Abstract
Objective
Oligomeric forms of amyloid β‐protein (oAβ) are believed to be principally responsible for neurotoxicity in Alzheimer's disease, but it is not known whether anti‐Aβ antibodies are capable of lowering oAβ levels in humans.
Methods
We developed an ultrasensitive immunoassay and used it to measure oAβ in CSF from 104 AD subjects participating in the ABBY and BLAZE Phase 2 trials of the anti‐Aβ antibody crenezumab. Patients received subcutaneous (SC) crenezumab (300mg) or placebo every two weeks or else intravenous (IV) crenezumab (15mg/kg) or placebo every four weeks for 68 weeks. Ninety‐eight of the 104 patients had measurable baseline oAβ levels, and these were compared to levels at week 69 in placebo (N=28), SC (N=35) and IV (N=35) treated patients.
Results
Among those receiving crenezumab, 89% of SC and 86% of IV patients had lower levels of oAβ at week 69 versus baseline. The difference in the proportion of patients with decreasing levels was significant for both treatment arms: p=0.0035 for SC and p=0.01 for IV crenezumab vs. placebo. The median percentage change was ‐48% in the SC arm and ‐43% in the IV arm. No systematic change was observed in the placebo group, with a median change of ‐13% and equivalent portions with negative and positive change.
Interpretation
Crenezumab lowered CSF oAβ levels in the large majority of treated patients tested. These results support engagement of the principal pathobiological target in AD and identify CSF oAβ as a novel pharmacodynamic biomarker for use in trials of anti‐Aβ agents.
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