title: Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy.
abstract: OBJECTIVE
  Mipomersen, an antisense oligonucleotide targeting apolipoprotein B synthesis, significantly reduces LDL-C and other atherogenic lipoproteins in familial hypercholesterolemia when added to ongoing maximally tolerated lipid-lowering therapy. Safety and efficacy of mipomersen in patients with severe hypercholesterolemia was evaluated.
  
  
  RESULTS
  Randomized, double-blind, placebo-controlled, multicenter trial. Patients (n  = 58) were ≥18 years with LDL-C ≥7.8 mmol/L or LDL-C ≥5.1 mmol/L plus CHD disease, on maximally tolerated lipid-lowering therapy that excluded apheresis. Weekly subcutaneous injections of mipomersen 200 mg (n  = 39) or placebo (n  = 19) were added to lipid-lowering therapy for 26 weeks.
  
  
  RESULTS
  percent reduction in LDL-C from baseline to 2 weeks after the last dose of treatment. Mipomersen (n = 27) reduced LDL-C by 36%, from a baseline of 7.2 mmol/L, for a mean absolute reduction of 2.6 mmol/L. Conversely, mean LDL-C increased 13% in placebo (n = 18) from a baseline of 6.5 mmol/L (mipomersen vs placebo p<0.001). Mipomersen produced statistically significant (p<0.001) reductions in apolipoprotein B and lipoprotein(a), with no change in high-density lipoprotein cholesterol. Mild-to-moderate injection site reactions were the most frequently reported adverse events with mipomersen. Mild-to-moderate flu-like symptoms were reported more often with mipomersen. Alanine transaminase increase, aspartate transaminase increase, and hepatic steatosis occurred in 21%, 13% and 13% of mipomersen treated patients, respectively. Adverse events by category for the placebo and mipomersen groups respectively were: total adverse events, 16(84.2%), 39(100%); serious adverse events, 0(0%), 6(15.4%); discontinuations due to adverse events, 1(5.3%), 8(20.5%) and cardiac adverse events, 1(5.3%), 5(12.8%).
  
  
  CONCLUSIONS
  Mipomersen significantly reduced LDL-C, apolipoprotein B, total cholesterol and non-HDL-cholesterol, and lipoprotein(a). Mounting evidence suggests it may be a potential pharmacologic option for lowering LDL-C in patients with severe hypercholesterolemia not adequately controlled using existing therapies. Future studies will explore alternative dosing schedules aimed at minimizing side effects.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00794664.
authors.affiliation: Cardiometabolic Risk Reduction and Research Center of New England, Bedford, New Hampshire, United States of America. mpfmcgowan@gmail.com
authors.forename: Mary P
authors.initials: MP
authors.lastname: McGowan
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Richard
authors.initials: R
authors.lastname: Ceska
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Burgess
authors.forename: Handrean
authors.initials: H
authors.lastname: Soran
authors.forename: Ioanna
authors.initials: I
authors.lastname: Gouni-Berthold
authors.forename: Gilbert
authors.initials: G
authors.lastname: Wagener
authors.forename: Scott
authors.initials: S
authors.lastname: Chasan-Taber
mesh_terms: D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy*; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D009841:Oligonucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D020319:Oligodeoxyribonucleotides, Antisense; D009841:Oligonucleotides; C524142:mipomersen