Schering-Plough reports results of phase III ezetimibe study

Novel cholesterol absorption inhibitor reduced cholesterol, potentially may support more patients reaching goal

Schering-Plough International today presented for the first time Phase III clinical data on ezetimibe, the first in a new class of potential lipid-management drugs known as cholesterol absorption inhibitors. The Phase III study showed that ezetimibe reduced low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC), and also had a beneficial effect on high-density lipoprotein cholesterol (HDL-C), with a safety profile similar to that of placebo. In addition, the study showed a trend for ezetimibe in lowering triglycerides (TG).

The results of the randomised, double-blind, placebo-controlled, parallel-group study involving 827 patients with primary hypercholesterolaemia were presented by investigators at the 72nd annual meeting of the European Atherosclerosis Society. The data show that ezetimibe tablets 10 mg once daily significantly reduced LDL-C (-17.7 per cent vs. + 0.8 per cent for placebo, p<0.01) and total cholesterol (-12.4 per cent vs. + 0.6 per cent for placebo, p<0.01), and raised HDL-C (+1.0 per cent vs. -1.3 per cent for placebo, p<0.01).¹ Apo-B and Lp(a) (protein components of lipid molecules) were also significantly improved. Triglycerides were reduced (-1.7 per cent vs. 2.4 per cent for placebo, p=0.09). Ezetimibe was administered to more than 600 patients in the study and was well tolerated.

A pre-defined subanalysis on the effect of ezetimibe tablets 10 mg once daily on lipid-soluble vitamin absorption was conducted in a subgroup of patients (ezetimibe n=85, placebo n=28) from the Phase III study. The vitamins examined in the analysis were Vitamin A, D, two components of Vitamin E and alpha and beta carotenoids. The analysis found no significant effect on the absorption of these fat-soluble vitamins.

"The results of this study show that ezetimibe reduced LDL-C and total cholesterol levels with a favourable effect on other lipid parameters," said Dr Robert H. Knopp, lead investigator of the study and Director of the Northwest Lipid Research Clinic, Seattle. "As ezetimibe targets the exogenous cholesterol pathway, its action could be complimentary and additive to that of statins. Ezetimibe used in co-administration with a statin may offer a new approach to cholesterol management through which target LDL-C levels may be achieved," he concluded.

Ezetimibe, discovered by Schering-Plough Research Institute, works by selectively inhibiting the absorption of dietary and biliary cholesterol across the intestine. This is known as the exogenous cholesterol pathway, and is one of the two pathways by which cholesterol is obtained by the body. The second pathway, known as the endogenous cholesterol pathway, refers to the biosynthesis of cholesterol predominately by the liver. It is this pathway that is the target for the class of pharmaceuticals known as statins, which are the most commonly prescribed therapy for hypercholesterolaemia.

Many patients on statin therapy fail to reach their recommended goal for LDL-C. A recent study showed that more than half of European patients currently taking lipid-modifying therapy do not reach their target cholesterol levels.² While higher statin doses can support more patients reaching target, higher doses of statins can be associated with dose-related side effects such as liver toxicity.^3,4 In previously reported Phase I studies of ezetimibe in co-administration with atorvastatin and simvastatin, ezetimibe achieved an 18 per cent additive reduction in LDL-C over baseline,⁵ similar to the results reported in the ezetimibe monotherapy study.

"Cholesterol absorption inhibition is an exciting development in the management of hyperlipidaemia," said Professor Michel Farnier from Point Medical, Dijon, France. "An approach that could support more effective management of a patient's lipid profile, while sparing the need for higher-dose statins, may represent a powerful new therapeutic option for patients."

Additional LDL-C reductions seen in pharmacodynamic study with fenofibrate
Results from a pharmacodynamic interaction study also presented here today showed that the co-administration of ezetimibe and fenofibrate, a fibric-acid derivative or fibrate, provided significant additional LDL-C reductions compared to either drug alone. At Day 14 of the study, LDL-C levels were reduced by 36.3 per cent with ezetimibe and fenofibrate; 22.3 per cent with ezetimibe alone; 13.5 per cent with fenofibrate alone; and -10.1 per cent with placebo (p<0.03 co-administration compared to either drug alone or placebo).

The study evaluated lipid levels in 32 patients with hypercholesterolaemia. After patients had been maintained on a strict diet, they were randomised to one of four arms: fenofibrate 200 mg and ezetimibe 10 mg (n=8), ezetimibe 10 mg (n=8), fenofibrate 200 mg (n=8) or placebo (n=8). Lipid levels were assessed at baseline, Day 7 and Day 14.

This small study was primarily designed to evaluate pharmacokinetic and/or pharmacodynamic interactions between ezetimibe and fenofibrate. Larger clinical studies are needed to confirm the LDL-C effects and to detect any significant differences in HDL-C and TG in the two drug combination compared to either drug alone.

Additional LDL-C reductions seen in pharmacodynamic study with fluvastatin
Results from another small pharmacodynamic study presented here today showed that the co-administration of ezetimibe tablets 10 mg with fluvastatin 20 mg, provided significant additional LDL-C reductions compared to either drug alone.

"The results seen in this study are consistent with another small co-administration study with ezetimibe and another statin, atorvastatin, presented at the American College of Cardiology meeting in March 2001," said Dr Teddy Kosoglou, a lead study investigator and Director of Clinical Pharmacology, Schering-Plough Research Institute. "In that study, co-administration of ezetimibe tablets 10 mg reduced LDL-C levels by an additional 16 per cent⁸.

The study with ezetimibe and fluvastatin was primarily designed to evaluate pharmacokinetic and/or pharmacodynamic interactions between the two drugs. In the study, ezetimibe had no clinically significant effects on the pharmacokinetics or pharmacodynamics of fluvastatin or vice versa. Larger clinical studies are needed to confirm the LDL-C effects and to detect any significant differences in HDL-C and TG in the two-drug combination compared to either drug alone.

It has been demonstrated that high levels of total cholesterol and LDL-C are risk factors for developing coronary heart disease (CHD), which is the leading cause worldwide of death among men and women and accounted for 6.3 million deaths worldwide in 1990.⁶ In 2000, CHD contributed to almost a third of all global deaths.⁷

Schering-Plough Corporation in May 2000 formed a partnership with Merck & Co., Inc. to develop and market in the United States ezetimibe in three ways: as a once-daily fixed-combination tablet with ZOCOR (simvastatin), Merck's cholesterol-management medicine; as a once-daily monotherapy; and in co-administration with statins. Schering-Plough has exclusive rights to develop and market ezetimibe in major international markets.

Schering-Plough International is the worldwide pharmaceutical marketing arm of Schering-Plough Corporation (NYSE: SGP) of Kenilworth, N.J., U.S.A., a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.

For further information, please contact Neil McGregor-Paterson, at Shire Hall International on +44 (0) 7765 848 795 or Robert J. Consalvo from Schering-Plough on +1 908 298 7409

References: