title: Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study.
abstract: BACKGROUND
  Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease.
  
  
  METHODS
  We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model.
  
  
  RESULTS
  29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI -57 to -31; p<0·0001) at week 56 and 38% (-52 to -24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities.
  
  
  CONCLUSIONS
  Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia.
  
  
  BACKGROUND
  FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.
authors.affiliation: Institute for Translational Medicine and Therapeutics, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. mcuchel@mail.med.upenn.edu
authors.forename: Marina
authors.initials: M
authors.lastname: Cuchel
authors.forename: Emma A
authors.initials: EA
authors.lastname: Meagher
authors.forename: Hendrik
authors.initials: H
authors.lastname: du Toit Theron
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Blom
authors.forename: A David
authors.initials: AD
authors.lastname: Marais
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: Maurizio R
authors.initials: MR
authors.lastname: Averna
authors.forename: Cesare R
authors.initials: CR
authors.lastname: Sirtori
authors.forename: Prediman K
authors.initials: PK
authors.lastname: Shah
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.forename: Claudia
authors.initials: C
authors.lastname: Stefanutti
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Vigna
authors.forename: Anna M E
authors.initials: AM
authors.lastname: Du Plessis
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Propert
authors.forename: William J
authors.initials: WJ
authors.lastname: Sasiela
authors.forename: LeAnne T
authors.initials: LT
authors.lastname: Bloedon
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008297:Male
chemical_list: C473731:BMS201038; D001562:Benzimidazoles; D002352:Carrier Proteins; D008078:Cholesterol, LDL; C106092:microsomal triglyceride transfer protein