title: Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings.
abstract: BACKGROUND
  CER-001 comprises recombinant human apolipoprotein A-I complexed with phospholipids that mimics natural, nascent, pre-β high-density lipoprotein (HDL). We present animal model data showing dose-dependent increases in cholesterol efflux with CER-001 and its subsequent elimination by reverse lipid transport, together with inhibition of atherosclerotic plaque progression. We report the first phase I study results with CER-001 in humans, starting at 0.25 mg/kg, which is 1/80th of the safe dose (20 mg/kg) established in 4-week multiple-dose animal studies dosed every second day.
  
  
  METHODS
  Healthy volunteers, 18-55 years old with a low-density lipoprotein-cholesterol:HDL-cholesterol ratio greater than 3.0, received single intravenous escalating doses of CER-001 (0.25-45.0 mg/kg) and placebo in a double-blind randomised cross-over fashion. Subjects were followed up for 3 weeks post-dose. Assessments included adverse event monitoring, blood sampling, and clinical laboratory measurements.
  
  
  RESULTS
  Thirty-two subjects were enrolled. All CER-001 doses (0.25-45 mg/kg) were safe and well tolerated, with an adverse event profile similar to placebo. Effects on clinical chemistry, haematology and coagulation parameters were comparable to placebo. No adverse effects of CER-001 on electrocardiograms were observed. No antibodies to apolipoprotein A-I were detected following single-dose administration of CER-001. Plasma apolipoprotein A-I levels increased in a dose-related manner and returned to baseline by 24 h post-dose for doses up to 10 mg/kg but remained in circulation for >72 h post-dose for doses >10 mg/kg. CER-001 caused elevations in plasma cholesterol and total and unesterified cholesterol in the HDL fraction. Mobilisation of unesterified cholesterol in the HDL fraction was seen with CER-001 at doses as low as 2 mg/kg.
  
  
  CONCLUSIONS
  CER-001 is well tolerated when administered to humans as single doses up to 45 mg/kg and mobilises and eliminates cholesterol via reverse lipid transport.
authors.affiliation: Cerenis Therapeutics, 265 rue de la Découverte-Bât. A, 31670, Labège, France. Keyserling@cerenis.com.
authors.forename: Constance H
authors.initials: CH
authors.lastname: Keyserling
authors.affiliation: Cerenis Therapeutics, 265 rue de la Découverte-Bât. A, 31670, Labège, France.
authors.forename: Ronald
authors.initials: R
authors.lastname: Barbaras
authors.affiliation: Cerenis Therapeutics, 265 rue de la Découverte-Bât. A, 31670, Labège, France.
authors.forename: Renee
authors.initials: R
authors.lastname: Benghozi
authors.affiliation: Cerenis Therapeutics, 265 rue de la Découverte-Bât. A, 31670, Labège, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Dasseux
mesh_terms: D000328:Adult; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood* / Q000494:pharmacology / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood*; D008076:Cholesterol, HDL / Q000037:antagonists & inhibitors / Q000097:blood; D008078:Cholesterol, LDL / Q000037:antagonists & inhibitors / Q000097:blood; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010743:Phospholipids / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; C000591544:CER-001; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D010743:Phospholipids; D011994:Recombinant Proteins; D002784:Cholesterol