title: Safety and Tolerability of ACP-501, a Recombinant Human Lecithin:Cholesterol Acyltransferase, in a Phase 1 Single-Dose Escalation Study.
abstract: BACKGROUND
  Low high-density lipoprotein-cholesterol (HDL-C) in patients with coronary heart disease (CHD) may be caused by rate-limiting amounts of lecithin:cholesterol acyltransferase (LCAT). Raising LCAT may be beneficial for CHD, as well as for familial LCAT deficiency, a rare disorder of low HDL-C.
  
  
  OBJECTIVE
  To determine safety and tolerability of recombinant human LCAT infusion in subjects with stable CHD and low HDL-C and its effect on plasma lipoproteins.
  
  
  RESULTS
  A phase 1b, open-label, single-dose escalation study was conducted to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of recombinant human LCAT (ACP-501). Four cohorts with stable CHD and low HDL-C were dosed (0.9, 3.0, 9.0, and 13.5 mg/kg, single 1-hour infusions) and followed up for 28 days. ACP-501 was well tolerated, and there were no serious adverse events. Plasma LCAT concentrations were dose-proportional, increased rapidly, and declined with an apparent terminal half-life of 42 hours. The 0.9-mg/kg dose did not significantly change HDL-C; however, 6 hours after doses of 3.0, 9.0, and 13.5 mg/kg, HDL-C was elevated by 6%, 36%, and 42%, respectively, and remained above baseline ≤4 days. Plasma cholesteryl esters followed a similar time course as HDL-C. ACP-501 infusion rapidly decreased small- and intermediate-sized HDL, whereas large HDL increased. Pre-β-HDL also rapidly decreased and was undetectable ≤12 hours post ACP-501 infusion.
  
  
  CONCLUSIONS
  ACP-501 has an acceptable safety profile after a single intravenous infusion. Lipid and lipoprotein changes indicate that recombinant human LCAT favorably alters HDL metabolism and support recombinant human LCAT use in future clinical trials in CHD and familial LCAT deficiency patients.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01554800.
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.). bobs@mail.nih.gov.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Shamburek
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.).
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bakker-Arkema
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.).
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Shamburek
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.).
authors.forename: Lita A
authors.initials: LA
authors.lastname: Freeman
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.).
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Amar
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.).
authors.forename: Bruce
authors.initials: B
authors.lastname: Auerbach
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.).
authors.forename: Brian R
authors.initials: BR
authors.lastname: Krause
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.).
authors.forename: Reynold
authors.initials: R
authors.lastname: Homan
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.).
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Adelman
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.).
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Collins
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.).
authors.forename: Maureen
authors.initials: M
authors.lastname: Sampson
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.).
authors.forename: Anna
authors.initials: A
authors.lastname: Wolska
authors.affiliation: From the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (R.D.S., A.M.S., L.A.F., M.J.A., A.W., A.T.R.); AlphaCore Pharma LLC., Ann Arbor, MI (R.B.-A., B.A., B.R.K., R.H.); VascularStrategies LLC., Plymouth Meeting, PA (S.J.A., H.L.C.); and Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD (M.S.).
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*
chemical_list: D011994:Recombinant Proteins; D007862:Phosphatidylcholine-Sterol O-Acyltransferase
keywords: acute coronary syndrome; cardiovascular diseases; cholesterol; cholesterol, HDL; lecithin cholesterol acyltransferase; lecithin cholesterol acyltransferase deficiency