title: Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial.
abstract: OBJECTIVE
  A randomized, double-blind, placebo-controlled study was conducted to investigate the safety and efficacy of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, in patients who are statin intolerant and at high risk for cardiovascular disease (CVD).
  
  
  RESULTS
  Thirty-three subjects, not receiving statin therapy because of statin intolerance, received a weekly subcutaneous dose of 200 mg mipomersen or placebo (2:1 randomization) for 26 weeks. The primary endpoint was per cent change in LDL cholesterol (LDL-c) from the baseline to Week 28. The other efficacy endpoints were per cent change in apoB and lipoprotein a [Lp(a)]. Safety was determined using the incidence of treatment-emergent adverse events (AEs) and clinical laboratory evaluations. After 26 weeks of mipomersen administration, LDL-c was reduced by 47 ± 18% (P < 0.001 vs. placebo). apoB and Lp(a) were also significantly reduced by 46 and 27%, respectively (P < 0.001 vs. placebo). Four mipomersen (19%) and two placebo subjects (17%) discontinued dosing prematurely due to AEs. Persistent liver transaminase increases ≥ 3× the upper limit of normal were observed in seven (33%) subjects assigned to mipomersen. In selected subjects, liver fat content was assessed, during and after treatment, using magnetic resonance spectroscopy. Liver fat content in these patients ranged from 0.8 to 47.3%. Liver needle biopsy was performed in two of these subjects, confirming hepatic steatosis with minimal inflammation or fibrosis.
  
  
  CONCLUSIONS
  The present data suggest that mipomersen is a potential therapeutic option in statin-intolerant patients at high risk for CVD. The long-term follow-up of liver safety is required.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT00707746.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Maartje E
authors.initials: ME
authors.lastname: Visser
authors.forename: Gilbert
authors.initials: G
authors.lastname: Wagener
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Baker
authors.forename: Richard S
authors.initials: RS
authors.lastname: Geary
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Donovan
authors.forename: Ulrich H W
authors.initials: UH
authors.lastname: Beuers
authors.forename: Aart J
authors.initials: AJ
authors.lastname: Nederveen
authors.forename: Joanne
authors.initials: J
authors.lastname: Verheij
authors.forename: Mieke D
authors.initials: MD
authors.lastname: Trip
authors.forename: Dick C G
authors.initials: DC
authors.lastname: Basart
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D053299:Apolipoprotein B-100 / Q000037:antagonists & inhibitors*; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000517:prevention & control; D008078:Cholesterol, LDL / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000627:therapeutic use*; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009841:Oligonucleotides; C524142:mipomersen; D000410:Alanine Transaminase