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Reuters Health Information (2007-01-10): Investigational agent reduces LDL cholesterol in familial hypercholesterolemia

Drug & Device Development

Investigational agent reduces LDL cholesterol in familial hypercholesterolemia

Last Updated: 2007-01-10 17:00:31 -0400 (Reuters Health)

NEW YORK (Reuters Health) - The first research evaluating the use of an inhibitor of microsomal triglyceride transfer protein (MTP) provides proof of concept that it can lower LDL cholesterol in patients with familial hypercholesterolemia, investigators report in the New England Journal of Medicine for January 11. However, there are drawbacks.

Homozygous familial hypercholesterolemia is caused by loss-of-function mutations in the low-density lipoprotein (LDL) receptor genes, Dr. Daniel J. Rader and his associates explain. The condition is resistant to all current drug therapy for high cholesterol levels and is associated with premature cardiovascular death, often by 30 years of age.

"In the absence of the LDL receptor, the body can't clear LDL cholesterol from the blood, thus predisposing to heart disease," Dr. Rader told Reuters Health.

Dr. Rader, from the University of Pennsylvania School of Medicine in Philadelphia, and his team explain that MTP transfers triglycerides onto apolipoprotein B in the liver during assembly of very-low-density lipoprotein (VLDL), the precursor to LDL. In the absence of functional MTP, the liver cannot secrete VLDL. "Thus, the pharmacologic inhibition of microsomal triglyceride transfer protein might be a strategy for reducing LDL production."

To test the potential of the MTP inhibitor BMS-201038 (Bristol-Myers Squibb), the researchers treated three men and three women, 18 to 40 years of age, diagnosed with homozygous familial hypercholesterolemia. Total cholesterol levels ranged from 684 to 1212 mg/dL at baseline.

After discontinuing all lipid-lowering treatments for 4 weeks and starting a low-fat diet, the patients received BMS-201038 at 0.03, 0.1, 0.3, and 1.0 mg/kg/day, each for 4 weeks followed by a 4-week washout period.

The highest dose reduced plasma levels of apolipoprotein B-containing lipoproteins. LDL cholesterol was reduced 51%, total cholesterol fell by 58%, triglycerides by 65%, and apolipoprotein B by 56% (p < 0.001 for each).

The most potentially serious adverse events, which occurred in four subjects, were elevated liver aminotransferase levels and accumulation of hepatic fat.

Because familial hypercholesterolemia is quite rare, the inhibitor has been granted orphan-drug status by the US Food and Drug Administration. As a result of these promising findings, the FDA will fund a phase III trial of the MTP inhibitor for treatment of familial hypercholesterolemia, to be initiated within the upcoming year.

While acknowledging the seriousness of the ALT and liver fat elevations, Dr. Rader said that levels tended to decrease after the initial spike even while patients were on the same dose, raising hope that ultimately the drug will be found safe and effective.

The cardiologist also pointed out the "bigger picture," noting that "there is still an unmet medical need for agents to lower cholesterol among the 2% to 3% of patients with 'garden variety' elevated cholesterol who cannot tolerate statins because of muscle and joint pain." He proposes that BMS-201038 may also benefit these patients.

N Engl J Med 2007;356:148-156.

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