ta-8995 and Dyslipidemias

Although biomarkers are used as surrogate measures for drug targeting and approval and are generally based on plausible biological hypotheses, some are found to not correlate well with clinical outcomes. Over-reliance on inadequately validated biomarkers in drug development can lead to harm to trial subjects and patients and to research waste. To shed greater light on the process and ethics of biomarker-based drug development, we conducted a systematic portfolio analysis of cholesterol ester transfer protein inhibitors, a drug class designed to improve lipid profiles and prevent cardiovascular events. Despite years of development, no cholesterol ester transfer protein inhibitor has yet been approved for clinical use.. We searched PubMed and Clinicaltrials.gov for clinical studies of 5 known cholesterol ester transfer protein inhibitors: anacetrapib, dalcetrapib, evacetrapib, TA-8995, and torcetrapib. Published reports and registration records were extracted for patient demographic characteristics and study authors' recommendations of clinical usage or further testing. We used Accumulating Evidence and Research Organization graphing to depict the portfolio of research activities and a Poisson model to examine trends. We identified 100 studies for analysis that involved 96 944 human subjects. The data from only 41 201 (42%) of the human subjects had been presented in a published report. For the 3 discontinued cholesterol ester transfer protein inhibitors, we found a pattern of consistently positive results on lipid-modification end points followed by negative results using clinical end points.. Inefficiencies and harms can arise if a biomarker hypothesis continues to drive trials despite successive failures. Regulators, research funding bodies, and public policy makers may need to play a greater role in evaluating and coordinating biomarker-driven research programs.

Topics: Amides; Anticholesteremic Agents; Benzodiazepines; Biomarkers, Pharmacological; Cholesterol Ester Transfer Proteins; Drug Approval; Drug Discovery; Dyslipidemias; Endpoint Determination; Esters; Humans; Lipids; Oxazolidinones; Predictive Value of Tests; Quinolines; Reproducibility of Results; Sulfhydryl Compounds; Time Factors; Treatment Outcome

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.. 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.. 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.. 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.. Dezima.

Topics: Adolescent; Adult; Aged; Atorvastatin; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Denmark; Double-Blind Method; Dyslipidemias; Female; Fluorobenzenes; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Netherlands; Pyrimidines; Pyrroles; Quinolines; Rosuvastatin Calcium; Sulfonamides; Treatment Outcome; Young Adult