First Administration of the Fc-Attenuated Anti-β Amyloid Antibody GSK933776 to Patients with Mild Alzheimer's Disease: A Randomized, Placebo-Controlled Study

Objective To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the Fcinactivated anti-beta amyloid (A beta) 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 patientsacross the two studies developed anti-GSK933776 antibodies. Plasma GSK933776 half-life (t(1/2)) was 10-15 days after repeat dosing. After each of three administrations of GSK933776, plasma levels of total A beta 42 and A beta increased whereas plasma levels of free A beta decreased dose dependently; no changes were observed for placebo. For total A beta 42 the peak: trough ratio was <= 2 at doses >= 3 mg/kg; for total A beta the ratio was <= 2 at 6 mg/kg. CSF concentrations of A beta showed increases from baseline to week 12 for A beta X-38 (week 12: baseline ratio: 1.65; 95% CI: 1.38, 1.93) and A beta 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-A beta mAb GSK933776 engaged its target in plasma and CSF without causing brain ARIA-E/H in patients with mild AD or MCI.