Background

GSK933776 is a humanized mouse IgG1 monoclonal antibody directed against the N-terminus of the Aβ peptide. Its Fc region has been engineered to reduce FC-receptor binding and complement activation; this was done in an effort to weaken the antibody's effector function and minimize risk of side effects such as ARIA.

Findings

GSK conducted two Phase 1 trials with this antibody.

Between 2007 and 2011, a first-in-human dose-escalation study in Australia, Norway, and Sweden compared single and repeat doses of antibody infusion, ranging from 0.001 to 6 mg/kg, in 50 people with mild Alzheimer's disease. Outcomes were adverse events and plasma and CSF pharmacology. The trial reported no instances of ARIA. Three patients developed antibodies against GSK933776. After each administration, plasma levels of total Aβ increased, while plasma levels of free Aβ decreased. For detailed results, see Andreasen et al., 2015).

In 2010 and 2011, an open-label trial at five sites in Germany and Sweden compared one-time infusions of either 1, 3, or 6 mg/kg of antibody doses to characterize the time course of their effect, if any, on the concentration of CSF Aβ, as well as plasma Aβ and CSF tau. The trial also assessed pharmacokinetic and safety parameters. It enrolled 15 people with mild Alzheimer's disease or MCI, in whom the clinical diagnosis was supported by the presence of an AD-like CSF Aβ/tau signature. The participants agreed to have a lumbar catheter inserted; this enabled frequent CSF sampling to establish a time course of target engagement. This trial reported evidence of dose-dependent target engagement, i.e., decreases of CSF Aβ ranging from 6 to 12 percent. Plasma measurements showed increased Aβ levels, but CSF tau showed no significant change. The results of this study are published (see Leyhe et al., 2014). 

As of April 2015, this antibody was in Phase 2 for retinal amyloidosis in connection with dry age-related macular degeneration; however, GSK had no current plans for developing it further for Alzheimer's disease. For all clinical trials with this antibody, see clinicaltrials.gov.