title: Mipomersen preferentially reduces small low-density lipoprotein particle number in patients with hypercholesterolemia.
abstract: BACKGROUND
  Because of variability in lipoprotein cholesterol content, low-density lipoprotein (LDL) cholesterol frequently underrepresents or overrepresents the number of LDL particles. Mipomersen is an antisense oligonucleotide that reduces hepatic production of apolipoprotein B-100, the sole apolipoprotein of LDL.
  
  
  OBJECTIVE
  To characterize the effects of mipomersen on lipoprotein particle numbers as well as subclass distribution using nuclear magnetic resonance (NMR) spectroscopy.
  
  
  METHODS
  We compared the tertiary results for the direct measurement of LDL particle numbers by NMR among 4 placebo-controlled, phase 3 studies of mipomersen that had similar study designs but different patient populations: homozygous familial hypercholesterolemia (HoFH), severe hypercholesterolemia, heterozygous familial hypercholesterolemia with established coronary artery disease, or hypercholesterolemia with high risk for coronary heart disease (HC-CHD).
  
  
  RESULTS
  HoFH patients had the highest median total LDL particles at baseline compared with HC-CHD patients, who had the lowest. At baseline, the HoFH population uniquely had a greater mean percentage of large LDL particles (placebo, 60.2%; mipomersen, 54.9%) compared with small LDL particles (placebo, 33.1%; mipomersen, 38.9%). In all 4 studies, mipomersen was associated with greater reductions from baseline in the concentrations of small LDL particles compared with those of large LDL particles, and both total LDL particles and small LDL particles were statistically significantly reduced.
  
  
  CONCLUSIONS
  Mipomersen consistently reduced all LDL particle numbers and preferentially reduced the concentration of small LDL particles in all 4 phase 3 studies.
authors.affiliation: Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, São Paulo, Brazil. Electronic address: raul.santos@incor.usp.br.
authors.forename: Raul D
authors.initials: RD
authors.lastname: Santos
authors.affiliation: Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Raal
authors.affiliation: Genzyme Corporation, Cambridge, MA, USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Donovan
authors.affiliation: Lipoprotein and Metabolic Disorders Institute, Raleigh, NC, USA; Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Cromwell
mesh_terms: D000328:Adult; D053299:Apolipoprotein B-100 / Q000037:antagonists & inhibitors / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019906:Nuclear Magnetic Resonance, Biomolecular; D009841:Oligonucleotides / Q000008:administration & dosage*
chemical_list: D053299:Apolipoprotein B-100; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D009841:Oligonucleotides; C524142:mipomersen
keywords: Antisense RNA; Apolipoprotein B; Apolipoprotein C-III; Intermediate-density lipoprotein; Lipoprotein particles