Safety and Tolerability of Dalcetrapib

doi:10.1016/j.amjcard.2009.02.061

The American Journal of Cardiology

Volume 104, Issue 1, 1 July 2009, Pages 82-91

https://doi.org/10.1016/j.amjcard.2009.02.061 Get rights and content

Efficacy and safety data for dalcetrapib (RO4607381/JTT-705) are presented, following a report of increased mortality and cardiac events with another cholesteryl ester transfer protein inhibitor, torcetrapib, associated with off-target adverse effects (hypertension and the activation of the renin-angiotensin-aldosterone system). The efficacy and clinical safety of dalcetrapib 300, 600, and 900 mg or placebo were assessed (n = 838) in 4 pooled 4-week phase IIa trials (1 monotherapy, n = 193; 3 statin combination, n = 353) and 1 12-week phase IIb trial (with pravastatin, n = 292). Nonclinical safety, assessed by the induction of aldosterone production and aldosterone synthase (cytochrome P450 11B2) messenger ribonucleic acid, was measured in human adrenocarcinoma (H295R) cells exposed to dalcetrapib or torcetrapib. Dalcetrapib increased high-density lipoprotein cholesterol by up to 36% and apolipoprotein A-I by up to 16%. The incidence of adverse events (AEs) was similar between placebo (42%) and dalcetrapib 300 mg (50%) and 600 mg (42%), with more events with dalcetrapib 900 mg (58%) (p <0.05, pooled 4-week studies). Six serious AEs (3 with placebo, 1 with dalcetrapib 300 mg, and 2 with dalcetrapib 600 mg) were considered “unrelated” to treatment. Cardiovascular AEs were similar across treatment groups, with no dose-related trends and no clinically relevant changes in blood pressure or electrocardiographic results. Findings were similar in the 12-week study. In vitro, torcetrapib but not dalcetrapib increased aldosterone production and cytochrome P450 11B2 messenger ribonucleic acid levels. In conclusion, dalcetrapib alone or in combination with statins was effective at increasing high-density lipoprotein cholesterol and was well tolerated, without clinically relevant changes in blood pressure or cardiovascular AEs and no effects on aldosterone production as assessed nonclinically.

Section snippets

Methods

Five double-blind, randomized, placebo-controlled phase II trials of dalcetrapib were conducted in patients with dyslipidemia, CHD, or CHD risk equivalents. Inclusion criteria are listed in Table 1. Exclusion criteria were body mass index ≥35 kg/m² (≥40 kg/m² for the 12-week study); uncontrolled hypertension; diabetes (except for 2 studies in which it was considered a CHD risk equivalent); clinically significant arterial, hepatic, renal, cardiac, or cerebral disease; hepatic transaminase >1.5

Results

In the 4-week studies, a total of 546 of 551 randomized patients received ≥1 dose of study medication (safety population), and 546 patients were included in the efficacy (intent-to-treat) population (Figure 1). In the 12-week study, 292 patients were randomized (safety population), and 287 patients were in the efficacy population (Figure 1). For the phase IIa studies, patients in the dalcetrapib 300 and 900 mg groups were of greater (p <0.05) mean age and body mass index and had greater (p

Discussion

In this analysis, dalcetrapib effectively increased levels of HDL cholesterol and apolipoprotein A-I. The pooled and 12-week data presented support the findings of the 2 previously published individual trials5, 6 (included in this analysis). Dalcetrapib reduced CETP activity and increased CETP mass. Although comparisons with torcetrapib are limited because of study differences, a phase I study reported CETP decreases of up to 53% with torcetrapib.¹⁰ A comparative in vitro study has reported

Acknowledgment

We thank the investigators, study staff members, and patients who participated in these studies. Editorial assistance was provided to the authors by Teresa Haigh and Emma Marshman (Prime Healthcare). Portions of these data were presented at the 2008 Annual Scientific Session of the American College of Cardiology, Chicago, Illinois, and the European Atherosclerosis Society Congress 2008, Istanbul, Turkey.

