title: First administration of the Fc-attenuated anti-β amyloid antibody GSK933776 to patients with mild Alzheimer's disease: a randomized, placebo-controlled study.
abstract: OBJECTIVE
  To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the Fc-inactivated anti-β amyloid (Aβ) monoclonal antibody (mAb) GSK933776 in patients with mild Alzheimer's disease (AD) or mild cognitive impairment (MCI).
  
  
  METHODS
  This was a two-part, single blind, placebo-controlled, first-time-in-human (FTIH) study of single (n = 18) and repeat dose (n = 32) intravenous GSK933776 0.001-6 mg/kg (ClinicalTrials.gov: NCT00459550). Additional safety data from an open-label, uncontrolled, single dose study of intravenous GSK933776 1-6 mg/kg (n = 18) are included (ClinicalTrials.gov: NCT01424436).
  
  
  RESULTS
  There were no cases of amyloid-related imaging abnormalities-edema (ARIA-E) or -hemorrhage (ARIA-H) after GSK933776 administration in both studies. Three patients across the two studies developed anti-GSK933776 antibodies. Plasma GSK933776 half-life (t1/2) was 10-15 days after repeat dosing. After each of three administrations of GSK933776, plasma levels of total Aβ42 and Aβ increased whereas plasma levels of free Aβ decreased dose dependently; no changes were observed for placebo. For total Aβ42 the peak:trough ratio was ≤2 at doses ≥3 mg/kg; for total Aβ the ratio was ≤2 at 6 mg/kg. CSF concentrations of Aβ showed increases from baseline to week 12 for Aβ X-38 (week 12:baseline ratio: 1.65; 95%CI: 1.38, 1.93) and Aβ X-42 (week 12:baseline ratio: 1.18; 95%CI: 1.06, 1.30) for values pooled across doses.
  
  
  CONCLUSIONS
  In this FTIH study the Fc-inactivated anti-Aβ mAb GSK933776 engaged its target in plasma and CSF without causing brain ARIA-E/H in patients with mild AD or MCI.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00459550.
authors: Geriatriska Kliniken, Karolinska Universitetssjukhuset, Huddinge, Stockholm, Sweden.
authors: Niels
authors: N
authors: Andreasen
authors: GlaxoSmithKline Quantitative Sciences, Stockley Park, United Kingdom.
authors: Monica
authors: M
authors: Simeoni
authors: Memory Clinic, Skanes University Hospital, Malmo, Sweden.
authors: Henrik
authors: H
authors: Ostlund
authors: Clinical Operations, TrialCo AB, Gothenburg, Sweden.
authors: Pia I
authors: PI
authors: Lisjo
authors: Division of Medicine and Laboratory Sciences, Clinical Neuroscience Group, Akershus University Hospital, Lørenskog, Norway.
authors: Tormod
authors: T
authors: Fladby
authors: Clinical Immunology, GlaxoSmithKline, Upper Merion, Pennsylvania, United States of America.
authors: Amy E
authors: AE
authors: Loercher
authors: Discipline of Psychiatry, School of Medicine, University of Queensland, Mental Health Center, Royal Brisbane & Women's Hospital, Herston, Australia.
authors: Gerard J
authors: GJ
authors: Byrne
authors: CPSSO Projects Clinical Platforms and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors: Frances
authors: F
authors: Murray
authors: Platform Technology and Science-Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, United Kingdom.
authors: Paul T
authors: PT
authors: Scott-Stevens
authors: Memory Clinic, Sahlgrenska University Hospital, Mölndal, Sweden.
authors: Anders
authors: A
authors: Wallin
authors: Quantitative Sciences, GlaxoSmithKline, Upper Merion, Pennsylvania, United States of America.
authors: Yinghua Y
authors: YY
authors: Zhang
authors: Aleris Diagnostic AB Sabbatsberg, Stockholm, Sweden.
authors: Lena H
authors: LH
authors: Bronge
authors: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology, Queen Square, London, United Kingdom.
authors: Henrik
authors: H
authors: Zetterberg
authors: Geriatriska Kliniken, Karolinska Universitetssjukhuset, Huddinge, Stockholm, Sweden.
authors: Agneta K
authors: AK
authors: Nordberg
authors: Quantitative Sciences, GlaxoSmithKline, Stevenage, United Kingdom.
authors: Astrid J
authors: AJ
authors: Yeo
authors: Biopharm Project Management, GlaxoSmithKline, Stevenage, United Kingdom.
authors: Shahid A
authors: SA
authors: Khan
authors: Neurosciences Therapeutic Area, GlaxoSmithKline, Shanghai, China.
authors: Jan
authors: J
authors: Hilpert
authors: Quantitative Sciences, GlaxoSmithKline, Stevenage, United Kingdom.
authors: Prafull C
authors: PC
authors: Mistry
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments; D007518:Isoantibodies / Q000097:blood; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D007141:Immunoglobulin Fc Fragments; D007518:Isoantibodies; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)