TRAILBLAZER-ALZ 6
(2025)Objective
To determine whether modified donanemab dosing regimens can reduce the frequency and severity of amyloid-related imaging abnormalities with edema/effusions (ARIA-E) while maintaining amyloid plaque reduction in early symptomatic Alzheimer's disease.
Study Summary
• Dose skipping (18.6%) and Cmax (18.3%) arms did not meet the prespecified success criteria
• Results were consistent at 52 weeks: 15.6% (modified titration) vs 24.2% (standard), with 87% probability of ≥20% RRR
• Modified titration showed significantly lower ARIA-E radiographic severity (P=0.011) with 86.3% having no ARIA-E by MRI vs 76.3% in standard arm
• Comparable amyloid reduction, p-tau217 reduction, cumulative exposure, and pharmacokinetics between modified titration and standard arms
Intervention
Modified titration donanemab dosing (350 mg, 700 mg, 1050 mg, then 1400 mg monthly) compared with standard dosing (three 700 mg doses, then 1400 mg monthly), dose skipping, and Cmax regimens
Inclusion Criteria
Adults aged 60-85 years with gradual progressive memory decline ≥6 months, MMSE 20-28, and amyloid PET scan consistent with amyloid pathology
Study Design
Arms: Standard donanemab (n=208) vs Modified titration (n=212) vs Dose skipping (n=210) vs Cmax (n=213)
Patients per Arm: 208 / 212 / 210 / 213
Outcome
• Other alternative arms did not meet success criteria
• Modified titration had significantly lower radiographic ARIA-E severity (P=0.011)
• Cox analysis showed significantly lower percentage with first ARIA-E in modified titration arm (P=0.016)
• Comparable amyloid plaque reduction and p-tau217 reduction across arms
Bottom Line
A gradual up-titration of donanemab (350→700→1050→1400 mg) significantly reduces ARIA-E frequency and severity compared with standard dosing while maintaining equivalent amyloid plaque reduction, pharmacokinetics, and p-tau217 lowering. This regimen should be considered as a safer alternative dosing approach in early symptomatic Alzheimer's disease.
Major Points
- ARIA-E at 24 weeks: 23.7% (standard), 13.7% (modified titration), 18.6% (dose skipping), 18.3% (Cmax)
- Modified titration met the primary endpoint with 94.1% posterior probability of ≥20% RRR; posterior RRR 0.405 (SD 0.123)
- Modified titration had significantly lower radiographic ARIA-E severity (P=0.011) and 86.3% had no ARIA-E vs 76.3% in standard arm
- Dose skipping and Cmax arms did not meet prespecified success criteria
- Amyloid plaque reduction, p-tau217 reduction, cumulative exposure, and pharmacokinetics were comparable between modified titration and standard arms
- 52-week data confirmed durability: 15.6% (modified titration) vs 24.2% (standard); 87% probability of ≥20% RRR
Study Design
- Study Type
- Multicenter, randomized, double-blind phase 3b study
- Randomization
- Yes
- Blinding
- Double-blind (placebo infusions used to preserve blinding across different dosing schedules)
- Sample Size
- 843
- Follow-up
- 76-week double-blind period; primary analysis at 24 weeks, supportive data at 52 weeks
- Countries
- United States
Primary Outcome
Definition: Relative risk reduction (RRR) of ARIA-E frequency at 24 weeks for each alternative dosing arm vs standard arm (success if posterior probability of ≥20% RRR was >80%)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| ARIA-E 23.7% (standard arm) | ARIA-E 13.7% (modified titration); 18.6% (dose skipping); 18.3% (Cmax) | - |
Limitations & Criticisms
- Predominantly White (>91%) US-based population limits generalizability
- Tau pathology not required for enrollment (differs from TRAILBLAZER-ALZ 2 randomized population)
- Ongoing study with primary analysis based on 24-week data; long-term clinical efficacy outcomes not yet reported
- Dose skipping and Cmax arms did not show significant ARIA-E reduction, limiting clinical alternatives to modified titration
- Cox proportional hazard model without adjustment for baseline ARIA risk factors beyond treatment groups
Citation
Alzheimer's Dement. 2025;21:e70062