DT‐02‐03: TARGET ENGAGEMENT IN AN AD TRIAL: CRENEZUMAB LOWERS Aβ OLIGOMER LEVELS IN CSF
Ting Yang, Yifan Dang, Beth L. Ostaszewski, David Mengel, Verena Steffen, Christina Rabe, Tobias Bittner, Dominic M. Walsh, Dennis J. Selkoe · Alzheimer s & Dementia · 2018
Crenezumab is an investigational anti-Aβ antibody intended to predominantly target Aβ oligomers (AβO) and is currently in development for prodromal-to-mild Alzheimer's disease. We used an ultrasensitive in-house immunoassay to measure AβO levels in CSF from AD subjects before and after treatment with crenezumab vs. placebo. CSF samples at baseline and week 69 were available from 104 subjects from the ABBY (Cummings 2018) and BLAZE Phase 2 trials. 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. AβO levels were measured using an optimized Erenna-based immunoassay employing the aggregate-preferring mAb, 1C22, for capture, and 3D6 for detection (Yang 2015). Operators were blinded to sample identity. To minimize variance arising from plate-to-plate and day-to-day differences, baseline and 69 week samples from the same patient were measured in neighboring wells of the same plate. Paired CSF samples were analyzed from placebo (N=31), SC (N=36) and IV (N=37) treated patients from both BLAZE and ABBY. Of 104 paired samples analyzed, 98 had baseline CSF AβO values above the lower limit of quantification (LLoQ). In those 98 patients, treatment with crenezumab was associated with a consistent decrease in AβO levels. Specifically, 86% of IV and 89% of SC patients had lower levels of AβO at week 69 than at baseline. The median percentage change was -42% in the IV arm and -48% in the SC arm, with 21% and 13% of patients falling below the LLoQ after treatment. In contrast, no systematic change was observed in the placebo group, with a median change of -13% and equivalent portions with negative and positive change (54% of the placebo patients had lower AβO levels at week 69). The difference in proportions of patients with decreasing levels was significant for both treatment arms: p=0.001 for SC, and p=0.01 for IV crenezumab vs. placebo. Crenezumab lowers AβO levels in CSF in the large majority of tested patients. These results strongly suggest engagement of the principal target and recommend assaying CSF AβO in future trials of anti-Aβ agents . Crenezumab treatment lowers CSF Abeta oligomer levels. Boxplots of the AbetaO levels at baseline and week 69. Dots represent mean levels of individual patient. Samples yielding values below the LLoQ are shown in red. Boxes = 25-75 percentile; horizontal bar = median.