California, USA Novartis Pharmaceuticals, Basel, Switzerland

Apo: Apolipoprotein; CETP: Cholesterol ester transfer protein; DGAT: Diacylglycerol acyl transferases; EU: European Union; FH: Familial hypercholesterolemia; HDL-C: High density lipoprotein cholesterol; LDL: Low density lipoprotein; MTP: Microsomal triglyceride transfer protein; PCSK9: Proprotein convertase subtilisin/kexin type 9; VLDL: Very low density lipoprotein.

High-risk patients not at target, especially those who cannot tolerate intensive statin treatment, can experience significant LDL-C reductions with MTP inhibition. This also holds true for patients with very high baseline LDL-C levels, including those with heterozygous FH. Due to their great triglyceride-lowering capacity together with insulin sensitizing effects, these drugs may be a relevant treatment option for dyslipidaemia in insulin-resistant states, that is, metabolic syndrome, type 2 diabetes and chronic kidney disease. Patients with severe hypertriglyceridaemia may also benefit. 6

However, the effectiveness of MTP inhibitors in correcting lipid abnormalities other than homozygous FH and in reducing CVD events should be established in the clinical setting. The use of MTP inhibitors might be limited by adverse effects, with gastrointestinal disturbances being the most common [102]; these may be triggered by high-fat diet. Steatorrhoea may also occur with intestine-active MTP inhibitors due to increased fat availability in the intestinal lumen [72]. Fat intake restriction and administration of these drugs away from meals ameliorates these adverse effects [72].




Safety concerns have been raised by liver steatosis associated with the use of liver-active MTP inhibitors, an effect attributed to the accumulation of unsecreted lipids in the liver [105]. Liver steatosis may be suggested by aminotransferase elevation, reported in up to 67% lomitapide-treated patients [101,102]. It should be acknowledged that this safety issue is very important because NAFLD may progress to necroinflammation (steatohepatitis) and fibrosis (cirrhosis), increasing the risk of hepatocellular carcinoma [106,107]. Moreover, as NAFLD is considered an emerging risk predictor of vascular events [108], its development may counteract potential cardiovascular benefits of MTP inhibitors. Overall, these drugs may apply in certain patient populations, for example, those with FH. Future clinical studies are needed to assess the longterm safety and cardiovascular efficacy of MTP inhibitors. Mipomersen The most advanced ASO is mipomersen (Isis Pharmaceuticals, Genzyme, Massachusetts, USA), a 20-nucleotide second-generation ASO targeting human apo B-100 [109]. The production and secretion of apo B-48 from enterocytes, essential for chylomicron formation, is not inhibited by this agent. In two Phase II trials, mipomersen demonstrated prolonged, dose-dependent reductions in LDL-C, apo B, triglycerides and Lp(a) in patients with heterozygous FH and hypercholesterolaemia taking statins [110,111]. In another study in subjects with mild-to-moderate hyperlipidemia (n = 50), mipomersen dose-dependently reduced all apo B-containing lipoproteins at 13 weeks [112]. All subjects treated with mipomersen experienced injection site reactions, whereas 18% had transaminase elevations >3 times the upper limit of normal [112]. Alanine aminotransferase (ALT) elevation is a dose-dependant, common side effect of mipomersen that resolves with treatment discontinuation. In a placebo-controlled Phase II study, including 21 statin-treated patients with heterozygous FH, a trend towards an increase in intrahepatic triglyceride content was observed with mipomersen, although one patient developed mild hepatic steatosis that reversed with treatment discontinuation [113]. More recent data indicates an increase in intrahepatic triglyceride content, following more prolonged treatment with mipomersen [114]. Mipomersen has been assessed in several Phase III studies [114-118], whereas others are currently ongoing. In a multi-centre study in 51 patients ‡ 12 years old with homozygous FH who were on low-fat diet and maximum tolerated dose of a lipid-lowering drug, mipomersen was associated with reductions in LDL-C, apo B and Lp(a) levels (-24.7, -26.8 and -31.1%, respectively) [115]. In 124 adult patients with heterozygous FH, CHD and LDL-C ‡ 100 mg/dl (‡ 2.6 mmol/l) on maximally tolerated statin treatment, mipomersen (200 mg/week) for 26 weeks significantly reduced LDL-C, apo B and Lp(a) levels 6.2

