Abstract
INTRODUCTION
TRAILBLAZER-ALZ 6 (NCT05738486) is a multicenter, double-blind, ongoing phase 3b study in early symptomatic Alzheimer’s disease.
METHODS
Participants (n = 843) were randomized 1:1:1:1 (standard + three alternative donanemab dosing arms). Primary outcome was relative risk reduction (RRR) of amyloid-related imaging abnormalities with edema/effusions (ARIA-E) at 24 weeks assessed with Bayesian logistic regression. Amyloid plaque levels by positron emission tomography and serum donanemab pharmacokinetics were measured.
RESULTS
ARIA-E frequencies for standard, modified titration, dose skipping, and Cmax arms were 23.7%, 13.7%, 18.6%, and 18.3%, respectively, at 24 weeks and similar at 52 weeks: 24.2%, 15.6%, 18.6%, and 18.8%, respectively. Modified titration met the 24-week primary outcome with 94% probability of achieving ≥ 20% RRR versus the standard arm. Modified titration also had significantly lower ARIA-E severity, but similar cumulative exposure and mean amyloid reduction compared to the standard arm.
DISCUSSION
Gradual up-titration of dose significantly reduced ARIA-E risk while demonstrating comparable pharmacokinetics/pharmacodynamics compared to standard dosing.
Highlights
In TRAILBLAZER-ALZ 6, the amyloid-related imaging abnormalities-edema/effusions (ARIA-E) frequency was 13.7% in the modified titration arm compared to 23.7% in the standard arm at week 24.
The modified titration arm met the primary endpoint of ARIA-E relative risk reduction at 24 weeks versus the standard arm.
The modified titration versus standard arm at week 24 had comparable non-ARIA-E related safety profile, amyloid reduction, plasma phosphorylated tau217 reduction, cumulative exposure, and pharmacokinetics.
Data at week 52 were consistent with week 24 results.
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This post is Copyright: Hong Wang,
Emel Serap Monkul Nery,
Paul Ardayfio,
Rashna Khanna,
Diana Otero Svaldi,
Ivelina Gueorguieva,
Sergey Shcherbinin,
Scott W. Andersen,
Paula M. Hauck,
Staci E. Engle,
Dawn A. Brooks,
Emily C. Collins,
Nick C. Fox,
Steven M. Greenberg,
Stephen Salloway,
Mark A. Mintun,
John R. Sims | April 2, 2025