ORLANDO — Lomitapide is a powerful lipid-lowering agent with a potentially serious drawback, according to interim results of an ongoing phase III study in patients with homozygous familial hypercholesterolemia.
Lomitapide is first in a new class of investigational lipid-lowering drugs known as microsomal triglyceride transfer protein inhibitors. These agents reduce LDL cholesterol levels by inhibiting apolipoprotein B lipidation, a novel mechanism that results in reduced secretion of atherogenic apo B–containing lipoproteins, Dr. Marina Cuchel said at the annual scientific sessions of the American Heart Association.
Homozygous familial hypercholesterolemia is a rare but daunting therapeutic challenge. Affected patients have extraordinarily severe dyslipidemia from birth that often is resistant to lipid-lowering drugs. They typically develop clinical cardiovascular disease before reaching adulthood.
The 14 participants in the phase III open-label lomitapide study who have been on the drug for at least 6 months had a baseline mean LDL cholesterol level of 351 mg/dL, a total cholesterol level of 444 mg/dL, a non-HDL cholesterol level of 404 mg/dL, and an apo B level of 278—while on maximum tolerated doses of statins and other standard lipid-lowering drugs as well as apheresis and a low-fat diet. At a mean age of 33 years, 12 of the 14 (86%) had cardiovascular disease.
At week 26 of the phase III study, patients on lomitapide at a median dose of 40 mg/day— the most effective dose—along with concomitant maximal background lipid-lowering therapies, showed a mean 57% reduction in LDL from baseline. Ten of the 14 patients had an LDL level below 165 mg/dL, including 6 with an LDL level of less than 100 mg/dL, reported Dr. Cuchel of University of Pennsylvania Institute for Translational Medicine, Philadelphia.
Total cholesterol was down by 53% from baseline, non-HDL cholesterol by 56%, and apo B by 53%. Triglycerides dropped from a mean baseline of 112 to 57 mg/dL, and HDL decreased from 40 to 32 mg/dL.
The most common side effects with lomitapide were mild to moderate diarrhea, abdominal discomfort, and nausea and vomiting. To date, three patients have dropped out of the study because of GI side effects before reaching the 6-month mark on lomitapide. Two of 14 patients developed transient elevations in liver function tests of at least five times the upper limit of normal. Both responded to temporary reductions in lomitapide dosing.
The most problematic adverse effect associated with lomitapide is accumulation of liver fat. Hepatic fat content climbed from a mean baseline of 1.3% to 7.9% after 26 weeks on the investigational drug.
The long-term clinical implications of this adverse effect remain unclear. It appears to be intrinsic to inhibition of microsomal triglyceride transfer protein. In the six patients who have been on lomitapide for 1 year or longer, liver fat content stabilized or retreated from its 6-month high to a mean value of 3.7% at 56 weeks, Dr. Cuchel continued.
To date, the phase III study has enrolled 22 of a planned 25 subjects. The trial is funded by the Food and Drug Administration's Office of Orphan Drug Development and Aegerion Pharmaceuticals Inc.
Dr. Cuchel said she has no conflicts of interest to disclose.