compared with placebo (-28.0 vs + 5.2%, -26.3 vs + 7% and -21.1 vs 0%, respectively; all p < 0.001) [114]. Of note, this was the first trial to incorporate baseline and posttreatment hepatic fat assessments by MRI. Mipomersen induced a variable, modest, statistically significant increase in hepatic fat compared with placebo in most patients [114]. The clinical implications of this effect, as well as transaminase elevations, are unknown and should be clarified by large, longer-term clinical trials. In another study, 58 adult patients with LDL-C ‡ 300 mg/ dl (7.8 mmol/l) or LDL-C ‡ 200 mg/dl (5.1 mmol/l) plus CHD on maximally tolerated lipid-lowering therapy excluding aphaeresis were randomly assigned to mipomersen (200 mg/week) (n = 39) or placebo (n = 19) for 26 weeks [117]. LDL-C levels were reduced by 36% with mipomersen and increased by 13% with placebo (p < 0.001). Furthermore, mipomersen decreased apo B by 36% and Lp(a) by 33% (both p < 0.001 vs placebo), whereas HDL-C remained unaltered [117]. In 7 of the 12 mipomersen patients, the MRI revealed increased liver fat content, 3 of whom had steatosis [117]. Importantly, liver fat content significantly fell in 5 of the 6 patients who had a follow-up MRI after treatment cessation [117]. In a larger study, 158 adults with established or at high risk for CHD and baseline LDL-C levels ‡ 100 mg/dl (2.59 mmol/l) on maximally tolerated lipid-lowering therapy were randomized to mipomersen (200 mg/week) or placebo for 26 weeks [116]. Mipomersen induced similar reductions in LDL-C and apo B levels (-37 and -38%, respectively; p < 0.001 vs placebo) and a smaller decrease in Lp(a) (-24%; p < 0.001 vs placebo) [116]. A small study (n = 33) assessed the efficacy and safety of mipomersen (200 mg/week) in high-risk statin-intolerant patients [118]. Changes in LDL-C and apo B were somewhat greater than those of previous studies, that is, 47.3 and 46.2%, respectively, whereas Lp(a) was reduced by 27.1%. Liver fat content, assessed in selected subjects with magnetic resonance spectroscopy during and after treatment, ranged from 0.8 to 47.3%. Liver needle biopsy was performed in two of these subjects, confirming hepatic steatosis with minimal inflammation or fibrosis [118]. Apart from ALT and liver fat increase, injection site reactions and flu-like symptoms were the most common adverse effects in all mipomersen studies. Based on the aforementioned studies, it seems that certain patient populations may benefit from mipomersen treatment. These include patients with homozygous FH, who frequently do not reach treatment goals with the maximum tolerated lipid-lowering therapy and patients with severe heterozygous FH, who may not reach treatment goals due to very high baseline LDL-C levels or intolerance to high-dose statins. Mipomersen may also be of value in patients with severe hypercholesterolaemia and CHD who usually fall short of the very low recommended LDL-C treatment goals with other drugs. Finally, high risk,


