- Researchers at the University
of Pennsylvania School of Medicine have demonstrated
the potential of a new type of therapy for patients who suffer from
levels. The findings are in the January 11 issue of The
New England Journal of Medicine (NEJM). In this study,
patients with homozygous familial
hypercholesterolemia (FH), a high-risk condition refractory
to conventional therapy, had a remarkable 51% reduction in low-density
lipoprotein (LDL) or “bad cholesterol” levels.
"Our study shows that targeted inhibition of the microsomal
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 Smilow Center for Translational Research (SCTR)
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 MTP inhibition could eventually
be used for such patients.”
Genetic defects in MTP lead to profoundly low levels of LDL. Using
this information, Bristol-Myers
Squibb began to search for inhibitors of this protein and discovered
the study drug, originally known as BMS-201038. Bristol-Myers Squibb
then donated it to Penn for use in clinical trials in patients with
severe cholesterol problems. Rader and his team at Penn designed
and carried out the current study in homozygous FH patients with
support from the Doris
Duke Charitable Foundation. Due to the success in this study,
Penn has licensed the drug to Aegerion
Pharmaceuticals, Inc. for further development as AEGR-733.
Patients who suffer from homozygous FH typically respond poorly
to standard drug therapy and have a very high risk of premature
disease. Homozygous FH is caused by loss-of-function mutations
in both alleles
of the LDL receptor gene. It is a rare form of hypercholesterolemia
affecting 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. 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 an inhibitor of MTP in six patients with homozygous FH.
Patients received the MTP 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
to the highest dose studied. In addition to the 51% reduction in
LDL cholesterol, treatment at this dose also decreased total cholesterol
levels by 58%, triglyceride levels by 65% and apolipoprotein
B levels by 56% from baseline. In contrast to statin drugs,
which have relatively little effect on cholesterol levels in homozygous
FH patients, the MTP inhibitor was shown to reduce the liver’s
ability to produce LDL. The most notable adverse events in the study
were loose stools and elevation of liver transaminase
levels and accumulation of hepatic fat in some but not all of the
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."
Cuchel, MD, PhD, a co-investigator in this study at
Penn, is now the principal investigator of a Phase
III study for this compound in homozygous FH patients that is
funded by the US
Food and Drug Administration Orphan Drug program and planned
for later this year.
Rader points out that this study is a superb example of “translational
research” in which discoveries in basic science are “translated”
into use in humans for the development of novel therapies. Rader
is an internationally recognized leader in translational research
in the areas of cholesterol metabolism and heart disease prevention.
Penn recently created a new Cardiovascular
Institute that is charged with promoting translational research
in the diagnosis, treatment, and prevention of cardiovascular disease.
Additionally, Penn was recently awarded a large National
Institutes of Health grant to foster the further development
of translational research under the auspices of the newly created
Institute for Translational
Medicine and Therapeutics.
The results of this study are in The New England Journal of
Medicine. The article is titled “Inhibition of Microsomal
Triglyceride Transfer Protein in Homozygous Familial Hypercholesterolemia.”
Co-authors from Penn: Marina Cuchel, MD, PhD; LeAnne T. Bloedon,
MS, RD; Philippe O. Szapary, MD; Daniel M. Kolansky, MD; Megan L.
Wolfe, BS; John S. Millar, PhD; Evan S. Siegelman, MD; and Daniel
J. Rader, MD. Other researchers: Antoine Sarkis, MD, Hotel Dieu
de France Hospital, St. Joseph University, Beirut, Lebanon; Katsunori
Ikewaki, MD, Jikei University School of Medicine, Tokyo, Japan;
and Richard E. Gregg, MD, from Bristol-Myers Squibb Pharmaceutical
Research Institute, Lawrenceville, NJ.
This study was supported by a Distinguished
Clinical Scientist Award (to Rader) from the Doris Duke Charitable
Foundation and grants from the National
Center for Research Resources.
Editor’s Notes: Daniel J. Rader, MD, receives
lecture fees, consulting fees, and grant support from Bristol Myers-Squibb,
as well as from other companies that manufacture lipid-lowering
drugs, and has equity interest in Aegerion Pharmaceuticals, which
holds the license to develop BMS-201038.
LeAnne Bloedon serves as a consultant for Aegerion Pharmaceuticals.
Philippe O. Szapary, MD, is an employee of and has equity interest
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