Donanemab Shows Durable Amyloid Clearance and Consistent Safety in Early-Start Patients

A post hoc characterization of TRAILBLAZER-ALZ 2 (NCT04437511) participants who continued receiving donanemab (Kisunla; Eli Lilly and Company) into the trial's long-term extension (LTE) period found that most achieved amyloid plaque clearance and demonstrated similar cognitive outcomes to those who continued on placebo.

The data, presented at the 2026 Advanced Therapeutics in Movement & Related Disorders (ATMRD) Congress in Washington, DC, revealed that baseline amyloid level was the strongest predictor of time to amyloid clearance, while baseline cognition did not predict treatment duration.

Background

TRAILBLAZER-ALZ 2 was a phase 3, randomized, double-blind, placebo-controlled study of donanemab in adults with early symptomatic Alzheimer's disease (AD).² Over three years, donanemab-treated patients demonstrated sustained slowing of clinical progression, with clinical benefit evident across three years in participants who met treatment course completion criteria by 52 weeks.¹ Donanemab received FDA approval in July 2024 for the treatment of early symptomatic AD based on the trial's primary results.³

Led by Curtis Schreiber, MD, a board certified neurologist in Bolivar, Missouri, most participants in TRAILBLAZER-ALZ 2 met treatment course completion criteria by week 76 and were switched to placebo. However, a subset of 157 participants in the early-start arm did not meet treatment completion criteria during the 76-week placebo-controlled period and continued receiving donanemab into the LTE (the DONA-DONA group). The objective of the current analysis was to characterize this subgroup and identify factors that may have contributed to the need for continued treatment.

Baseline Characteristics

At entry into the placebo-controlled period, the DONA-DONA group (n = 157) differed meaningfully from the DONA-PBO group (n = 393) across several baseline characteristics. Mean age was 69.3 (SD, 5.6) for DONA-DONA versus 73.9 (SD, 6.0) years for DONA-PBO; APOE4 carrier rates were 80.3% versus 63.4%.

Mean amyloid plaque level was 122.0 centiloids versus 94.8 in DONA-PBO. The DONA-DONA group also had higher rates of superficial siderosis (9.5% vs 3.5%), microhemorrhages (1.9% vs 0.3%), and superficial siderosis at baseline (3.8% vs 3.7%).¹ Mean CDR-SB at entry was 3.01 versus 3.19, and mean ADAS-cog was 107.2 versus 105.9, suggesting broadly similar but slightly higher amyloid burden and vascular risk features in the DONA-DONA group.

Amyloid Outcomes and Treatment Duration

Among DONA-DONA participants, 30.8% had reached amyloid plaque clearance (less than 24.1 centiloids) without completing their course of treatment by the end of the placebo-controlled period (76 weeks). Of DONA-DONA participants with a 154-week PET scan (n = 125), 58.8% had attained amyloid plaque clearance (less than 24.1 centiloids) by LTE end.¹ In addition, amyloid levels declined progressively across the LTE in the DONA-DONA group. Baseline amyloid level was identified as the strongest predictor of time to amyloid clearance (less than 24.1 centiloids), while baseline cognition was not predictive of treatment duration.

Importantly, investigators noted that most donanemab-treated participants achieved amyloid clearance, including those who did not meet treatment completion criteria during the initial placebo-controlled period, and that clinical benefit was evident across three years with fewer cumulative doses.

Safety

Overall, no new safety signals were identified in the LTE. In the DONA-DONA group (n = 157) versus DONA-PBO (n = 393), rates of patients with at least one TEAE were 58.6% versus 59.8%. ARIA-E occurred in 24.2% versus 19.1% (severe: 5.7% vs 5.9%); ARIA-H occurred in 24.2% versus 19.7% (moderate: 4.6% vs 3.1%). Headache was reported in 14.0% versus 13.5%. Superficial siderosis of the CNS occurred in 10.2% versus 4.6%. Infusion-related reactions were reported in 7.6% versus 4.8%.¹

A greater proportion of DONA-DONA participants experienced recurrent ARIA-E compared with DONA-PBO (8.9% vs 4.1%), though isolated ARIA-H rates were numerically higher in DONA-PBO during the placebo-controlled period (15.3% vs 16.0%). Treatment pauses occurred in 43% of DONA-DONA versus 31% of DONA-PBO participants, with mean pause durations of 14.4 weeks and 9.3 weeks, respectively.

Cognitive outcomes as measured by CDR-SB showed no difference between DONA-DONA and DONA-PBO groups, consistent with the overall TRAILBLAZER-ALZ 2 finding that early amyloid removal translates to sustained clinical benefit.

Click here for more ATMRD 2026 coverage.

REFERENCES
1. Schreiber CP, Schilling T, Doty EG, et al. Characterization of "early-start" participants that continued receiving donanemab in the TRAILBLAZER-ALZ 2 long-term extension period. Poster presented at: Advanced Therapeutics in Movement & Related Disorders (ATMRD) Congress, 5th Annual Congress; June 4-8, 2026; Washington, DC.
2. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer's disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527. doi:10.1001/jama.2023.13239. https://doi.org/10.1001/jama.2023.13239
3. FDA approves treatment for adults with Alzheimer's disease. News release. US Food and Drug Administration. July 2, 2024. Accessed June 6, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-adults-alzheimers-disease