7


M. Florentin et al.

statin-intolerant subjects who cannot achieve target LDL-C levels with other treatments may be candidates for mipomersen. Mipomersen was approved by the FDA in January 2013 for homozygous FH with a warning for the possible clinical consequences of liver fat accumulation, while the European Medicines Agency (EMA) has not approved this drug so far. Two ongoing clinical trials conducted in patients with FH or severe hypercholesterolaemia with or without CHD or CHD risk equivalent are currently assessing the effects of mipomersen on lipid profile [119,120]. A small study (n = 17) will assess the LDL-C lowering effect of mipomersen in patients with severe LDL hypercholesterolaemia treated with regular aphaeresis [121]. Phase I of the study will test how weekly therapy with mipomersen for 6 months affects LDL-C and Phase II will assess whether this will reduce aphaeresis time and frequency or if aphaeresis can be stopped completely. The estimated study completion date is November 2014 [121]. The results of these studies may extend the FDA indications for mipomersen and/or affect the EMA decision regarding this drug. PCSK9 inhibitors Two PCSK9 mAbs, namely evolocumab (AMG145; Amgen, Thousand Oaks, USA) and alirocumab (REGN727; Sanofi/ Regeneron Pharmaceuticals Inc, Paris, France), have been tested for their efficacy in Phase I/II trials in humans, whereas Phase III trials are ongoing. In 167 heterozygous FH patients on stable statin therapy (with or without ezetimibe) and LDL-C ‡ 100 mg/dl (2.6 mmol/l), evolocumab 350 mg and 420 mg decreased LDL-C by 43 and 55%, respectively (p < 0.001 vs placebo) [122]. Significant reductions were also observed in apo B, non-HDL-C and Lp(a) concentrations. In the LAPLACE-TIMI 57 trial, 631 patients with LDLC ‡ 85 mg/dl (2.2 mmol/l) on stable statin therapy (with or without ezetimibe) were randomized into 6 treatment arms with evolocumab at 70, 105 and 140 mg every 2 weeks or 280, 350 or 420 mg once a month and two placebo groups [123]. Evolocumab induced significant dose-dependent reductions in LDL-C up to 66%. In the GAUSS trial, evolocumab at various doses induced a significant dose-dependent decrease in LDL-C from 40.8 to 50.7% compared with baseline in 160 statin-intolerant patients [124]. The last Phase II study (MENDEL) evaluated the efficacy of evolocumab in 406 patients with LDL-C ‡ 100 mg/dl (2.6 mmol/l) [125]. The treatment groups were identical to those of LAPLACE-TIMI 57, with a complementary group receiving ezetimibe 10 mg. The dose-dependent reductions in LDL-C were similar to those observed in the LAPLACETIMI 57 trial with the monthly regimen (43.6 -- 52.5%), but smaller with the every 2 weeks regimen (37.3 -- 47.2%), suggesting that the monthly regimen may be a more favourable treatment option. 6.3

8

Finally, the efficacy of evolocumab in homozygous FH patients was tested in a pilot study including 8 patients (2 receptor negative and 6 receptor defective) [126]. Evolocumab 420 mg every 2 weeks and once a month decreased LDL-C by 26.3 and 19.3%, respectively, in receptor-defective patients, but induced no LDL-C reduction in receptor negative patients [126]. These preliminary results need to be confirmed in larger trials. Overall, the subcutaneous administration of evolocumab has been associated with a reduction in LDL-C (41 -- 66%) that depends on the dose and frequency of injection. Furthermore, PCSK9 mAbs have been shown to decrease Lp(a) by 9 -- 27% and modestly elevate HDL-C by 5 -- 12% [122-125]. Of note, the evolocumab-induced Lp(a) reduction contrasts with other drugs which upregulate the LDL-R that may be clinically important as high Lp(a) levels have been associated with CHD and stroke [127]. PROFICIO is an ongoing, clinical trial program including several Phase III studies with a combined planned enrolment of > 28,000 patients. In fact, results from three of them are awaited [128-130], whereas others are currently ongoing. An ongoing Phase III trial will evaluate the safety and efficacy of evolocumab compared with ezetimibe in 500 statin-intolerant hypercholesterolaemic patients [131]. The primary hypothesis is that evolocumab will be well tolerated and result in greater LDL-C reduction compared with ezetimibe. The estimated study completion date is April 2018 [131]. The GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound (GLAGOV) trial will evaluate whether LDL-C lowering with evolocumab results in greater change in percent atheroma volume compared with placebo in 950 subjects with CHD on hypolipidaemic therapy [132]. The Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk trial will assess the impact of additional LDL-C reduction with combined evolocumab/ statin therapy on MACE in 22,500 patients with CVD [133]. The estimated study completion date is January 2018. Finally, the Open label Study of Long term Evaluation against LDL-C Trial 2 (OSLER-2) will contribute to the evaluation of long-term safety, tolerability and efficacy of evolocumab in 3515 subjects with hyperlipidaemia and mixed dyslipidaemia [134]. The estimated study completion date is January 2017. Similarly to evolocumab, the administration of alirocumab was associated with significant LDL-C reduction, that is, 45 -- 65% in healthy subjects, 38 -- 72% in patients with heterozygous FH or primary hypercholesterolemia resistant to statins, 68% in heterozygous FH patients under statin therapy with or without ezetimibe and 73% in patients with primary hypercholesterolaemia resistant to statin therapy [135-138]. Alirocumab also exerted appreciable reductions in apo B, Lp (a) and triglycerides by maximums of 56, 34 and 19%, respectively and a slight elevation in HDL-C (maximum 8.5%) [135,136].




