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Clinical Trial
. 2025 Apr;21(4):e70062.
doi: 10.1002/alz.70062.

Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction

Hong Wang  1 , Emel Serap Monkul Nery  1 , Paul Ardayfio  1 , Rashna Khanna  1 , Diana Otero Svaldi  1 , Ivelina Gueorguieva  1 , Sergey Shcherbinin  1 , Scott W Andersen  1 , Paula M Hauck  1 , Staci E Engle  1 , Dawn A Brooks  1 , Emily C Collins  1 , Nick C Fox  2 , Steven M Greenberg  3 , Stephen Salloway  4   5 , Mark A Mintun  1 , John R Sims  1
Affiliations
Clinical Trial

Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction

Hong Wang et al. Alzheimers Dement. 2025 Apr.

Erratum in

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.

Keywords: Alzheimer's disease; amyloid; amyloid‐related imaging abnormalities; donanemab; phosphorylated tau217; titration.

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Conflict of interest statement

HW, ESMN, PA, RK, DOS, IG, SS‐Eli Lilly and Company, SWA, PMH, SEE, DAB, ECC, MAM, and JRS are employees and minor shareholders of Eli Lilly and Company. NCF reports consulting fees from Biogen, Eisai, Eli Lilly, and Roche (all paid to UCL); he has received fees for serving on a data safety monitoring board for Biogen and on an advisory board for Abbvie; acknowledges grant support from the Alzheimer's Society (UK), Alzheimer's Research UK, Rosetrees Trust, the Sigrid Rausing Trust, and the UK NIHR UCLH Biomedical Research Centre. SMG reports receiving consulting fees from Eli Lilly and Company and participates in safety data monitoring boards or advisory boards for IQVIA/Washington University. SS‐Butler Hospital receives research support for conducting clinical trials through grants or contracts from Biogen, Eisai, Genentech, Roche, CognitionRx, Lilly, and Janssen; he has received consulting fees from Abbvie, Acumen, Alector, Biogen, Biohaven, Cognition, Eisai, Fujirebio, Genentech, Kisbee, Laqbcorp, Lilly, Merck, Neurophet, NovoNordisk, Prothena, Quest, and Roche. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Study design. All participants received a dosing regimen that included donanemab, but at different dose levels and frequency. Placebo was given at the indicated visits to preserve the blind for the different dosing schedules. The double‐blind period of the study was 76 weeks. Total donanemab amounts were scheduled to be the same for the four dosing regimens. After week 16, participants in all arms were scheduled to receive 1400 mg of donanemab once monthly until dose‐stopping criteria were met or the end of the study. An additional MRI occurred at week 52 and additional amyloid PET scans occurred at weeks 52 and 76. APOE, apolipoprotein E; Cmax, maximum serum concentration; MRI, magnetic resonance imaging; PBO, placebo; PET, positron emission tomography
FIGURE 2
FIGURE 2
ARIA‐E severity and time to first incidence through 24 weeks. A, ARIA‐E maximum radiographic severity based on Cochran–Mantel–Haenszel test (P = 0.011). B, Kaplan–Meier curve showing hazard of time to first ARIA‐E event based on MRI only. The percentage of participants with ARIA‐E events is calculated using the number of participants who experienced ARIA‐E by the given timepoint as the numerator and the number of participants still active in the study as the denominator. Participants at risk are the number of participants still active in the study and who have not yet experienced ARIA‐E. Log‐rank unstratified P value (2 sided) = 0.016. ARIA‐E, amyloid‐related imaging abnormalities with edema/effusions; MRI, magnetic resonance imaging
FIGURE 3
FIGURE 3
ARIA‐E by APOE ɛ4 genotype. Post hoc analyses based on safety MRI. Bar graphs show (A) the frequency of ARIA‐E by APOE ɛ4 genotype and (B) symptomatic ARIA‐E by APOE ɛ4 genotype. APOE, apolipoprotein E; ARIA‐E, amyloid‐related imaging abnormalities with edema/effusions; MRI, magnetic resonance imaging
FIGURE 4
FIGURE 4
Pharmacokinetics and biomarkers. A, Observed cumulative exposure AUC(0‐12 weeks) from standard and modified titration arms. B, Donanemab concentration‐time profiles. Solid line: median of serum concentrations; shaded areas: 90% prediction intervals (including between‐participant and residual error). Population pharmacokinetic methodology was used. C, Reduction in amyloid levels after 24 weeks. The ANCOVA model was used for 24‐week values with the following variables: baseline amyloid (in CL) + dosing regimen + baseline age. ANOVA was used for baseline measures with dosing regimen as the variable. D, Plasma p‐tau217 as assessed on Eli Lilly and Company's Meso Scale Discovery platform using the mixed model for repeated measures with an unstructured variance‐covariance. ANCOVA, analysis of covariance; ANOVA, analysis of variance; AUC, area under the curve; CL, Centiloid; n, number of participants within each specific category; p‐tau, phosphorylated tau; Q4W, every 4 weeks; SE, standard error
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References

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