title: Infusion of Reconstituted High-Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial.
abstract: BACKGROUND
  CSL112 is a new formulation of human apolipoprotein A-I (apoA-I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double-blind, multicenter, dose-ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease.
  
  
  RESULTS
  Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2-hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug-related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA-I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7-, 3.4-, and 6.8-g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (>3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7-, 3.4-, and 6.8-g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion-site bruising. CSL112 resulted in rapid (T(max)≈2 hours) and dose-dependent increases in apoA-I (145% increase in the 6.8-g group) and total cholesterol efflux (up to 3.1-fold higher than placebo) (P<0.001).
  
  
  CONCLUSIONS
  CSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA-I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation.
  
  
  BACKGROUND
  URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420.
authors: Duke Clinical Research Institute, Durham, NC (P.T., M.A.B., J.H.A.).
authors: Pierluigi
authors: P
authors: Tricoci
authors: CSL Behring, King of Prussia, PA (D.M.A., Z.Y., C.L.S., S.D.W.).
authors: Denise M
authors: DM
authors: D'Andrea
authors: Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore and Johns Hopkins University School of Medicine, Baltimore, MD (P.A.G.).
authors: Paul A
authors: PA
authors: Gurbel
authors: CSL Behring, King of Prussia, PA (D.M.A., Z.Y., C.L.S., S.D.W.).
authors: Zhenling
authors: Z
authors: Yao
authors: University of Pennsylvania, Philadelphia, PA (M.C.).
authors: Marina
authors: M
authors: Cuchel
authors: Black Hills Cardiovascular Research, Rapid City, SD (B.W.).
authors: Brion
authors: B
authors: Winston
authors: diaDexus, Inc., San Francisco, CA (R.S.).
authors: Robert
authors: R
authors: Schott
authors: Maine Research Associates, Auburn, ME (R.W.).
authors: Robert
authors: R
authors: Weiss
authors: Duke Clinical Research Institute, Durham, NC (P.T., M.A.B., J.H.A.).
authors: Michael A
authors: MA
authors: Blazing
authors: Cardiac and Vascular Research Center of Northern Michigan, Petoskey, MI (L.C.).
authors: Louis
authors: L
authors: Cannon
authors: Gill Heart Institute, University of Kentucky, Lexington, KY (A.B.).
authors: Alison
authors: A
authors: Bailey
authors: University of Florida College of Medicine-Jacksonville, Jacksonville, FL (D.J.A.).
authors: Dominick J
authors: DJ
authors: Angiolillo
authors: CSL Limited, Parkville, Victoria, Australia (A.G.).
authors: Andreas
authors: A
authors: Gille
authors: CSL Behring, King of Prussia, PA (D.M.A., Z.Y., C.L.S., S.D.W.).
authors: Charles L
authors: CL
authors: Shear
authors: CSL Behring, King of Prussia, PA (D.M.A., Z.Y., C.L.S., S.D.W.).
authors: Samuel D
authors: SD
authors: Wright
authors: Duke Clinical Research Institute, Durham, NC (P.T., M.A.B., J.H.A.).
authors: John H
authors: JH
authors: Alexander
mesh_terms: D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000097:blood; D050197:Atherosclerosis / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D002784:Cholesterol / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008075:Lipoproteins, HDL / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D016896:Treatment Outcome; D014481:United States
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D015415:Biomarkers; C584257:CSL112; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D002784:Cholesterol
keywords: apolipoprotein; atherosclerosis; clinical trial; coronary disease; plaque