Currently, several Phase III trials with alirocumab, including the group of ODYSSEY trials, are underway or were recently completed and their results are awaited. The ODYSSEY CHOICE I [139] (n = 700 patients) and ODYSSEY CHOICE II [140] (n = 200 patients) trials will assess the LDL-C lowering effect of alirocumab, either as monotherapy or added to current lipid-lowering medication, in patients with hypercholesterolaemia. The former will be completed in May 2015 and the latter in June 2016. Two studies in patients with heterozygous FH not adequately controlled with their current treatment, namely ODYSSEY FH I [141] (n = 471) and ODYSSEY FH II [142] (n = 249), evaluated the LDL-C lowering effect of alirocumab at 24 weeks. In these studies, the reduction in LDL-C was nearly 49% from baseline, with the mean LDL-C concentration at 24 and 52 weeks reaching approximately 70 mg/dl (1.81 mmol/ l) [143]. The ODYSSEY OLE trial will assess the long-term safety (up to 120 weeks) of alirocumab when added to lipidlowering therapy in 1200 patients with heterozygous FH who have completed one of the 4 parent alirocumab studies (including the previous two ones) [144]. Furthermore, the ODYSSEY High FH study (n = 105) will assess the efficacy and safety of alirocumab in patients with heterozygous FH and LDL-C ‡ 160 mg/dl (4.14 mmol/l) while taking lipid modifying therapy [145]. The primary end point is LDL-C reduction at 24 weeks and the estimated study completion date is January 2015. The ODYSSEY Combo I trial evaluated the LDL-C lowering effect of alirocumab in 306 high cardiovascular risk patients with hypercholesterolaemia treated with maximally tolerated statin therapy with or without other drugs [146]. The results are expected soon. The ODYSSEY Combo II trial (n = 720) has similar design with the previous study, with the difference that alirocumab was not compared with placebo, but with ezetimibe [147]. In this study, alirocumab reduced LDL-C levels 50.6% from baseline compared with a 20.7% reduction among those who received ezetimibe (p < 0.0001) [143]. The ODYSSEY ALTERNATIVE trial will assess alirocumab safety and efficacy in 314 statin-intolerant patients with primary hypercholesterolaemia and moderate, high or very high cardiovascular risk [148] and will be completed in the next months. The ODYSSEY Long Term study evaluated the long-term safety and tolerability of alirocumab in 2341 high cardiovascular risk patients with hypercholesterolaemia not adequately controlled with their current therapy [149]. Alirocumab resulted in significantly larger reductions in LDL-C levels compared with placebo. In a post hoc analysis of this trial, alirocumab significantly reduced the risk of MACE compared with those who received placebo and a maximally tolerated statin treatment for 65 weeks [143]. Finally, the ongoing ODYSSEY Outcomes trial will assess the effect of alirocumab on the occurrence of cardiovascular events in 18,000 patients who experienced an ACS 4 -- 52 weeks before randomization and are on standard

lipid-modification treatment for ACS [150]. The estimated study completion date is January 2018. No direct comparisons have been made between evolocumab and alirocumab; indirectly, though it seems that their LDL-C lowering capacity is similar. Importantly, these drugs did not induce the adverse effects associated with statin use [122-125,135-138], making them a tempting option for statin-intolerant patients. Overall, it seems that PCSK9 inhibition may become a favourable option for lipid management in high-risk patients not achieving their treatment goals with current lipidlowering treatment well as in statin-intolerant patients. Of course, studies with cardiovascular outcomes are warranted to elucidate the exact role of this novel drug class. Apo A-I stimulation and reconstituted HDL and apo A-I 6.4.1 RVX-208 (Resverlogix, Alberta, Canada) 6.4

