title: Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia.
abstract: OBJECTIVE
  Mipomersen, an apolipoprotein (apo) B synthesis inhibitor, has been shown to produce potent reductions in apoB and LDL-cholesterol levels in animal models as well as healthy human volunteers. A randomized, double-blind, placebo-controlled, dose-escalation study was designed to evaluate the efficacy and safety of mipomersen monotherapy with or without dose loading in subjects with mild-to-moderate hyperlipidaemia.
  
  
  RESULTS
  Fifty subjects with LDL-cholesterol levels between 119 and 266 mg/dL were enrolled into five cohorts at a 4:1 randomization ratio of active to placebo. Two 13-week dose regimens were evaluated at doses ranging from 50 to 400 mg/week. Mipomersen produced dose-dependent reductions in all apoB containing lipoproteins. In the 200 and 300 mg/week dose cohorts, mean reductions from baseline in LDL cholesterol were -45 ± 10% (P= 0.000) and -61 ± 8% (P= 0.000), corresponding to a -46 ± 11% (P= 0.000) and -61 ± 7% (P= 0.000) decrease in apoB levels. Triglyceride levels were also lowered with median reductions up to 53% (P= 0.021). The most common adverse events were injection site reactions. Seven of 40 subjects (18%) showed consecutive transaminase elevations >3× upper limit of normal. Five of these subjects received 400 mg/week, four of whom had apoB levels below the limit of detection. As a consequence, the 400 mg/week cohort was discontinued.
  
  
  CONCLUSIONS
  Mipomersen administered as monotherapy in subjects with mild-to-moderate hyperlipidaemia produced potent reductions in all apoB-containing lipoproteins. Higher doses were associated with hepatic transaminase increases.
authors: Department of Vascular Medicine, Academic Medical Center Amsterdam, Meibergdreef 9, PO Box 22660, 1100 DD, Amsterdam, The Netherlands.
authors: Fatima
authors: F
authors: Akdim
authors: Diane L
authors: DL
authors: Tribble
authors: JoAnn D
authors: JD
authors: Flaim
authors: Rosie
authors: R
authors: Yu
authors: John
authors: J
authors: Su
authors: Richard S
authors: RS
authors: Geary
authors: Brenda F
authors: BF
authors: Baker
authors: Rainard
authors: R
authors: Fuhr
authors: Mark K
authors: MK
authors: Wedel
authors: John J P
authors: JJ
authors: Kastelein