Modulation of β-amyloid by a single dose of GSK933776 in patients with mild Alzheimer's disease: a phase I study.
BACKGROUND
In this study, we evaluated the safety and pharmacodynamic effects of the Fc-inactivated anti-β-amyloid (anti-Aβ) monoclonal antibody GSK933776 in patients with mild Alzheimer's disease and mild cognitive impairment. Aβ and tau levels were investigated in cerebrospinal fluid (CSF), and the relationship between Aβ levels and Aβ modulation in plasma was explored. The feasibility of a continuous sampling method using a lumbar catheter was assessed.


METHODS
This trial was a phase I, open-label, uncontrolled, single-dose, exploratory experimental medicine study of intravenous GSK933776 at doses of 1 mg/kg, 3 mg/kg or 6 mg/kg (n = 6/group). The time course of plasma and CSF concentrations of GSK933776 and Aβ was assessed. Sample size was based on feasibility, and no formal statistical analyses were performed.


RESULTS
Following administration of GSK933776 at doses of 1 mg/kg, 3 mg/kg and 6 mg/kg, there were decreases from baseline in CSF Aβ1-42 (from 0 to 12 hours) by 22.8 pg/ml (6.2%), 43.5 pg/ml (9.2%) and 60.5 pg/ml (12.5%), respectively. Plasma concentrations of total Aβ18-35 and Aβ4228-42 increased immediately after infusion and CSF tau concentration increased slightly, but did not significantly change, following administration of all doses of GSK933776. Pharmacokinetics confirmed the presence of GSK933776 in the CSF, which exhibited a dose-response relationship. One patient underwent minor surgery without sequelae following a ruptured lumbar catheter.


CONCLUSIONS
GSK933776 demonstrated pharmacological activity and target engagement in CSF and plasma, and the continuous sampling method via a catheter successfully assessed the Aβ changes following single-dose administration of GSK933776.


BACKGROUND
ClinicalTrials.gov Identifier: NCT01424436. Registered 4 August 2011.
Department of Psychiatry and Psychotherapy, University Hospital of Tübingen, Calwerstrasse 14, D-72076 Tübingen, Germany ; Center of Old Age Psychiatry, Psychiatric University Hospital, Wilhelm Klein-Strasse 27, CH-4012 Basel, Switzerland.
Thomas
T
Leyhe
Karolinska Institute, Alzheimer Research Centre, Solnavägen 1, 171 77 Solna, Stockholm Sweden.
Niels
N
Andreasen
Quantitative Sciences, GlaxoSmithKline, Stockley Park West, 1-3 Iron Bridge Road, Uxbridge, Middlesex UB11 1BT, UK.
Monica
M
Simeoni
Department of Neurology, University Hospital RWTH Aachen, Pauwelstrasse 30, Aachen, Germany.
Arno
A
Reich
Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081 Ulm, Germany.
Christine Af
CA
von Arnim
Clinical Pharmacology Sciences & Study Operations, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Xin
X
Tong
Genetics, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Astrid
A
Yeo
Genetics, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Shahid
S
Khan
Clinical Immunology, GlaxoSmithKline, Upper Merion, 709 Swedeland Road, King of Prussia, PA 19406, USA.
Amy
A
Loercher
Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Stockley Park West, 1-3 Iron Bridge Road, Uxbridge, Middlesex UB11 1BT, UK.
Michelle
M
Chalker
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Upper Merion, 709 Swedeland Road, King of Prussia, PA 19406, USA.
Charles
C
Hottenstein
Department of Psychiatry and Neurochemistry, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, V-husek Mölndal, SE-431 80, Sweden ; UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Henrik
H
Zetterberg
Neuroscienceina.
Jan
J
Hilpert
Quante, Hertfordshire SG1 2NY, UK.
Prafull
P
Mistry