In the SUSTAIN, a 24-week trial that included 176 patients with established CVD, RVX-208 significantly increased HDL-C as well as apo A-I and large HDL particles, both being important for the enhancement of reverse cholesterol transport [151]. The SUSTAIN also demonstrated the safety of RVX-208 when given daily for 6 months, although elevations in ALT reported in previous trials were infrequent and transient with no new increases observed beyond week 12 [151]. ASSURE was a 26-week, multi-centre, randomized, double-blind, parallel group, placebo-controlled trial that assessed the early impact in atherosclerosis regression with RVX-208 in high risk patients (n = 281) with CVD. The primary end point in ASSURE, a 0.6% reduction in plaque atheroma volume, was not met. However, several secondary IVUS and lipid end points were met with high statistical significance [151]. Future development of RVX-208 focuses on CHD patients with at least an additional risk factor and low baseline HDL-C levels. CER-001 CER-001 is a synthetic HDL, comprised of recombinant human apo A-I complexed with phospholipids intended to mimic natural nascent HDL and transiently increase apo A-I and HDL particles to accelerate reverse lipid transport. Administration of CER-001 in healthy volunteers with an LDL:HDL equal to or higher than 3.0 induced elevations in plasma cholesterol, as well as total and free cholesterol in HDL fraction, suggesting enhanced reverse cholesterol transport [152]. The Modifying Orphan Disease Evaluation study evaluated the effect of CER-001 using carotid MRI in 23 patients with homozygous FH [153]. Patients were taking statins and 83% of them ezetimibe as well, whereas 40% of them had CHD. CER-001 reduced carotid mean vessel wall area and mean vessel volume (p = 0.008) [153]. In contrast, in a recently published study (CHI-SQUARE), CER-001 did not reduce total atheroma volume in patients (n = 507) 6.4.2


9

M. Florentin et al.

with ACS [154]. Whether this agent will prove beneficial in other populations or in different treatment regimens warrants further study. CSL112 A very recent study quantified cholesterol transport markers in subjects infused with a novel formulation of apo A-I (CSL112). HDL cholesterol increased up to 81 ± 16.5%, whereas an immediate and strong rise in the ability of plasma to promote cholesterol efflux from cells ex vivo was observed [155]. Approaches targeting other pathways of HDL metabolism are in early stages of development.


6.4.3

CETP inhibitors Anacetrapib (Merck Sharp & Dohme Corp., New Jersey, USA)

6.5

6.5.1

Anacetrapib has been associated with significant dosedependent HDL-C and apo A-I elevations, as well as LDL-C, apo B and Lp(a) reductions in Phase I and II trials [156]. The Determining the EFficacy and tolerability of cholesteryl ester transfer protein INhibition with anacEtrapib (DEFINE), a multi-centre, randomized, double-blind, placebo-controlled trial (n = 1623) assessed the efficacy and safety of anacetrapib in patients with CHD or at risk for CHD (10-year Framingham Risk Score >20%) [157]. Anacetrapib demonstrated significant changes in LDL-C (-39.8%) and HDL-C (138.1%) compared with placebo (p < 0.001 for both) at 24 weeks. Significant respective changes were also observed in apo A-I and apo B levels (p < 0.001 for both vs placebo), as well as Lp(a) concentration (p < 0.05 vs placebo). Furthermore, anacetrapib conferred significant changes in C-reactive protein (18.3%) and triglycerides (-5.3%) [157]. Interestingly, a post hoc analysis of the DEFINE study showed a difference in the number of coronary revascularization procedures between the 2 groups at 76 weeks (8 [1.0%] in the anacetrapib group versus 28 [3.5%] in the placebo group, p = 0.001) [157]. These promising results should be interpreted with caution as this study was not designed to assess differences in CVD outcomes. A 2-year extension of the DEFINE trial is currently ongoing and will further evaluate the long-term safety and efficacy of anacetrapib in patients with established or at risk of CHD [158]. The effects of anacetrapib in lipid profile, when added to ongoing statin therapy, are being assessed in several Phase III trials. One of them involving patients with heterozygous FH has been completed and its results are awaited [159], whereas another one in Japanese patients with dyslipidaemia will be completed next year [160]. The primary outcome in both studies is the change in LDL-C from baseline, whereas HDL-C change is included in the secondary end points. Likewise, a Phase III, double-blind, randomized, placebocontrolled study will evaluate the effects of anacetrapib on 10

