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Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction
Wang H, Serap Monkul Nery E, Ardayfio P, Khanna R, Otero Svaldi D, Gueorguieva I, Shcherbinin S, Andersen SW, Hauck PM, Engle SE, et al.. Alzheimer's & Dementia, 2025-04-02
Topic: Brain proteins, microglia and lab models
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 C max 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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APA 7th
Wang, H., Serap Monkul Nery, E., Ardayfio, P., Khanna, R., Otero Svaldi, D., Gueorguieva, I., et al. (2025). Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction. Alzheimer's & Dementia. https://doi.org/10.1002/alz.70062
Vancouver
Wang H, Serap Monkul Nery E, Ardayfio P, Khanna R, Otero Svaldi D, Gueorguieva I, et al. Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction. Alzheimer's & Dementia. 2025. doi:10.1002/alz.70062. PMID: 40172303.
BibTeX
@article{wang2025-40172303,
author = {Wang, H. and Serap Monkul Nery, E. and Ardayfio, P. and Khanna, R. and Otero Svaldi, D. and Gueorguieva, I. and Shcherbinin, S. and Andersen, S. W. and Hauck, P. M. and Engle, S. E. and others},
title = {{Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction}},
journal = {Alzheimer's \& Dementia},
year = {2025},
doi = {10.1002/alz.70062},
pmid = {40172303},
url = {https://doi.org/10.1002/alz.70062}
}
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Key findings
- Results ARIA-E frequencies for standard, modified titration, dose skipping, and C max 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.
Why it matters
In this ongoing trial, a modified titration of donanemab reduced the frequency and severity of ARIA-E compared with standard dosing while maintaining similar amyloid reduction. This suggests that changing how the drug dose is increased may lower a key safety risk.
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Study details
- Study designphase-3-trial
- Participants843
- Effect sizeARIA-E 13.7% (modified titration) vs 23.7% (standard) at 24 weeks
- Evidence strengthModerate
Limitations
Industry-sponsored; primary outcome is a safety biomarker rather than cognition or function; ongoing study with 52-week data described as consistent but not the primary analysis.
How this study scored 76/100
Published in a leading specialty journal, and it is a large phase 3 trial. We have no data on free to read, so that was left out: it earned 74 of the 98 points we could judge it on, which is 76 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & Dementia) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (OpenAlex, 2026-10-29) |
| Study design | 11 / 12 | A large phase 3 trial |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 2 / 4 | 843 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomized / blinded | 1 / 2 | Randomized (as stated in the record) |
| Times cited | 4 / 7 | Cited 63 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 21.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 5 / 6 | Cited 34.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 6 other studies in this library |
| Still being cited | 3 / 4 | Cited 63 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author John Randall Sims: h-index 41 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40172303) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 74 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 74 of the 98 points we could judge it on is 76 out of 100. |
| Total | 76 / 100 | — |
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