The TRAILBLAZER-ALZ 2 study (NCT04437511) demonstrated significant clinical benefits of donanemab-azbt in early symptomatic Alzheimer disease (AD). Here are the key findings:
Efficacy Outcomes
Cognitive & Functional Decline:
35% slower decline on the Integrated Alzheimer’s Disease Rating Scale (iADRS) vs placebo at 76 weeks in the low/medium tau population[2][6].
39% reduced risk of progressing to the next disease stage (e.g., mild to moderate dementia)[3][6].
47% of participants showed no clinical progression at 1 year (vs 29% on placebo)[3].
Amyloid Clearance:
84% reduction in amyloid plaques at 18 months (vs 59% in earlier trials)[6].
85 centiloid reduction in amyloid PET levels by week 76[1].
Tau Pathology Impact
Low/Medium Tau Group:
Strongest treatment effect (35% iADRS benefit)[2][5].
High-tau subgroup showed no significant clinical benefit, reinforcing the importance of early intervention[2][5].
Safety Profile
ARIA Incidence:
24% developed ARIA-Edema (ARIA-E), mostly asymptomatic[3][5].
25% experienced microhemorrhages (ARIA-H)[3][6].
3 fatal ARIA cases reported (2 directly attributed, 1 post-serious ARIA)[3].
Infusion Reactions:
Occurred in 13% of participants (vs 4% placebo), manageable with rate adjustments[2][6].
Study Design Highlights
Population: 1,736 participants aged 60–85 with early AD (mild cognitive impairment/mild dementia) and confirmed amyloid/tau pathology[1][4].
Dosing Protocol:
700 mg IV monthly × 3 doses → 1400 mg monthly thereafter[1].
Blinded dose reduction to placebo if amyloid clearance achieved[1][5].
Imaging Requirements:
Mandatory MRIs pre-infusions 2–4 and 7[5].
Exclusion criteria: >4 microhemorrhages or severe white matter disease[5].
Regulatory & Practical Implications
First Phase 3 anti-amyloid trial to demonstrate disease-modifying effects via iADRS[3][6].
Supports finite treatment duration (~6–18 months) for patients achieving amyloid clearance[1][5].
Eli Lilly submitted for FDA approval in 2023, positioning it as a potential third amyloid-targeting therapy[3][4].
This trial confirms donanemab’s role in slowing early AD progression but underscores the need for tau stratification and vigilant MRI monitoring to mitigate ARIA risks[2][5].
Citations:
[1] https://www.neurology.org/doi/10.1212/WNL.98.18_supplement.1688
[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC10352931/
[5] https://jamanetwork.com/journals/jama/fullarticle/2807533
[6] https://atrinews.usc.edu/resources/donanemab-significantly-slowed-cognitive-and-functional-decline
[7] https://pubmed.ncbi.nlm.nih.gov/37459141/
[8] https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.13700
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