title: The effect of an apolipoprotein A-I-containing high-density lipoprotein-mimetic particle (CER-001) on carotid artery wall thickness in patients with homozygous familial hypercholesterolemia: The Modifying Orphan Disease Evaluation (MODE) study.
abstract: BACKGROUND
  Patients with homozygous familial hypercholesterolemia (HoFH) are at extremely elevated risk for early cardiovascular disease because of exposure to elevated low-density lipoprotein cholesterol (LDL-C) plasma levels from birth. Lowering LDL-C by statin therapy is the cornerstone for cardiovascular disease prevention, but the residual risk in HoFH remains high, emphasizing the need for additional therapies. In the present study, we evaluated the effect of serial infusions with CER-001, a recombinant human apolipoprotein A-I (apoA-I)-containing high-density lipoprotein-mimetic particle, on carotid artery wall dimensions in patients with HoFH.
  
  
  RESULTS
  Twenty-three patients (mean age 39.4 ± 13.5 years, mean LDL-C 214.2 ± 81.5 mg/dL) with genetically confirmed homozygosity or compound heterozygosity for LDLR, APOB, PCSK9, or LDLRAP1 mutations received 12 biweekly infusions with CER-001 (8 mg/kg). Before and 1 hour after the first infusion, lipid values were measured. Magnetic resonance imaging (3-T magnetic resonance imaging) scans of the carotid arteries were acquired at baseline and after 24 weeks to assess changes in artery wall dimensions. After CER-001 infusion, apoA-I increased from 114.8 ± 20.7 mg/dL to 129.3 ± 23.0 mg/dL. After 24 weeks, mean vessel wall area (primary end point) decreased from 17.23 to 16.75 mm(2) (P = .008). A trend toward reduction of mean vessel wall thickness was observed (0.75 mm at baseline and 0.74 mm at follow-up, P = .0835).
  
  
  CONCLUSIONS
  In HoFH, 12 biweekly infusions with an apoA-I-containing high-density lipoprotein-mimetic particle resulted in a significant reduction in carotid mean vessel wall area, implying that CER-001 may reverse atherogenic changes in the arterial wall on top of maximal low-density lipoprotein-lowering therapy. This finding supports further clinical evaluation of apoA-I-containing particles in patients with HoFH.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: g.k.hovingh@amc.uva.nl.
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Loek P
authors.initials: LP
authors.lastname: Smits
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stefanutti
authors.affiliation: Cardiovascular Trials Unit, Central Manchester University Hospital NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Handrean
authors.initials: H
authors.lastname: Soran
authors.affiliation: Cardiovascular Trials Unit, Central Manchester University Hospital NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: See
authors.initials: S
authors.lastname: Kwok
authors.affiliation: Department of Vascular Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Graaf
authors.affiliation: Lipid Clinic, Department of Medicine, Université de Montreal, Chicoutimi, Quebec, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.affiliation: Cerenis Therapeutics Holdings, Toulouse, France.
authors.forename: Constance H
authors.initials: CH
authors.lastname: Keyserling
authors.affiliation: Cerenis Therapeutics Holdings, Toulouse, France.
authors.forename: Heather
authors.initials: H
authors.lastname: Klepp
authors.affiliation: Cerenis Therapeutics Holdings, Toulouse, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Frick
authors.affiliation: Cerenis Therapeutics Holdings, Toulouse, France.
authors.forename: John F
authors.initials: JF
authors.lastname: Paolini
authors.affiliation: Cerenis Therapeutics Holdings, Toulouse, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Dasseux
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Stroes
mesh_terms: D000328:Adult; D016632:Apolipoprotein A-I / Q000494:pharmacology* / Q000627:therapeutic use; D059168:Carotid Intima-Media Thickness; D008078:Cholesterol, LDL / Q000097:blood*; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D010743:Phospholipids / Q000494:pharmacology* / Q000627:therapeutic use; D035583:Rare Diseases; D011994:Recombinant Proteins / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016632:Apolipoprotein A-I; C000591544:CER-001; D008078:Cholesterol, LDL; D008055:Lipids; D010743:Phospholipids; D011994:Recombinant Proteins