Antibody Reduces Amyloid-Beta in Alzheimer’s

Major Finding: Monthly infusion with 200 mg gantenerumab, a monoclonal antibody to amyloid-beta, resulted in an average 15% decline in the amount of brain amyloid-beta in patients with mild to moderate Alzheimer’s disease.

Data Source: Randomized trial of 16 patients with mild to moderate Alzheimer’s disease given monthly infusions with 60 or 200 mg gantenerumab or placebo for up to seven total infusions.

Disclosures: Dr. Ostrowitzki and several of her coauthors are employees of Hoffmann-La Roche, which supported the study. Two additional coauthors are employees of GE Healthcare.

Treatment with a monoclonal antibody directed against amyloid-beta peptides produced a dose-dependent reduction of amyloid in the brains of patients with Alzheimer’s disease in a randomized, placebo-controlled, double-blind study with 16 patients.

While promising, the study’s small size limited the results, and the authors acknowledged the continued uncertainty of the clinical significance of amyloid reduction in Alzheimer’s disease patients.

“It is still unclear whether any reduction in brain amyloid level will translate into clinical efficacy,” wrote Dr. Susanne Ostrowitzki, a researcher at Hoffmann-La Roche in Basel, Switzerland, and her associates (Arch. Neurol. 2011 Oct. 10 [doi:10.1001/archneurol.2011.1538]). “A phase II clinical trial is underway to investigate whether a clinical benefit can be achieved in gantenerumab-treated patients with prodromal Alzheimer disease.”

Gantenerumab, the fully-human monoclonal antibody they tested, binds to amyloid-beta plaques. Researchers at Hoffmann-La Roche are testing gantenerumab as a potential therapeutic agent for patients with Alzheimer’s disease.

The current study enrolled patients with mild to moderate disease, and compared two to seven intravenous infusions of the antibody, at a dosage of 60 or 200 mg per infusion every 4 weeks, against placebo infusions. The report focused on data collected on a subset of 16 patients from a dose escalation study who underwent measurement of brain amyloid-beta location and amount by positron emission tomography (PET) imaging of C

At the end of treatment, the four patients in the placebo group had an average increase of 21% in their standard uptake value ratio (SUVR), measured by PET, compared with baseline. The six patients who received 60-mg dosages of gantenerumab had an average increase in SUVR of 5%, and the six patients treated with 200-mg dosages had an average decrease in their SUVR of 15%. The increases and decreases in SUVR appeared consistent across all brain regions examined except in the pons, a region known to have limited amyloid deposition. The effect of the antibody on amyloid deposits appeared rapidly, following two to seven antibody infusions.

The researchers failed to see consistent changes in cognitive measures in patients that correlated with the amyloid changes, but noted that the number of patients was small and the treatment period relatively brief. “Individual changes in cognitive measures did not correlate with changes in levels of amyloid,” they wrote.

Additional studies run by the researchers on freshly-harvested human primary microglia cells indicated that phagocytosis was the likely mechanism by which gantenerumab treatment led to reduced amyloid levels. This finding suggests that the antibody, at appropriate dosages, produces reduced amyloid levels without significantly changing vascular permeability by inflammation or by blocking amyloid-beta clearance pathways.

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