Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with heterozygous familial hypercholesterolemia.

BACKGROUND AND AIMS: This multicenter, randomized, double-blind, placebo-controlled study assessed the lipid-modifying efficacy/safety profile of anacetrapib 100 mg added to ongoing statin ± other lipid-modifying therapies (LMT) in Japanese patients with heterozygous familial hypercholesterolemia (HeFH). METHODS: Patients 18-80 years with a genotype-confirmed/clinical diagnosis of HeFH who were on a stable dose of statin ± other LMT for ≥6 weeks and with an LDL-C concentration ≥100 mg/dL were randomized to anacetrapib 100 mg (n = 34) or placebo (n = 34) for 12 weeks, followed by a 12-week off-drug reversal phase. The primary endpoints were percent change from baseline in LDL-C (beta-quantification method [BQ]) and safety/tolerability. RESULTS: At Week 12, treatment with anacetrapib reduced LDL-C (BQ) compared to placebo and resulting in a between-group difference of 29.8% (95% CI: -38.6 to -21.0; p < 0.001) favoring anacetrapib. Anacetrapib also reduced non-HDL-C (23. 6%; p < 0.001), ApoB (14.1%; p < 0.001) and Lp(a) (48.7%; p < 0.001), and increased HDL-C (110.0%; p < 0.001) and ApoA1 (48.2%; p < 0.001) versus placebo. Anacetrapib 100 mg added to ongoing therapy with statin ± other LMT for 12 weeks was generally well-tolerated. There were no differences between the groups in the proportion of patients who discontinued drug due to an adverse event or abnormalities in liver enzymes, creatinine kinase, blood pressure, electrolytes or adjudicated cardiovascular events. CONCLUSIONS: In Japanese patients with HeFH, treatment with anacetrapib 100 mg for 12 weeks resulted in substantial reductions in LDL-C and increases in HDL-C and was well tolerated. (ClinicalTrials.govNCT01824238).

Lipids, safety parameters, and drug concentrations after an additional 2 years of treatment with anacetrapib in the DEFINE study.

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has previously been shown to reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk of coronary heart disease in the 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial. Here, we report the results of the 2-year extension to the DEFINE study where patients (n = 803) continued on the same assigned treatment as in the original 76-week study. Treatment with anacetrapib during the 2-year extension was well tolerated with a safety profile similar to patients on placebo. No clinically important abnormalities in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the extension. At the end of the extension study, relative to the original baseline value, anacetrapib reduced Friedewald-calculated LDL-C by 39.9% and increased HDL-C by 153.3%, compared to placebo. The apparent steady state mean plasma trough concentration of anacetrapib was ∼640 nmol/L. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 of the 2-year extension of the 76-week DEFINE base study. In conclusion, an additional 2 years of treatment with anacetrapib were well tolerated with durable lipid-modifying effects on LDL-C and HDL-C.

Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease.

The aim of this study was to assess the effects on lipids and safety during a 12-week reversal period after 18 months of treatment with anacetrapib. The cholesteryl ester transfer protein inhibitor anacetrapib was previously shown to reduce low-density lipoprotein cholesterol by 39.8% (estimated using the Friedewald equation) and increase high-density lipoprotein (HDL) cholesterol by 138.1%, with an acceptable side-effect profile, in patients with or at high risk for coronary heart disease in the Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial. A total of 1,398 patients entered the 12-week reversal-phase study, either after completion of the active-treatment phase or after early discontinuation of the study medication. In patients allocated to anacetrapib, placebo-adjusted mean percentage decreases from baseline were observed at 12 weeks off the study drug for Friedewald-calculated low-density lipoprotein cholesterol (18.6%), non-HDL cholesterol (17.6%), and apolipoprotein B (10.2%); placebo-adjusted mean percentage increases were observed for HDL cholesterol (73.0%) and apolipoprotein A-I (24.5%). Residual plasma anacetrapib levels (about 40% of on-treatment apparent steady-state trough levels) were also detected 12 weeks after cessation of anacetrapib. No clinically important elevations in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the reversal phase. Preliminary data from a small cohort (n = 30) revealed the presence of low concentrations of anacetrapib in plasma 2.5 to 4 years after the last anacetrapib dose. In conclusion, after the cessation of active treatment, anacetrapib plasma lipid changes and drug levels decreased to approximately 40% of on-treatment trough levels at 12 weeks after dosing, but modest HDL cholesterol elevations and low drug concentrations were still detectable 2 to 4 years after the last dosing.

Small molecule antagonists of complement receptor type 3 block adhesion and adhesion-dependent oxidative burst in human polymorphonuclear leukocytes.

The leukocyte integrin complement receptor type 3 (CR3, Mac-1, CD11b/CD18) is the predominant beta(2) integrin receptor of polymorphonuclear leukocytes (PMNs). This cell surface receptor plays a central role in innate immunity against pathogens as well as being a major cellular effector of inflammation and tissue injury. Two small molecules, compounds 1 and 2, have been identified, that interact with CR3 and prevent CR3 from binding to its natural ligand, C3bi. Compounds 1 and 2 have IC(50) values of 0.14 and 0.33 microM, respectively, for the inhibition of binding of monomeric C3bi-alkaline phosphatase to immobilized CR3. Both compounds also inhibit binding of CR3 to biotinylated sheep red blood cells opsonized with C3bi, with IC(50) values in the micromolar range. Inhibition of ligand binding by the compounds is not easily reversed and requires light, suggesting the formation of a covalent adduct through photoactivation. Compounds 1 and 2 also inhibit adhesion of human PMNs to fibrinogen in response to tumor necrosis factor (TNF) or PMA, with IC(50) values of 2.5 to >10 microM. They block the adhesion-dependent production of H(2)O(2) stimulated by TNF or phorbol 12-myristate 13-acetate (PMA) with IC(50) values of 0.2 to 0.8 microM and 1 to 3 microM, respectively. Limited structure-activity relationship studies based on compound 2 indicate the importance of the two benzothiazole rings, an ethyl side chain, and the length of the carbon chain linking the rings. Further modification of these groups may help in making compounds appropriate for in vivo studies.