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Hovingh G.K.,University of Amsterdam | Kastelein J.J.P.,University of Amsterdam | Kastelein J.J.P.,Dezima Pharma BV | Van Deventer S.J.H.,Dezima Pharma BV | And 8 more authors.
The Lancet | Year: 2015

Background Dyslipidaemia remains a significant risk factor for cardiovascular disease and additional lipid-modifying treatments are warranted to further decrease the cardiovascular disease burden. We assessed the safety, tolerability and efficacy of a novel cholesterol esterase transfer protein (CETP) inhibitor TA-8995 in patients with mild dyslipidaemia. Methods In this randomised, double-blind, placebo-controlled, parallel-group phase 2 trial, we recruited patients (aged 18-75 years) from 17 sites (hospitals and independent clinical research organisations) in the Netherlands and Denmark with fasting LDL cholesterol levels between 2·5 mmol/L and 4·5 mmol/L, HDL cholesterol levels between 0·8 and 1·8 mmol/L and triglyceride levels below 4·5 mmol/L after washout of lipid-lowering treatments. Patients were randomly allocated (1:1) by a computer-generated randomisation schedule to receive one of the following nine treatments: a once a day dose of 1 mg, 2·5 mg, 5 mg, or 10 mg TA-8995 or matching placebo; 10 mg TA-8995 plus 20 mg atorvastatin; 10 mg TA-8995 plus 10 mg rosuvastatin or 20 mg atorvastatin or 10 mg rosuvastatin alone. We overencapsulated statins to achieve masking. The primary outcome was percentage change in LDL cholesterol and HDL cholesterol from baseline at week 12, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01970215. Findings Between Aug 15, 2013, and Jan 10, 2014, 364 patients were enrolled. At week 12, LDL cholesterol levels were reduced by 27·4% in patients assigned to the 1 mg dose, 32·7% in patients given the 2·5 mg dose, 45·3% in those given the 5 mg dose, and 45·3% in those given the 10 mg dose (p<0·0001). LDL cholesterol levels were reduced by 68·2% in patients given 10 mg TA-8995 plus atorvastatin, and by 63·3% in patients given rosuvastatin plus 10 mg TA-8995 (p<0·0001). A daily dose of 1 mg TA-8995 increased HDL cholesterol levels by 75·8%, 2·5 mg by 124·3%, 5 mg by 157·1%, and 10 mg dose by 179·0% (p<0·0001). In patients receiving 10 mg TA-8995 and 20 mg atorvastatin HDL cholesterol levels increased by 152·1% and in patients receiving 10 mg TA-8995 and 10 mg rosuvastatin by 157·5%. We recorded no serious adverse events or signs of liver or muscle toxic effects. Interpretation TA-8995, a novel CETP inhibitor, is well tolerated and has beneficial effects on lipids and apolipoproteins in patients with mild dyslipidaemia. A cardiovascular disease outcome trial is needed to translate these effects into a reduction of cardiovascular disease events. Funding Dezima. © 2015 Elsevier Ltd.


Ford J.,Dezima Pharma BV | Ford J.,Xention Ltd | Lawson M.,Mitsubishi Pharma Europe Ltd. | Fowler D.,Mitsubishi Pharma Europe Ltd. | And 15 more authors.
British Journal of Clinical Pharmacology | Year: 2014

Aims Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Methods Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150 mg (Caucasian males, 18-55 years), 25 mg (Caucasian males, > 65 years and Caucasian females, 18-55 years), 25, 50, 100 and 150 mg (Japanese males, 18-55 years). Study 2: Caucasian males (18-55 years) received 1, 2.5, 10 or 25 mg once daily TA-8995 or placebo for 21-28 days. Blood and urine for pharmacokinetics and/or pharmacodynamics were collected. Tolerability was assessed by adverse events, vital signs, electrocardiograms and laboratory safety tests. Results Peak TA-8995 concentrations occurred approximately 4 h post-dose. Mean half-lives ranged from 81 to 166 h, without an obvious dose relationship. Exposure increased less than proportionally to dose. TA-8995 was not excreted in urine. Following 2.5 to 25 mg once daily dosing, TA-8995 demonstrated nearly complete inhibition of CETP activity (92-99%), increased high density lipoprotein-cholesterol (HDL-C) by 96 to 140% and decreased low density liporotein-cholesterol (LDL-C) by 40% to 53%. There were dose-related increases in apolipoproteins A-1 and E, HDL2-C and HDL3-C, and decreases in apolipoprotein B and lipoprotein A. There was no evidence of significant effects of age, gender, ethnicity or food on pharmacokinetics or pharmacodynamics. All doses were well tolerated. Conclusions TA-8995 is a potent CETP inhibitor and warrants further investigation. © 2014 The British Pharmacological Society.


Arsenault B.J.,University of Quebec | Arsenault B.J.,University Laval | Boyer M.,University of Quebec | Boyer M.,University Laval | Kastelein J.J.P.,Dezima Pharma BV
Current Opinion in Lipidology | Year: 2015

Purpose of review: This article summarizes the latest studies relevant to cholesteryl ester transfer protein (CETP) inhibition and cardiovascular risk and proposes a series of patient populations that might eventually derive benefits from CETP inhibition. Recent findings: Results of recently published genetic epidemiology studies have helped shape our understanding of the association between lipoprotein-lipid levels and cardiovascular disease risk. These studies have confirmed the proatherogenic role of apolipoprotein B-containing lipoproteins and triglycerides and renewed our interest for lipoprotein(a) as a significant and causal predictor of cardiovascular risk. The association between HDL cholesterol levels and cardiovascular risk, albeit strong and consistent, is unlikely to be of causative nature, at least according to genetic epidemiology. However, a handful of intriguing studies have highlighted a predictive role for HDL cholesterol efflux capacities in predicting cardiovascular risk independently of HDL cholesterol levels. Potent CETP inhibitors, currently under investigation, significantly decrease apolipoprotein B-containing lipoproteins and lipoprotein(a) and increase both HDL cholesterol levels and HDL cholesterol efflux capacities. Summary: Two phase 3 cardiovascular outcomes trials testing the hypothesis that CETP inhibition will reduce cardiovascular outcomes in high-risk patients are well underway. The future of CETP inhibition will depend on the outcomes of these trials. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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