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Lomitapide Shows Promise as Lipid-Lowering Therapy

FDA review expected by end of the year (Nov. 2)

Research led by investigators at the Perelman School of Medicine at the University of Pennsylvania has resulted in positive phase III clinical trial results for a new medicine to treat patients with a rare and deadly cholesterol disorder.

Penn researchers report in The Lancet that lomitapide (Aegerion Pharmaceuticals), a first-in-class microsomal triglyceride transfer protein (MTP) inhibitor, substantially reduced low-density lipoprotein (LDL) cholesterol — the “bad” cholesterol — in patients with homozygous familial hypercholesterolemia (HoFH). Lomitapide works by inhibiting MTP, which is required for the production of very-low-density lipoprotein (VLDL) — the precursor to LDL.

Patients with HoFH have markedly elevated blood levels of cholesterol — generally greater than 500 mg/dL — because of genetic mutations in the LDL receptor gene, which result in impaired ability of the liver to remove LDL from the blood. Heart and vascular disease often develop in childhood, and the average age of death even with current therapies is about 30 years. HoFH patients do not respond well to the usual treatments for elevated cholesterol, such as statins. The only effective therapy for these patients is apheresis — an invasive and time-consuming procedure that involves removing excess LDL from the bloodstream.

The new, open-label study included a 6-month phase designed to assess the efficacy of lomitapide when added to standard of care, and an additional year-long phase to assess the drug’s safety and tolerability. Twenty-three adult HoFH patients completed both the efficacy and the safety phases. All of the patients received lomitapide along with conventional lipid-lowering therapies, including statins and, in some cases, apheresis. The lomitapide dose was gradually increased from 5 mg to a maximum tolerated dose of up to 60 mg per day. The median dosage was 40 mg per day.

At the end of the efficacy phase, LDL cholesterol levels were reduced by an average of 50% from baseline. Approximately one-third of the patients experienced levels of LDL cholesterol that were less than 100 mg/dL (close to the recommended therapeutic goals) at some point during the study, and concomitant lipid-lowering therapy was modified in a subset of these patients during the safety phase. Despite these changes in treatment, the patients’ mean LDL cholesterol levels were still reduced by 38% at the end of the study.

On October 17, 2012, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended by a vote of 13 to 2 that the agency approve lomitapide to reduce LDL in patients with HoFH. The FDA is scheduled to make a final decision on approval of the medication by the end of year.

Source: Perelman School of Medicine; November 2, 2012.

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