Source: DGNews  |  Posted 4 years ago

By Crina Frincu-Mallos, PhD

NEW YORK, NY -- October 7, 2007 -- Statin intolerance or suboptimal response to standard-of-care therapy results in failure to achieve target LDL-C levels in many patients with cardiovascular disease, and the MTP-inhibitor AEGR-733 shows potential as a novel treatment option for dyslipidemia, researchers reported here at the XVI International Symposium on Drugs Affecting Lipid Metabolism (DALM).

One therapeutic target in the statin-intolerant patient population is represented by the apolipoprotein B (apo-B)-containing lipoproteins. "Microsomal triglyceride transfer protein (MTP) is an intracellular lipid-transfer protein found in the ER, responsible for transferring triglycerides onto apo-B" in the form of chylomicrons in the intestine and liver, explained lead author Frederick F. Samaha, MD, Chief of Cardiology and Associate Professor of Medicine, Division of Cardiology, Philadelphia Veterans Affairs Medical Center, the University of Pennsylvania Health System, Philadelphia, Pennsylvania, United States, in a poster presentation on October 6.

To determine the LDL-C lowering efficacy and safety of the MTP-inhibitor AEGR-733 alone and in combination with ezetimibe, Dr. Samaha and colleagues enrolled 84 patients with hypercholesterolemia in a phase 2 multicentre prospective randomised trial.

The patient population came from six lipid-treatment centres and consisted of men and women 18-70 years of age, with baseline LDL in the range of 130 to 250 mg/dL, and 400 mg/dL TGs. The patients were randomised and assigned to daily doses of ezetimibe 10 mg (n = 23), ARGR-733 (n = 28) at three dose-levels (5 mg, 7.5 mg, and 10 mg), or the combination AEGR-733 plus ezetimibe (n = 28) over the course of this 12-week study.

All patients were monitored for adverse events and 4 patients in the ezetimibe, 9 patients in the AEGR-733 single-agent, and 4 patients in the combination arms respectively had to be discontinued from the trial due to persistent increases in transaminase levels, said Dr. Samaha.

Patients in the ezetimibe arm experienced a 22% in LDL-C by week 12 of the study, while patients assigned to AEGR-733 alone showed dose-dependent reductions in LDL-C levels ranging from 19% to 30% (P =.013 for 10 mg AEGR-733 single-agent vs ezetimibe alone).

The synergistic effect of AEGR-733 when used in combination with ezetimibe was significant: patients experienced dose-dependent decreases in LDL-C levels ranging from 35% to 46% (P <.001 for 10 mg AEGR-733 in combination vs ezetimibe alone), explained Dr. Samaha.

Additionally, researchers said, "significant reductions in total cholesterol (-35% ± 21%, P <.001) and apo-B (-37%, P <.001) were observed in the group receiving AEGR-733 in combination with ezetimibe".

The adverse events were mild, most common being GI disorders experienced by 37.9% of patients in the ezetimibe arm, versus 64.3% of patients in the AEGR-733 arm, and 42.9% of patients in the combination arm.

Low doses of the MTP inhibitor AEGR-733 were effective in reducing the levels of atherogenic apolipoprotein-containing lipoproteins, including LDL-C, non-HDL-C, and apo-B in patients with hypercholesterolemia, providing "a viable approach" for LDL-C reduction in statin-intolerant or low-responding patients, the researchers concluded.

Funding was provided by Aegerion Pharmaceuticals, Inc.

[Presentation title: Efficacy and Safety of the MTP-Inhibitor AEGR-733 as monotherapy and in Combination with Ezetimibe-a Phase 2 Trial. Abstract 330]