top of statin on LDL-C in Japanese participants with heterozygous FH (n = 64) [161]. Another study with similar design and end points is being conducted in adult patients with homozygous FH (n = 45) [162]. Both studies will be completed this year. The Randomized EValuation of the Effects of Anacetrapib through Lipid-modification trial will assess the efficacy of anacetrapib (100 mg) in cardiovascular outcomes in patients ‡ 50 years with a history of CVD and currently being treated with a statin [163]. The primary assessment will involve an intention-to-treat comparison between anacetrapib and placebo on major coronary events. The trial is expected to enrol 30,000 participants who will be followed for up to 4 years. The estimated completion date is January 2017 [163]. Another ongoing study will evaluate the effects of two different doses of anacetrapib (i.e., 25 and 100 mg) on top of statin on lipid profile in patients with CHD or other atherosclerotic vascular disease and multiple risk factors and/or high LDL-C/low HDL-C or needing to meet a specific LDL-C/HDL-C goal. The number of patients to be enrolled is 450 and the estimated completion date is February 2015 [164]. A larger study (n = 800) with similar design and end points is still recruiting patients; the completion date is August 2015 [165]. The available evidence suggests that anacetrapib is a welltolerated drug, with mild, common (e.g., headache, gastrointestinal disorders and myalgia), transient side effects [166,167]. Whether the beneficial lipid effects of anacetrapib will be translated into CVD reduction will hopefully be answered by studies with cardiovascular end points. We should note though that the pharmacokinetics of anacetrapib may be an obstacle for its widespread use, as residual concentrations of anacetrapib remain significantly elevated after treatment cessation. In the DEFINE study, anacetrapib levels were approximately 40% of the on-treatment levels 12 weeks after treatment termination [168]. Moreover, in a small subset of patients, low concentrations of anacetrapib were detectable in plasma as late as 4 years after the last treatment dose [168]. So far, no clinically important differences in liver enzymes, blood pressure, electrolytes or adverse events have been reported in anacetrapib-treated patients compared with the placebo group. However, the long-term safety and potent side effects attributed to the extended presence of the drug in the human body remain unknown. Evacetrapib (Eli Lilly and Co., Indianapolis, Indiana)

6.5.2

Evacetrapib is another CETP inhibitor currently under investigation. In a 12-week Phase II trial, evacetrapib significantly increased HDL-C (up to approximately 130%) and reduced LDL-C (up to 36%) in patients with dyslipidemia (n = 398) (p < 0.001 vs placebo for both) [169]. Furthermore, triglycerides were significantly reduced with the administration of the highest dose of evacetrapib (10.8%; p = 0.006 vs placebo). The combination of evacetrapib with a statin resulted in




greater reductions in LDL-C but no greater elevation in HDL-C levels compared with evacetrapib monotherapy. Importantly, evacetrapib did not affect blood pressure or serum aldosterone levels [169]. An ongoing Phase III trial will assess the efficacy of evacetrapib in the prevention of cardiovascular events in patients with CVD (estimated 11,000 participants) [170]. The primary outcome will be time to first occurrence of cardiovascular death, myocardial infarction, stroke, coronary revascularization procedure or hospitalization for unstable angina. The expected completion date of the study is September 2015 [170].

DEZ-001 (Dezima Pharma, Amsterdam, the Netherlands)

6.5.3

A less well recognized CETP inhibitor, DEZ-001, has completed single and multiple ascending dose studies in healthy volunteers, demonstrating beneficial effects on HDL-C and LDL-C levels along with a favourable safety profile. The company plans to support clinical development of DEZ-001 to Phase III studies [171].

