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Clinical Trial
. 2025 May;21(5):e70293.
doi: 10.1002/alz.70293.

TRAILBLAZER-ALZ 4: A phase 3 trial comparing donanemab with aducanumab on amyloid plaque clearance in early, symptomatic Alzheimer's disease

Stephen Salloway  1   2 , Andrew Pain  3 , Elly Lee  4 , Michelle Papka  5 , Margaret B Ferguson  3 , Hong Wang  3 , Haoyan Hu  3 , Ming Lu  3 , Ena Oru  3 , Paul A Ardayfio  3 , Deirdre B Hoban  3 , Emily C Collins  3 , Dawn A Brooks  3 , John R Sims  3
Affiliations
Clinical Trial

TRAILBLAZER-ALZ 4: A phase 3 trial comparing donanemab with aducanumab on amyloid plaque clearance in early, symptomatic Alzheimer's disease

Stephen Salloway et al. Alzheimers Dement. 2025 May.

Abstract

Introduction: The phase 3, open-label TRAILBLAZER-ALZ 4 study compared the effect of donanemab versus aducanumab on amyloid plaque (AP) clearance in participants with early symptomatic Alzheimer's disease.

Methods: Participants (n = 148) were randomized 1:1 to receive intravenous donanemab (700 mg every 4 weeks for three doses, then 1400 mg every 4 weeks thereafter) or aducanumab (per label). AP was measured with florbetapir F 18 positron emission tomography. AP clearance was defined as < 24.1 Centiloids.

Results: At 6, 12, and 18 months, AP clearance was achieved in 37.9%, 70.0%, and 76.8%, respectively, of donanemab-treated participants versus 1.6%, 24.6%, and 43.1% of aducanumab-treated participants (P < 0.001). Median time to clearance was 359 versus 568 days for donanemab- versus aducanumab-treated participants (P < 0.001). Amyloid-related imaging abnormality (ARIA)-edema/effusion occurred in 23.9% and 34.8% of donanemab- and aducanumab-treated participants, respectively.

Discussion: Donanemab treatment resulted in earlier and greater AP clearance compared to aducanumab. ARIA frequencies were consistent with prior studies.

Clinical trial registration: No: NCT05108922, TRAILBLAZER-ALZ 4 HIGHLIGHTS: Here we report the first direct comparator study of two amyloid-targeting therapies. This was the first investigation of donanemab on biomarker efficacy regardless of tau levels. Donanemab demonstrated superiority over aducanumab in amyloid plaque (AP) clearance. The depth and speed of AP removal did not affect amyloid-related imaging abnormality risk or incidence.

Keywords: aducanumab; amyloid clearance; amyloid‐related imaging abnormalities; amyloid‐targeting therapies; donanemab; infusion‐related reaction.

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Conflict of interest statement

Stephen Salloway: Butler Hospital receives research support for conducting clinical trials through grants or contracts from Biogen, Eisai, Genentech, Roche, CognitionRx, Eli Lilly and Company, 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. Dr. Salloway is an author for the Appropriate Use Recommendations for aducanumab, lecanemab, and donanemab. Elly Lee: Irvine Clinical research receives study‐related funds from Eli and Company, Eisai, Biogen, Prothena, Abbvie, BMS, Janssen, Acumen, Roche, and Neumora. Michelle Papka received consulting fees from Eli Lilly and Company. Andrew Pain, Margaret B. Ferguson, Hong Wang, Haoyan Hu, Ming Lu, Ena Oru, Paul A. Ardayfio, Deirdre B. Hoban, Emily C. Collins, Dawn A. Brooks, and John R. Sims are employees of and minor shareholders of Eli Lilly and Company. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
CONSORT diagram. CDR‐GS; Clinical Dementia Rating Scale Global Score; CONSORT, Consolidated Standards of Reporting Trials; MMSE, Mini‐Mental State Examination; MRI, magnetic resonance imaging
FIGURE 2
FIGURE 2
Superiority of donanemab versus aducanumab in AP clearance at 6 months in the (A) overall population and (B) low–medium tau subpopulation. AP, amyloid plaque; CL, Centiloids; n, number of participants; N, number of participants in the analysis population
FIGURE 3
FIGURE 3
Superiority of donanemab versus aducanumab in AP clearance at (A) 12 months and (B) 18 months, and (C) time to achieve AP clearance. P value for (A) and (B) derived from a longitudinal logistic regression model. P value for (C): 2‐sided log‐rank unstratified P value comparing donanemab versus aducanumab.*One participant who achieved amyloid clearance (< 24.1 CL) at week 52 did not meet the threshold for amyloid clearance at week 76. AP, amyloid plaque; CI, confidence interval; CL, Centiloids; LS, least squares; n, number of participants; N, number of participants in the analysis population
FIGURE 4
FIGURE 4
Donanemab and aducanumab treatment demonstrated changes in plasma biomarkers of (A) p‐tau217, (B) p‐tau181, (C) GFAP, and (D) NfL at 6, 12, and 18 months in the overall population. Data are shown as LSM (standard error). GFAP, glial fibrillary acidic protein; LS, least squares mean; n, number of participants; NfL, neurofilament light chain; PET, positron emission tomography; p‐tau181, phosphorylated tau 181; p‐tau217, phosphorylated tau 217
FIGURE 5
FIGURE 5
Time to first ARIA‐E based on safety magnetic resonance imaging: Kaplan–Meier analysis. ARIA‐E, amyloid‐related imaging abnormalities of edema/effusion
See this image and copyright information in PMC

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