title: Is mipomersen ready for clinical implementation? A transatlantic dilemma.
abstract: OBJECTIVE
  Mipomersen has been approved by the US Food and Drug Administration as an orphan drug for patients with homozygous familial hypercholesterolemia (HoFH). In contrast, the European Medicines Agency advised negatively on the use of mipomersen. In this review, we discuss the efficacy and safety considerations for this discrepancy.
  
  
  RESULTS
  On the basis of the results of clinical trials with mipomersen, safety concerns have been raised regarding cardiovascular risk reduction and development of hepatic steatosis. In addition, (long-term) tolerability concerns have been raised predominantly regarding injection site reactions. A pooled analysis of cardiovascular events in phase III trials with mipomersen did not provide evidence for either a positive or negative effect on cardiovascular disease. Although long-term studies with mipomersen are eagerly awaited, hepatic fat content appears to stabilize after 6-12 months notwithstanding continued mipomersen administration.
  
  
  CONCLUSIONS
  HoFH is a disease with an unmet medical need for new lipid-lowering therapies. On the basis of a mean 2.9 mmol/l LDL-cholesterol reduction, mipomersen is expected to reduce cardiovascular risk in HoFH. Available evidence suggests that the fat accumulation associated with this treatment differs from steatohepatitis, which is a progressive and damaging liver disease. No evidence is available suggesting that injection site reactions because of mipomersen treatment will result in safety issues.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sjouke
authors.forename: Deepak M W
authors.initials: DM
authors.lastname: Balak
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.forename: Vlad
authors.initials: V
authors.lastname: Ratziu
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000097:blood; D017326:Clinical Trials, Phase III as Topic; D017277:Drug Approval; D005060:Europe; D005234:Fatty Liver / Q000139:chemically induced; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D015201:Meta-Analysis as Topic; D009841:Oligonucleotides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014481:United States
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D009841:Oligonucleotides; C524142:mipomersen