Posttreatment Amyloid Levels Associated With Donanemab Benefit in Early AD
Key Clinical Summary
- In 1582 patients with early symptomatic Alzheimer disease, donanemab reduced amyloid plaque by 87 Centiloids over 76 weeks, slowing progression by 22.3% (iADRS) and 28.9% (CDR-SB) vs placebo.
- Lower posttreatment amyloid levels correlated with less cognitive and functional decline and reduced p-tau217, p-tau181, and GFAP, but not NfL.
- Findings support amyloid plaque removal as donanemab’s mechanism of action and suggest very low amyloid levels may yield the best clinical outcomes.
An exploratory post hoc analysis of a randomized clinical trial that demonstrated clinical benefit with donanemab in patients with early symptomatic Alzheimer disease (AD) suggests amyloid plaque removal was the mechanism of action, according to findings published in JAMA Neurology.
“In Assessment of Safety, Tolerability, and Efficacy of Donanemab in Early Symptomatic Alzheimer's Disease, a phase 3 trial in early symptomatic AD (TRAILBLAZER-ALZ 2), donanemab significantly reduced amyloid plaque by 87 Centiloids (CL) over 76 weeks. Donanemab slowed clinical progression by 22.3% and 28.9% relative to placebo as assessed by integrated AD Rating Scale (iADRS) and Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) scores, respectively,” wrote corresponding author Ming Lu, MD, of Eli Lilly and Company, Philadelphia, Pennsylvania, and study coauthors.
The exploratory analysis focused on correlations between posttreatment amyloid burden and changes in iADRS and CDR-SB scores as well as in 4 blood-based biomarkers: phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).
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Among 1582 participants included in the analysis, 766 received donanemab treatment and 816 received placebo every 4 weeks for up to 72 weeks. After grouping participants into 10 deciles based on lowest posttreatment amyloid value, researchers assessed links between each decile’s median amyloid level and least-squares mean changes for each clinical outcome and biomarker at 76 weeks.
The posttreatment amyloid burden was lower in patients who received donanemab than those who received placebo. Specifically, 99.6% of participants in the lowest 3 deciles were treated with donanemab, researchers reported, and all donanemab-treated participants in the lowest 3 deciles achieved amyloid clearance.
Across all participants, lower posttreatment amyloid levels were associated with slower cognitive and functional decline as gauged by iADRS and CDR-SB scores. Lower levels of posttreatment amyloid were also linked with decreases in p-tau217, p-tau181, and GFAP but not NfL.
“These findings suggest that donanemab treatment may have slowed participants’ clinical worsening through removing brain amyloid plaques,” researchers wrote.
In the light of the results, amyloid plaque may serve as a potential surrogate biomarker in amyloid-targeting therapies, the authors advised.
“This also suggests that achieving very low levels of amyloid plaques,” they added, “is associated with the best clinical outcomes.”
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