Association of Amyloid Reduction After Donanemab Treatment With Tau Pathology and Clinical Outcomes: The TRAILBLAZER-ALZ Randomized Clinical Trial

Abstract

Importance: β-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease.

Objective: To perform post hoc analyses of amyloid reduction after donanemab treatment and assess its association with tau pathology and clinical measures.

Design, setting, and participants: The Study of LY3002813 in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ) was a phase 2, placebo-controlled, randomized clinical trial conducted from December 18, 2017, to December 4, 2020, with a double-blind period of up to 76 weeks and a 48-week follow-up period. The study was conducted at 56 centers in the US and Canada. Enrolled were participants from 60 to 85 years of age with gradual and progressive change in memory function for 6 months or more, early symptomatic Alzheimer disease, elevated amyloid, and intermediate tau levels.

Interventions: Donanemab (an antibody specific for the N-terminal pyroglutamate β-amyloid epitope) dosing was every 4 weeks: 700 mg for the first 3 doses, then 1400 mg for up to 72 weeks. Blinded dose-reduction evaluations occurred at 24 and 52 weeks based on amyloid clearance.

Main outcomes and measures: Change in amyloid, tau, and clinical decline after donanemab treatment.

Results: The primary study randomized 272 participants (mean [SD] age, 75.2 [5.5] years; 145 female participants [53.3%]). The trial excluded 1683 of 1955 individuals screened. The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid (Spearman correlation coefficient r, -0.54; 95% CI, -0.66 to -0.39; P < .001). Modeling provides a hypothesis that amyloid would not reaccumulate to the 24.1-centiloid threshold for 3.9 years (95% prediction interval, 1.9-8.3 years) after discontinuing donanemab treatment. Donanemab slowed tau accumulation in a region-dependent manner as measured using neocortical and regional standardized uptake value ratios with cerebellar gray reference region. A disease-progression model found a significant association between percentage amyloid reduction and change on the integrated Alzheimer Disease Rating Scale only in apolipoprotein E (APOE) ε4 carriers (95% CI, 24%-59%; P < .001).

Conclusions and relevance: Results of post hoc analyses for donanemab-treated participants suggest that baseline amyloid levels were directly associated with the magnitude of amyloid reduction and inversely associated with the probability of achieving complete amyloid clearance. The donanemab-induced slowing of tau was more pronounced in those with complete amyloid clearance and in brain regions identified later in the pathologic sequence. Data from other trials will be important to confirm aforementioned observations, particularly treatment response by APOE ε4 status.

Trial registration: ClinicalTrials.gov Identifier: NCT03367403.

Figure 1.. Patient Flowchart

BACE indicates β-site amyloid precursor protein cleaving enzyme. ^aOne participant was randomly assigned to placebo but discontinued before receiving an infusion. ^bCombination therapy was discontinued from the study in the protocol amendment (Supplement 1).

Figure 2.. Association Between Amyloid Levels and the Magnitude of Amyloid Change at 24 Weeks

Median (IQR) amyloid levels (in centiloid [CL] units) at baseline and 24 weeks for participants receiving placebo (A), donanemab-treated participants with partial amyloid clearance at week 24 (B), and donanemab-treated participants with complete amyloid clearance at week 24 (C) demonstrating the change owing to donanemab treatment. Mean (SD) values along with partial vs complete amyloid clearance and treatment vs placebo comparisons can be found in eTable 2 in Supplement 2. Only participants with follow-up positron emission tomography scans are included.

Figure 3.. Amyloid Responses to Initiation and Discontinuation of Treatment

A, The change in amyloid over 24 weeks after treatment is dependent on baseline amyloid levels. B, Three logistic regression curves to estimate the probability of achieving complete amyloid clearance with donanemab after 24, 52, and 72 weeks of donanemab treatment. The black bars represent the histogram of participants with corresponding baseline amyloid levels. Complete amyloid clearance is defined as having less than 24.1 centiloids (CL). Shaded regions are 95% CIs. C, Exposure-response model of amyloid plaque level over time. Simulated amyloid plaque level over time using treatment exposure-response model (based on 304 participants) and stratified by participants, in the simulation, achieving less than 11 CL by 24 weeks and then discontinuing donanemab treatment. Shaded region indicates 95% prediction interval, the solid line is the predicted median, the orange region depicts participants receiving treatment (to week 24) and then stopping treatment (blue region), and the blue-dotted line displays 24.1 CL plaque clearance threshold.

Figure 4.. Change in Tau Standardized Uptake Value Ratios (SUVRs)

A, Association between baseline tau SUVR and change in tau SUVR at 76 weeks. Mean (SD) values at baseline and 76 weeks are shown in eTable 2 in Supplement 2. B, Adjusted change in tau was measured using Alzheimer disease (AD) signature–weighted neocortical SUVR and 3 regional SUVRs. Bars show mean (SE) and significance relative to placebo. Baseline characteristics for partial and complete amyloid clearance subgroups are shown in eTable 1 in Supplement 2 (no significant difference between baseline tau SUVR was observed). C, Percentage slowing of tau progression with donanemab was measured using AD signature–weighted neocortical SUVR and 3 regional SUVRs. D, Significant region-by-region Spearman correlations between amyloid SUVR metrics (absolute level at 24 weeks, change from baseline to 24 weeks, and percentage change from baseline to 24 weeks) and tau SUVR change at 76 weeks in donanemab-treated participants are indicated in blue. All participants shown underwent flortaucipir PET scans at baseline and 76 weeks. Participants receiving donanemab are designated as having partial or complete amyloid clearance based on the amyloid plaque level at 24 weeks. Complete amyloid clearance defined as less than 24.1 centiloids (CL); partial amyloid clearance is defined as 24.1 CL or greater. Tau level was measured using SUVR with modified cerebellar gray matter as a reference region. LS indicates least squares; PET, positron emission tomography. ^aP value < .05. ^bP value < .01.

Figure 5.. Modeled Association Between Change in Amyloid Plaque and Disease Progression Rate

Disease progression model-predicted percentage decrease in disease progression rate (measured by integrated Alzheimer Disease Rating Scale) (eMethods in Supplement 2), as a result of percentage decrease in amyloid plaque from baseline. With donanemab treatment, participants who achieve low amyloid plaque levels (simulated 100% decrease in amyloid from baseline) will experience a subsequent decrease in disease progression rate. Associations between amyloid positron emission tomography (PET; exposure-response model based on 304 participants from NCT02624778 and TRAILBLAZER-ALZ) and disease progression (model based on 187 carriers and 68 noncarriers from TRAILBLAZER-ALZ as the iADRS was not assessed in NCT02624778) are shown for the whole population (A) and in participants by apolipoprotein E (APOE) ε4 carrier genotype (B). The genotype of 1 participant was unknown. Lines represent means and 95% CIs (shaded). CI cannot be calculated in this model for the no effect in noncarriers.