Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia.
BACKGROUND
Patients with homozygous familial hypercholesterolemia have markedly elevated cholesterol levels, which respond poorly to drug therapy, and a very high risk of premature cardiovascular disease. Inhibition of the microsomal triglyceride transfer protein may be effective in reducing cholesterol levels in these patients.


METHODS
We conducted a dose-escalation study to examine the safety, tolerability, and effects on lipid levels of BMS-201038, an inhibitor of the microsomal triglyceride transfer protein, in six patients with homozygous familial hypercholesterolemia. All lipid-lowering therapies were suspended 4 weeks before treatment. The patients received BMS-201038 at four different doses (0.03, 0.1, 0.3, and 1.0 mg per kilogram of body weight per day), each for 4 weeks, and returned for a final visit after a 4-week drug washout period. Analysis of lipid levels, safety laboratory analyses, and magnetic resonance imaging of the liver for fat content were performed throughout the study.


RESULTS
All patients tolerated titration to the highest dose, 1.0 mg per kilogram per day. Treatment at this dose decreased low-density lipoprotein (LDL) cholesterol levels by 50.9% and apolipoprotein B levels by 55.6% from baseline (P<0.001 for both comparisons). Kinetic studies showed a marked reduction in the production of apolipoprotein B. The most serious adverse events were elevation of liver aminotransferase levels and accumulation of hepatic fat, which at the highest dose ranged from less than 10% to more than 40%.


CONCLUSIONS
Inhibition of the microsomal triglyceride transfer protein by BMS-201038 resulted in the reduction of LDL cholesterol levels in patients with homozygous familial hypercholesterolemia, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation.
Cuchel
Marina
M
University of Pennsylvania School of Medicine, Philadelphia, USA.
Bloedon
LeAnne T
LT
Szapary
Philippe O
PO
Kolansky
Daniel M
DM
Wolfe
Megan L
ML
Sarkis
Antoine
A
Millar
John S
JS
Ikewaki
Katsunori
K
Siegelman
Evan S
ES
Gregg
Richard E
RE
Rader
Daniel J
DJ
D000293:Adolescent; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D001055:Apolipoproteins B / Q000097:blood; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D008078:Cholesterol, LDL / Q000096:biosynthesis / Q000097:blood; D003131:Combined Modality Therapy; D005260:Female; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000178:diet therapy / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects; D008297:Male
D001055:Apolipoproteins B; C473731:BMS201038; D001562:Benzimidazoles; D002352:Carrier Proteins; D008078:Cholesterol, LDL; C106092:microsomal triglyceride transfer protein; D000410:Alanine Transaminase