Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes

Abstract

Introduction: Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented.

Methods: Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 μg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aβ positron emission tomography (PET) scans at 18 to 24 months.

Results: CAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid-related imaging abnormality cases (one symptomatic).

Discussion: Despite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD.

Highlights: This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.

Keywords: Alzheimer's disease; CAD106; active immunotherapy; amyloid; apolipoprotein E genotype; biomarkers; cognitively unimpaired; positron emission tomography; preclinical; prevention; vaccine.

FIGURE 1

A, Study design and planned participant enrollment. B, Participant disposition and primary reasons for premature withdrawal, *Actual duration of treatment between 6 and 48 months (median: 24 months). † Planned n = 690 (CAD106: 430; placebo: 260) down to 65 (CAD106: 42; placebo: 23) after the halt of recruitment and subsequent trial termination. First three injections every 6 weeks, then quarterly until study termination. ‡Participants prescreened and screened for both Cohort I with CAD106 and Cohort II with umibecestat (note that another 8970 out of the 35,333 participants were screened for Generation Study 2); §Termination for CAD106 on September 23, 2019; last injection October, 19 2019. IC, informed consent; N, total number of participants in the cohort or in the treatment groups; n, number of participants in each sub‐category

FIGURE 2

Mean and 95% CI of Aβ‐specific IgG titer in serum over time. The numbers across the x axis represent the total number of participants in the CAD106‐treated group that had a titer measurement at the corresponding visit (week) before study termination. All participants included in this graph were on treatment. *Aβ‐IgG was not measured in this study for serum at baseline or in placebo‐treated participants, but was assessed and not detected in a previous CAD106 study. Seven measurements at Weeks 9 and 15 were taken 2 weeks post‐injection; all other measurements were taken before the injection. Aβ, amyloid beta; CI, confidence interval; IgG, immunoglobulin G

FIGURE 3

A, Annualized change in the PET measurement of Aβ plaques at the Year 2 visit. B, Correlation between annualized change in PET Aβ and Aβ‐antibody response. The Year 2 visit occurred at Week 104 for participants assessed before study termination and between 18 and 24 months for other participants. Annualized change from baseline: change per participant/time interval (in days) × 365.25. The time interval was derived as (date of current assessment – date of baseline assessment + 1). Cmax is the maximum (or peak) serum concentration after dosing. Cmax for placebo is zero. A+ and A− are participants with and without elevated Aβ at the time of treatment initiation, respectively. *** P ≤ 0.001; ns, P > 0.05. Aβ, amyloid beta; ns, non‐significant; PET, positron emission tomography; r, Pearson correlation coefficient; SD, standard deviation