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Cholesteryl ester transfer protein (CETP) inhibitors are a new class of therapeutics for dyslipidemia that simultaneously improve two major cardiovascular disease (CVD) risk factors: elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol. However, the detailed molecular mechanisms underlying their efficacy are poorly understood, as are any potential mechanistic differences among the drugs in this class. Herein, we used electron microscopy (EM) to investigate the effects of three of these agents (Torcetrapib, Dalcetrapib and Anacetrapib) on CETP structure, CETP-lipoprotein complex formation and CETP-mediated cholesteryl ester (CE) transfer. We found that although none of these inhibitors altered the structure of CETP or the conformation of CETP-lipoprotein binary complexes, all inhibitors, especially Torcetrapib and Anacetrapib, increased the binding ratios of the binary complexes (e.g., HDL-CETP and LDL-CETP) and decreased the binding ratios of the HDL-CETP-LDL ternary complexes. The findings of more binary complexes and fewer ternary complexes reflect a new mechanism of inhibition: one distal end of CETP bound to the first lipoprotein would trigger a conformational change at the other distal end, thus resulting in a decreased binding ratio to the second lipoprotein and a degraded CE transfer rate among lipoproteins. Thus, we suggest a new inhibitor design that should decrease the formation of both binary and ternary complexes. Decreased concentrations of the binary complex may prevent the inhibitor was induced into cell by the tight binding of binary complexes during lipoprotein metabolism in the treatment of CVD.
Dyslipidemia management update
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Citation Excerpt :
Since CETP transports cholesteryl esters from HDL to VLDL or LDL in exchange for triglycerides, increased CETP activity is considered as a major determinant of low HDL-C. Several CETP inhibitors have been tested, including anacetrapib, evacetrapib, and dalcetrapib. These studies have shown that in patients already receiving statin therapy, the three CETP inhibitors increase HDL levels by approximately 140%, 80% and 30%, respectively [43–45], but similar to the niacin trial, treatment failed to reduce cardiovascular events [46]. These findings raised questions about whether medically increasing HDL-C has anti-atherogenic properties and whether simply measuring circulating HDL-C levels is enough to predict the risk of cardiovascular events.
Association of hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) is well established. Reducing low-density lipoprotein-cholesterol (LDL-C) and raising high-density lipoprotein-cholesterol (HDL-C) have been the therapeutic targets to reduce the risk of ASCVD. Cholesterol-lowering medications have been used to provide both primary and secondary prevention of ASCVD for many years by reducing the absorption and reabsorption, promoting excretion, or decreasing the synthesis of cholesterol. Within the past five years, several new classes of cholesterol-lowering drugs have been tested and approved for patients with hypercholesterolemia that are not well controlled by conventional therapy (ezetimibe, bile-acid sequestrants, and statins). These drugs include proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies, apolipoprotein A-100 (Apo B-100) antisense, and microsomal triglyceride transfer protein (MTP) inhibitor. Clinical trials revealed that adding PCSK9 antibodies to the preexisting statin therapy can further reduce LDL-C by 60%. ApoB antisense and MTP inhibitor are currently approved for patients with homozygous familial hypercholesterolemia. Several HDL-raising drugs have also been tested, but the results are not promising. Studies suggest that specifically raising reverse cholesterol transport rather than HDL-C level could be a novel therapeutic approach to reduce cardiovascular risk.
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There is a strong epidemiological relationship between high density lipoproteins and atherosclerotic coronary vascular disease (ASCVD). The process of reverse cholesterol transport (RCT) has been hypothesized to help explain this relationship. The corollary that raising HDL should reduce ASCVD is also drawn from this relationship. In recent years, the metabolism of HDL has become better understood. A hypothetical process for explaining RCT has been superimposed on the currently understood HDL metabolic pathways.
Outline of HDL metabolism and the superimposed RCT process. Literature review of studies of persons with genetic defects, HDL cholesterol raising clinical trials, Mendelian randomization studies and treatments with molecules that mimic HDL.
