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Randomized Controlled Trial
. 2015 Mar 19;10(3):e0098153.
doi: 10.1371/journal.pone.0098153. eCollection 2015.

First administration of the Fc-attenuated anti-β amyloid antibody GSK933776 to patients with mild Alzheimer's disease: a randomized, placebo-controlled study

Niels Andreasen  1 , Monica Simeoni  2 , Henrik Ostlund  3 , Pia I Lisjo  4 , Tormod Fladby  5 , Amy E Loercher  6 , Gerard J Byrne  7 , Frances Murray  8 , Paul T Scott-Stevens  9 , Anders Wallin  10 , Yinghua Y Zhang  11 , Lena H Bronge  12 , Henrik Zetterberg  13 , Agneta K Nordberg  1 , Astrid J Yeo  14 , Shahid A Khan  15 , Jan Hilpert  16 , Prafull C Mistry  14
Affiliations
Randomized Controlled Trial

First administration of the Fc-attenuated anti-β amyloid antibody GSK933776 to patients with mild Alzheimer's disease: a randomized, placebo-controlled study

Niels Andreasen et al. PLoS One. .

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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT00459550.

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Conflict of interest statement

Competing Interests: MS, AL, FM, PSS, YZ, PM, AY, SK & JH are employees of GSK, whose company funded this study. PIL is an employee of TrialCo AB. LH is an employee of Aleris Diagnostic AB Sabbatsberg. The Independent Data Monitoring Committee included Trident Clinical Research Pty Ltd who provided study conduct and monitoring. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Disposition of patients.
A = active; P = placebo; AP = active followed by placebo; PA = placebo followed by active; AA = received active in both parts.
Fig 2
Fig 2. GSK933776 plasma pharmacokinetics.
Time-course of plasma concentrations of GSK933776 by dose: medians (lines) and individual data (dots). LLQ is 100 ng/mL for the 0.1 mg/kg dose and 5 μg/mL for the 1, 3, and 6 mg/kg doses. SD = single dose; RD = repeat dose. Maximum plasma concentrations increased with dose.
Fig 3
Fig 3. GSK933776 plasma pharmacodynamics.
A) Geometric mean plasma Aβ concentration–time plots over the three dosing intervals (semi-log plot). Plasma levels of total Aβ42 and Aβ increased whereas plasma levels of free Aβ decreased in dose-dependent manner. Peak:trough ratios for Aβ decreased with increasing dose of GSK933776. B) Week 12 ratio to baseline for CSF Aβ (Aβ1–42 and AβX–42) concentrations. Presented as individual values and mean (95%CI). There were no significant changes from baseline for Aβ1–42 or AβX–42.
See this image and copyright information in PMC

References

    1. Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10: 698–712. 10.1038/nrd3505 - DOI - PubMed
    1. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, et al. (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73: 2061–2070. 10.1212/WNL.0b013e3181c67808 - DOI - PMC - PubMed
    1. Black RS, Sperling RA, Safirstein B, Motter RN, Pallay A, et al. (2010) A single ascending dose study of bapineuzumab in patients with Alzheimer disease. Alzheimer Dis Assoc Disord 24: 198–203. 10.1097/WAD.0b013e3181c53b00 - DOI - PMC - PubMed
    1. Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, et al. (2010) 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 9: 363–372. 10.1016/S1474-4422(10)70043-0 - DOI - PubMed
    1. Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei J, et al. (2012) Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol 69: 1002–1010. - PubMed

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