Other CETP inhibitors Three other CETP inhibitors, namely BAY 60-5521 (Bayer, Leverkusen, Germany) [172], JTT-302 (Japan Tobacco, Inc., Tokyo, Japan) [156] and DRL-17822 (Dr. Reddy’s Laboratories Ltd., Andhra Pradesh, India) [173] have undergone Phase II testing, but do not currently have any ongoing trials. 6.5.4

7.

Potential development issues

The residual cardiovascular risk after LDL-C lowering with statins and the futility of several agents in terms of CVD outcomes stresses the imperative need of developing novel lipid modifying drugs. The most promising drug classes seem to be MTP and PCSK-9 inhibitors. Whether the remaining CETP inhibitors will become a useful therapeutic option depends on the ongoing studies. Similarly, whether cholesterol absorption inhibitors other than ACAT inhibitors will be developed in the future remains unknown, although the role of novel agents targeting HDL and triglycerides warrants several large scale trials to be delineated. At this point, we will discuss some concerns regarding the development of the aforementioned or other drugs. The construction of agents targeting at molecular mechanisms is costly, whereas in order for studies to show superiority of new drugs, these need to be large and, thus, expensive to conduct. Moreover, these studies can only involve patients taking statins (or another treatment in cases of statin intolerance), as it would be unethical to leave these high-risk individuals untreated. Therefore, the net effect of novel agents cannot be easily evaluated.

8.

Conclusion

Scientific advances in cholesterol metabolism have provided novel potential targets for the treatment of lipid abnormalities. Emerging drugs aim at LDL-C reduction or improvement of other lipid disorders, mainly low HDL-C. Apo B-100 ASOs, MTP and PCSK-9 inhibitors have been associated with significant LDL-C reduction, whereas other drugs focusing on LDLC have so far failed. HDL-C elevation could potently be achieved with several drugs; it appears, though, that the quality and properties of HDL may be more important than high HDL-C concentration. Large, long-term clinical studies with cardiovascular end points are warranted to establish the role of HDL-C elevation per se as well as the safety and efficacy of these agents in CVD outcomes. 9.

Expert opinion

Hypercholesterolaemia is a major risk factor for the development of CVD. So far, only statins have been constantly associated with benefits in terms of cardiovascular outcomes. In contrast, the long term cardiovascular efficacy of several currently used and novel agents with beneficial lipidmodifying properties is ambiguous. Fibrates, for example, appear to reduce microvascular rather than macrovascular complications of diabetes, whereas several novel agents of various classes did not improve CVD. Thus, the fundamental objective of drugs in development is the amelioration of the residual risk after intense LDL-C lowering with statins. Mipomersen, is the most advanced ASO and is FDAapproved for FH. This may become a useful therapy for subjects with severe heterozygous or homozygous FH, severe hypercholesterolaemia and CVD and certain high-risk, statin-intolerant patients who do not reach treatment goals with their current therapy. MTP inhibitors have been demonstrated to effectively improve atherogenic dyslipidaemia and may apply in specific patient populations, such as those with FH or severe mixed dyslipidemia. Hepatic steatosis and subsequent NAFLD development, which could limit their use, may probably be overcome by concomitant treatment with other drugs (e.g., fibrates) Large, long-term studies are warranted to investigate this issue. The failure of torcetrapib and dalcetrapib was disappointing as CETP inhibition was a promising strategy for CVD reduction. It still remains unknown whether the specific molecules or the drug class are responsible for these findings. Ongoing studies with other CETP inhibitors will hopefully address this issue. Overall, the challenge of novel agents is not just to improve lipid abnormalities, rather CVD outcomes. Despite the progress in the field of lipid-modifying drugs, it is difficult to predict whether these will radically change CVD prevention and management, as some drugs failed and long-term clinical trials with others are lacking.


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Affiliation Matilda Florentin1, Michael S Kostapanos1 MD, Anastazia Kei1, Moses S Elisaf †2 MD FASA FRSH † Author for correspondence 1 Medical School, University of Ioannina, Department of Internal Medicine, Ioannina, Greece 2 Professor of Internal Medicine, Medical School, University of Ioannina, Department of Internal Medicine, Ioannina, Greece Tel: +30 26510 07509; Fax: +30 26510 07016; E-mail: [email protected]

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