A Study to Assess Adding Ezetimibe 30 mg to Ongoing Treatment With Ezetimibe 10 mg in Patients With Homozygous Sitosterolemia

Homozygous Sitosterolemia is an inherited, autosomal recessive disorder of sterol metabolism. Patients with homozygous sitosterolemia experience accelerated atherosclerosis with initial coronary heart disease (CHD) events occurring in childhood. Plasma concentrations of sitosterol and other dietary plant sterols are markedly elevated in homozygous sitosterolemic patients, and are characteristic of this disorder. Sitosterolemic individuals demonstrate a range of abnormalities in sterol absorption, metabolism, and excretion. Recent reports have shown that sitosterolemia can result from mutations in 1 of 2 ATP-binding cassette half-transporters (ABCG5 or ABCG8), which are responsible for regulation of non-cholesterol sterols in the body.

Current treatment of homozygous sitosterolemia consists of ezetimibe 10 mg, dietary restriction of plant and shellfish sterols, as well as the use of bile salt binding resins. Ezetimibe is the first member of a new class of cholesterol-lowering agents that inhibits the intestinal absorption of cholesterol and structurally-related noncholesterol sterols (plant sterols) across the intestinal wall. Importantly, ezetimibe is not an inhibitor or inducer of CYP450, reducing the potential for drug-drug interactions which renders ezetimibe a particularly appealing candidate with other drugs. Ezetimibe has proved to be generally safe and well-tolerated as monotherapy or when coadministered with statins, with an overall clinical adverse experience profile similar to placebo. In clinical studies with hypercholesterolemic patients, ezetemibe doses ranging from 0.25 to 40 mg daily for periods of 8 to 12 weeks were more effective than placebo in lowering plasma TC and LDL-C concentrations. There were no dose-related increase in adverse experiences or laboratory abnormalities in these studies. We will investigate whether a higher dose of ezetimibe is safe and efficacious in lowering plant sterols in patients with sitosterolemia.