Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid

Abstract

Objective: Oligomeric forms of amyloid β protein (oAβ) are believed to be principally responsible for neurotoxicity in Alzheimer disease (AD), 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 cerebrospinal fluid (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 2 weeks, or intravenous (IV) crenezumab (15mg/kg) or placebo every 4 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 versus 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. ANN NEUROL 2019;86:215-224.

Figure 1

Timeline of antibody injections and cerebrospinal fluid (CSF) collections for Alzheimer disease patients in the ABBY and BLAZE trials. (A) Schematic of the identical dosing regimens in the ABBY and BLAZE studies. CSF samples were collected at baseline (BL; week 1) and week 69. (B) Schematic illustrating patient distribution by clinical trial and treatment. IV = intravenous; oAβ = oligomers of amyloid β; SC = subcutaneous.

Figure 2

Pooled analysis of samples from the BLAZE and ABBY studies reveals that crenezumab treatment significantly lowers cerebrospinal fluid amyloid β oligomer (oAβ) levels. oAβ levels at baseline (BL) and week 69 are shown for the placebo, subcutaneous (SC), and intravenous (IV) groups. BL oAβ levels are shown as filled gray circles. Week 69 levels lower than their corresponding BL sample are in red, and those higher than their BL value are in black. Each symbol represents a single subject, and the BL and week 69 values for the same individual are connected by a straight line, the color of which indicates a negative (red) or positive (black) change. Values that did not change appreciably between baseline and week 69 are connected with a gray line. LLoQ = lower limit of reliable quantification.

Figure 3

Crenezumab treatment increases cerebrospinal fluid Aβ42 monomer levels. Baseline Aβ42 monomer levels are shown as filled gray circles. Week 69 levels lower than their corresponding baseline sample are in red, and those higher than their baseline value are in black. Each symbol represents a single subject, and the baseline and week 69 values for the same individual are joined by a straight line, the color of which indicates a negative (red) or positive (black) change. Values that did not change appreciably between baseline and week 69 are connected with a gray line. For Aβ42 monomers, only 1 patient showed levels above the upper limit of quantification and was omitted in this calculation of median change. IV = intravenous; SC = subcutaneous.

Figure 4

Addition of crenezumab does not alter the detection of oligomers of amyloid β (oAβ). Crenezumab or a control IgG4 antibody was spiked into (A) the amyloid‐beta–derived diffusible ligand (ADDL) standard or (B) 7 different control cerebrospinal fluid (CSF) samples at final concentrations of 5μg/ml, and the oAβ levels were measured. Samples treated with crenezumab are in blue and those treated with control antibody are in red. Each symbol is the mean of technical quadruplicates. DE = detected event.

Figure 5

Crenezumab (Cren) treatment reduces levels of oligomers of amyloid β (oAβ) in cerebrospinal fluid. Results are presented by trial (A, B: BLAZE; C, D: ABBY) and by treatment arm (A, C: intravenous [IV]; B, D: subcutaneous [SC]). oAβ levels measured at baseline (BL) and week 69 are shown for each subject. Baseline oAβ levels are shown as filled gray circles; week 69 levels lower than their corresponding baseline sample are in red, and those with oAβ levels higher than their baseline are in black. Baseline and week 69 levels for the same individual are joined by a straight line, the color of which indicates a negative (red) or positive (black) change. Values that did not change appreciably between baseline and week 69 are connected with a gray line. Pbo = placebo.

Figure 6

No correlation between changes from baseline in cerebrospinal fluid amyloid β oligomer (oAβ) and Aβ42 monomer levels. Results are presented by treatment arm (placebo, crenezumab subcutaneous [SC], crenezumab intravenous [IV]). Changes from baseline in oAβ and Abeta monomer levels are not significantly correlated.