Mutation studies of ABCA1, LCAT and SR-B1 genes in humans showed expected variations in HDLC but little association with ASCVD and there was no significant association between HDLC and ASCVD in Mendelian randomization studies. Elevations in HDLC due to treatment with niacin and cholesteryl ester transport protein inhibitors in randomized trials raised HDLC but did not significantly reduce risk of ASCVD. Treatment with molecules that mimic HDL did not seem to reduce ASCVD. Thus, recent evidence does not seem to support RCT as currently proposed. This hypothesis seems to need substantial revision.
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CETP inhibitors block the transfer of cholesteryl ester from HDL-C to VLDL-C and LDL-C, thereby raising HDL-C and lowering LDL-C. In this study, we explored the effect of CETP inhibitors on hepatic LDL receptor (LDLR) and PCSK9 expression and further elucidated the underlying regulatory mechanism.
We first examined the effect of anacetrapib (ANA) and dalcetrapib (DAL) on LDLR and PCSK9 expression in hepatic cells in vitro. ANA exhibited a dose-dependent inhibition on both LDLR and PCSK9 expression in CETP-positive HepG2 cells and human primary hepatocytes as well as CETP-negative mouse primary hepatocytes (MPH). Moreover, the induction of LDLR protein expression by rosuvastatin in MPH was blunted by cotreatment with ANA. In both HepG2 and MPH ANA treatment reduced the amount of mature form of SREBP2 (SREBP2-M). In vivo, oral administration of ANA to dyslipidemic C57BL/6J mice at a daily dose of 50 mg/kg for 1 week elevated serum total cholesterol by approximately 24.5% (p < 0.05%) and VLDL-C by 70% (p < 0.05%) with concomitant reductions of serum PCSK9 and liver LDLR/SREBP2-M protein. Finally, we examined the in vitro effect of two other strong CETP inhibitors evacetrapib and torcetrapib on LDLR/PCSK9 expression and observed a similar inhibitory effect as ANA in a concentration range of 1–10 μM.
Our study revealed an unexpected off-target effect of CETP inhibitors that reduce the mature form of SREBP2, leading to attenuated transcription of hepatic LDLR and PCSK9. This negative regulation of SREBP pathway by ANA manifested in mice where CETP activity was absent and affected serum cholesterol metabolism.
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A crucial question that must be addressed in the drug development process is whether the proposed therapeutic target will yield the desired effect in the clinical population. Pharmaceutical and biotechnology companies place a large investment on research and development, long before confirmatory data are available from human trials. Basic science has greatly expanded the computable knowledge of disease processes, both through the generation of large omics data sets and a compendium of studies assessing cellular and systemic responses to physiologic and pathophysiologic stimuli. Given inherent uncertainties in drug development, mechanistic systems models can better inform target selection and the decision process for advancing compounds through preclinical and clinical research.
The current state of niacin in cardiovascular disease prevention: A systematic review and meta-regression
2013, Journal of the American College of Cardiology
This study sought to assess the efficacy of niacin for reducing cardiovascular disease (CVD) events, as indicated by the aggregate body of clinical trial evidence including data from the recently published AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial.
Previously available randomized clinical trial data assessing the clinical efficacy of niacin has been challenged by results from AIM-HIGH, which failed to demonstrate a reduction in CVD event incidence in patients with established CVD treated with niacin as an adjunct to intensive simvastatin therapy.
Clinical trials of niacin, alone or combined with other lipid-altering therapy, were identified via MEDLINE. Odds ratios (ORs) for CVD endpoints were calculated with a random-effects meta-analyses. Meta-regression modeled the relationship of differences in on-treatment high-density lipoprotein cholesterol with the magnitude of effect of niacin on CVD events.
Eleven eligible trials including 9,959 subjects were identified. Niacin use was associated with a significant reduction in the composite endpoints of any CVD event (OR: 0.66; 95% confidence interval [CI]: 0.49 to 0.89; p = 0.007) and major coronary heart disease event (OR: 0.75; 95% CI: 0.59 to 0.96; p = 0.02). No significant association was observed between niacin therapy and stroke incidence (OR: 0.88; 95% CI: 0.5 to 1.54; p = 0.65). The magnitude of on-treatment high-density lipoprotein cholesterol difference between treatment arms was not significantly associated with the magnitude of the effect of niacin on outcomes.
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: This study was supported by F. Hoffmann-La Roche Ltd., Basel, Switzerland.

