Gantenerumab with Amyloid Removal in Patients with AD

According to researchers, there is genetic and neuropathologic evidence suggesting that the accumulation of amyloid-β (Aβ) peptides in the brain is a key event in the pathophysiology of Alzheimer disease (AD). The therapeutic potential of various approaches aimed at lowering the level of Aβ amyloid in the brain are currently under investigation. Gantenerumab, a fully human anti-β monoclonal antibody that binds specifically to Aβ plaques, has been studied in single- and multiple-dose phase-1 clinical trials. In a recent study of patients with mild-to-moderate AD, researchers examined the effect of up to 7 infusions of intravenous (IV) gantenerumab (60 or 200 mg) or placebo every 4 weeks on the level of brain Aβ amyloid. The study was designed to determine whether treatment with gantenerumab leads to a measurable reduction in the level of Aβ amyloid in the brain and to describe the mechanism of amyloid reduction. Results of the study were reported online in Archives of Neurology [doi:10.1001/archneurol.2011.1538]. The multicenter, randomized, double-blind, placebo-controlled, ascending-dose positron emission tomographic (PET) study was conducted in 3 university medical centers. Two consecutive cohorts of patients received 2 to 7 infusions of IV gantenerumab at 60 or 200 mg or placebo every 4 weeks. Brain slices from patients who had AD were coincubated with gantenerumab at increasing concentrations and with human microglial cells. The primary outcome measures were percent change in the ratio to regional carbon 11-labeled Pittsburgh compound B (PiB) retention in vivo and semiquantitative assessment of gantenerumab-induced phagocytosis ex vivo. There were 16 patients with end-of-treatment PET scans included in the analysis. The observed mean (95% confidence interval [CI]) treatment differences from the placebo group (n=4) in percent change over the specific PiB signal were –15.6% (95% CI, –42.7% to 11.6%) for the 60-mg group (n=6) and –35.7% (95% CI, –63.5% to –7.9%) for the 200-mg group (n=6). After adjusting for standard uptake value ratio, the researchers found that a nonparametric analysis of covariance on this percent change suggested that the 200-mg group differed from the placebo group (P=.06). The dose dependency of the amyloid-reducing effect was indicated by the nonparametric linear regression analysis on the baseline-adjusted percent change values over the specific PiB signal: slope of –0.13 (r2=0.29; P=.03). In the 200-mg group, focal magnetic resonance imaging signal changes were observed in 2 APOE ε4 homozygous patients following 2 and 4 doses of 200 mg of gantenerumab, respectively. Findings were most conspicuous on the fluid-attenuated inversion recovery sequence and were consistent with inflammation or vasogenic edema. They resolved spontaneously following discontinuation of dosing. Gantenerumab induced phagocytosis of human amyloid in a dose-dependent manner ex vivo: a decrease in Aβ amyloid plaque in sections of brain that were incubated with microglia cells was dependent on the concentration of gantenerumab, with a slight effect at 50 ng/mL of gantenerumab and substantial plaque clearance at 500 and 5000 ng/mL. Limitations to this analysis cited by the researchers include its small size as well as the unequal distribution of amyloid load at baseline between the treatment group and the placebo group. In addition, the researchers stressed that it is still unclear whether any reduction in brain amyloid level will translate into clinical efficacy. A phase 2 clinical trial is under way to investigate whether treating patients with prodromal AD will produce a clinical benefit. In conclusion, the researchers summarized their results, noting that “gantenerumab treatment resulted in a dose-dependent reduction in brain amyloid level, possibly through an effector cell-mediated mechanism of action.”