TRAILBLAZER-ALZ 6 updates support new donanemab dosing schedule for AD

In the 18-month results from the phase IIIb TRAILBLAZER-ALZ 6 trial, the newly recommended dosing schedule of donanemab results in a significant reduction in the incidence of amyloid-related imaging abnormalities with effusion/oedema (ARIA-E) compared with standard dosing in adults with early symptomatic Alzheimer’s disease (AD).

“ARIA-E frequency at 76 weeks remained significantly reduced in the modified titration arm, confirming the 24- and 52-week results compared with the standard arm,” said Dr Hong Wang from Eli Lilly and Company, Indianapolis, Indiana, US, during her presentation at AAIC 2025.

At 76 weeks, ARIA-E frequency with modified titration was 15.6 percent vs 24.2 percent with standard dosing (hazard ratio [HR], 0.624; p=0.036; posterior probability [PP] of relative risk reduction [RRR] ≥20%, 87.1 percent). For symptomatic ARIA-E, the corresponding rates were 2.8 percent vs 4.8 percent (HR, 0.584; p=0.299). [Wang, H, et al, AAIC 2025; J Prev Alzheimers Dis 2025;12:100266]

There were no new ARIA-E events identified after 52 weeks, and all initial symptomatic ARIA-E events occurred within the first 24 weeks, noted Wang.

The primary endpoint was met at week 24 with modified titration, as evidenced by the reduction in ARIA-E frequency (13.7 percent vs 23.7 percent; PP of RRR ≥20%, 94.1 percent), while achieving similar amyloid reduction. [Alzheimers Dement 2025;21:e70062]

Modified titration also led to a substantial reduction in cortical superficial siderosis vs standard dosing through week 76 (9 percent vs 15 percent) – a pattern that has been sustained from week 24 (6.6 percent vs 12.6 percent).

“Modified titration also improved maximum radiographic severity of ARIA-E, with no severe ARIA-E cases identified,” said Wang. Through week 76, 84.4 percent of participants on the modified titration regimen did not experience ARIA-E events, compared with 75.8 percent of those on the standard regimen.

On post hoc analysis, ARIA-E incidences were also lower with modified titration vs standard dosing through week 76 irrespective of APOE ɛ4 genotype: 24 percent vs 57 percent (PP of RRR ≥20%, 80.4 percent) for homozygote carriers, 16 percent vs 24 percent (PP of RRR ≥20%, 86.1 percent) for heterozygote carriers, and 13 percent vs 15 percent (PP of RRR ≥20%, 89.7 percent) for noncarriers.

Comparable safety, biomarker reductions

Week 76 saw similar incidences of serious adverse events (AEs; 23.1 percent vs 24.6 percent), study discontinuations due to an AE (2.8 percent vs 2.9 percent), and treatment discontinuations due to an AE (8 percent vs 7.7 percent) between the modified and standard dosing arms.

Biomarker reductions were also comparable between the modified and standard dosing arms (adjusted mean change from baseline, -70.9 vs -72.1 CL [amyloid PET ] and percent change, -42.5 percent vs -39.7 percent [plasma p-tau217]).

A meaningful advancement

Vessels with pre-existing amyloid vascular pathologic conditions become more susceptible to vascular extravasation events following anti-amyloid β therapy initiation in AD patients, which, in turn, could lead to ARIA-E. [Radiographics 2023;43:e230009] While typically asymptomatic, serious and fatal ARIA-E events can occur.

Wang and colleagues randomized 843 adults with early symptomatic AD and confirmed amyloid pathology 1:1:1:1 to donanemab standard dosing, modified titration, dose skipping, or Cmax. With standard dosing, IV donanemab was administered at a dose of 700 mg (two 350 mg/20 mL single-dose vials) at weeks 0, 4, and 8, then 1,400 mg at week 12. With modified titration, the corresponding doses were 350, 700, 1,050, and 1,400 mg, respectively. For dose skipping, week 0 dose was 700 mg, followed by 1,400 mg at weeks 8 and 12. For Cmax, the doses were 350 mg Q2W from baseline to week 10 and 700 mg at weeks 12 and 14.

From week 16 until the dose-stopping criteria were met or until end of study, donanemab was given at a dose of 1,400 mg across all dosing arms.

Donanemab received the US FDA nod in July 2024 based on the phase III TRAILBLAZER-ALZ 2 results. In July 2025, the US FDA approved a label update to reflect the new recommended titration dosing schedule. This new regimen is currently approved in the US, Australia, and Singapore, and is under regulatory review in other countries, noted Wang.

“This updated dosing strategy is a meaningful advancement for patients and their care teams,” commented Dr Elly Lee from the Irvine Center for Clinical Research, Irvine, California, US, in a press release. “By significantly reducing the risk of ARIA-E, we can offer patients and care teams greater confidence in the safety of [donanemab] while preserving its ability to reduce amyloid.”