A novel agent that inhibits microsomal triglyceride transfer protein significantly reduces low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia and may be a future option for patients with resistant hypercholesterolemia or intolerance to statins, according to an article in the January 11 issue of the New England Journal of Medicine.

"Our study shows that targeted inhibition of the microsomal triglyceride transfer protein (MTP) is highly effective in reducing cholesterol levels in these very high risk patients,” stated Daniel J. Rader, MD, Director of Preventive Cardiology and the Clinical and Translational Research Center at Penn, and principal investigator of this study.

“Furthermore, there are many other patients who have cholesterol levels that are difficult to treat or who are not tolerant to treatment with statins. New therapies are required for these patients as well, and it is possible that after further research protein inhibition could eventually be used for such patients.”

Genetic defects in microsomal triglyceride transfer protein lead to profoundly low levels of low-density cholesterol. Using this information, Bristol-Myers Squibb began to search for inhibitors of the protein and discovered the study drug, originally known as BMS-201038. Bristol-Myers Squibb then donated it to the University of Pennsylvania for use in clinical trials in patients with severe cholesterol problems. Due to the success in this study, Penn has licensed the drug for further development as AEGR-733.

Patients who suffer from homozygous familial hypercholesterolemia typically respond poorly to standard drug therapy and have a very high risk of premature cardiovascular disease. The disorder is caused by loss-of-function mutations in both alleles of the low-density lipoprotein receptor gene that affects approximately one in every million people.

Patients with this disorder typically have plasma cholesterol levels of more than 500 mg per deciliter. If untreated, patients develop cardiovascular disease before they are 20 years old and generally do not live past the age of 30 years. Because existing cholesterol lowering drugs are relatively ineffective in this patient population, new therapies to reduce LDL levels are needed.

In this study, researchers conducted a dose-escalation study to examine the safety, tolerability and effects on lipid levels of the inhibitor drug in six patients with homozygous disease. Patients received the inhibitor at four different doses, each for four weeks, and returned for a final visit after an additional four-week drug washout period. Analysis of lipid levels, safety laboratory analyses, and magnetic resonance imaging of the liver for hepatic fat content were performed throughout the study.

All patients tolerated titration to the highest dose studied. In addition to the 51 percent reduction in low-density cholesterol, treatment at this dose also decreased total cholesterol levels by 58 percent, triglyceride levels by 65 percent, and apolipoprotein B levels by 56 percent from baseline. In contrast to statin drugs, which have relatively little effect on cholesterol levels in these patients, the inhibitor reduced the liver’s ability to produce low-density lipoprotein.

The most notable adverse events were loose stools and elevation of liver transaminase levels and accumulation of hepatic fat in some but not all of the patients studied.

Rader concluded, “Although our study establishes proof of concept, a longer-term study in more patients will be required to determine the benefits and risks of this approach as a potential new therapy for homozygous familial hypercholesterolemia."

Marina Cuchel, MD, PhD, a co-investigator, is now the principal investigator of a Phase III study for this compound in patients with the genetic disorder that is funded by the U.S. Food and Drug Administration Orphan Drug program and planned for later this year.