The results conclude that treatment with crenezumab was associated with a consistent decrease in Aβ oligomer levels in the CSF.
“We think those oligomers are the principal toxic form of AB in Alzheimer disease, they’re neurotoxic.”
At the 2018 Alzheimer’s Association International Conference held in Chicago, Illinois, Dennis Selkoe, MD, presented the results from an exploratory analysis on crenezumab from the completed phase II BLAZE and ABBY clinical trials that showed the impact of crenezumab treatment throughout the duration on beta amyloid oligomer levels in cerebrospinal fluid (CSF) in subjects with mild to moderate Alzheimer disease.
The Coates Professor of Neurologic Diseases at Harvard Medical School and co-director of the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Health Center sat with NeurologyLive to discuss the results in further detail.
Researchers used an ultrasensitive in-house immunoassay to measure Aβ oligomer levels in CSF from 104 subjects from the ABBY and BLAZE trials before and after treatment with crenezumab versus placebo. Subjects received subcutaneous 300 mg crenezumab or placebo every 2 weeks or intravenous crenezumab (15 mg/kg) or placebo every 4 weeks for 68 weeks.
The results showed that treatment with crenezumab was associated with a consistent decrease in Aβ oligomer levels in the CSF; specifically, 86% of subjects receiving treatment intravenously and 89% receiving subcutaneous treatment had lower levels of Aβ oligomeric levels at week 69 than baseline. The difference in proportions of subjects with decreasing levels was significant for both treatment arms— P = .001 for subcutaneous, and P = .01 for intravenous crenezumab versus placebo.
This is the first time anyone has shown direct evidence of target engagement of toxic forms of amyloid in humans, Selkoe noted, and these results strongly suggest target engagement, recommending assaying CSF Aβ oligomers in future trials.
The safety and efficacy of crenezumab is currently being evaluated in 2 phase III clinical trials, CREAD 1 and CREAD 2, studying 750 subjects in each trial with prodromal or mild Alzheimer disease.