^†: Conflicts of interest: Dr. Stein has received grants for studies of lipid-modifying agents, has received consulting fees and honoraria for professional input regarding agents to modify lipid profile, and/or has delivered lectures for the American Association for Clinical Chemistry, Washington, District of Columbia; Abbott Laboratories, Abbott Park, Illinois; AstraZeneca, Wilmington, Delaware; the United States Food and Drug Administration, Washington, District of Columbia; F. Hoffmann-La Roche Ltd., Basel, Switzerland; Isis Pharmaceuticals, Inc., Carlsbad, California; Merck & Co., Whitehouse Station, New Jersey; the National Lipid Association, Jacksonville, Florida; Novartis International AG, Basel Switzerland; Reliant Pharmaceuticals, Inc., Liberty Corner, New Jersey; Daiichi Sankyo Co., Ltd., Tokyo, Japan; Schering-Plough Corporation, Kenilworth, New Jersey; Takeda Pharmaceutical Company Ltd., Osaka, Japan; and Wyeth, Madison, New Jersey. Dr. Stroes has received consulting fees and honoraria from F. Hoffmann-La Roche Ltd. and Novartis International AG. Dr. Steiner has received consulting fees and honoraria from F. Hoffmann-La Roche Ltd.; Solvay, Brussels, Belgium; Ethypharm S.A., Saint-Cloud, France; and Merck Frosst Canada Ltd. (Kirkland, Quebec, Canada)/Schering-Plough Corporation. Dr. Buckley has received research grants from AstraZeneca; Merck Sharp & Dohme, Dublin, Ireland; and Pfizer, Inc., New York, New York. Dr. Buckley has received honoraria and consulting fees and/or delivered lectures for AstraZeneca; Bristol-Myers Squibb, New York, New York; F. Hoffmann-La Roche Ltd.; Novartis International AG; Pfizer, Inc.; and Sanofi-Aventis, Paris, France. Dr. Capponi has received consulting fees and honoraria from F. Hoffmann-La Roche Ltd. Dr. Burgess is an employee of Hoffmann-La Roche Inc., Nutley, New Jersey. Drs. Niesor and Kallend are employees of F. Hoffmann-La Roche Ltd. Dr. Kastelein has received research grants, honoraria, or consulting fees for professional input and/or has delivered lectures for Pfizer, Inc.; Merck Sharp & Dohme; F. Hoffmann-La Roche Ltd.; Novartis International AG; Isis Pharmaceuticals, Inc.; Kowa Pharmaceutical Company Ltd., Nagoya, Japan; Schering-Plough Corporation; and AstraZeneca.

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Preventive cardiologySafety and Tolerability of Dalcetrapib†

Section snippets

Methods

Results

Discussion

Acknowledgment

Atherosclerosis

Am J Cardiol

Lancet

J Am Coll Cardiol

Lancet

Pharmacol Ther

J Am Coll Cardiol

J Lipid Res

J Lipid Res

HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events

N Engl J Med

High-density lipoproteins: a new potential therapeutic target for the prevention of cardiovascular disease

Arterioscler Thromb Vasc Biol

Emerging therapies targeting high-density lipoprotein metabolism and reverse cholesterol transport

Circulation

Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomised phase II dose response study

Circulation

Preventive cardiology
Safety and Tolerability of Dalcetrapib^†