More Evidence Lowering Amyloid Is Clinically Beneficial in Early Alzheimer’s

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donanemab (5 posts to January 2021)

More Evidence Lowering Amyloid Is Clinically Beneficial in Early Alzheimer’s

Reduced amyloid burden after treatment with the antiamyloid donanemab (Kisunla, Eli Lilly) correlated strongly with slower cognitive and functional decline in adults with early symptomatic Alzheimer’s disease (AD) in a secondary analysis of the phase 3 TRAILBLAZER-ALZ 2 trial.

The TRAILBLAZER-ALZ 2 study showed that donanemab effectively removed beta-amyloid plaques from the brain and demonstrated statistically significant slowing of cognitive and functional decline compared with placebo.

“This secondary analysis assessed the correlation between these two endpoints and showed that lower brain amyloid levels after treatment were directly associated with greater slowing of cognitive and functional decline,” Ming Lu, MD, associate vice president, Statistics, Eli Lilly and Company, and author on the secondary analysis, told Medscape Medical News. 

“These results support the growing body of knowledge that targeting beta-amyloid in the brain is a valid therapeutic approach and that patients may benefit from reducing beta-amyloid burden,” Lu said. 

The study was published online on October 13 in JAMA Neurology.

Lower Amyloid, Slower Decline

Results from the TRAILBLAZER-ALZ 2 trial showed treatment with donanemab significantly reduced amyloid plaque by 87 centiloids (CL) over 76 weeks and slowed clinical progression by 22% and 29% compared with placebo, as assessed by integrated AD Rating Scale (iADRS) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) scores, respectively.

These results led to approval of donanemab for early symptomatic AD in July 2024.

Yet, the relationship between amyloid removal and clinical benefit has remained uncertain, with mixed results across studies of similar drugs such as aducanumab and lecanemab.

To investigate, Lu and colleagues analyzed 1582 participants (mean age, 73 years) from TRAILBLAZER-ALZ 2 with confirmed amyloid and tau pathology; 766 were treated with donanemab (every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks), and 816 were given placebo.

They categorized participants into one of 10 groups (deciles) based on their lowest amyloid value observed after treatment. Cognitive decline was assessed using iADRS and CDR-SB scores over 76 weeks, and measured plasma biomarkers included phosphorylated tau (p-tau217 and p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).

Correlations between median amyloid levels and biomarker or clinical changes were calculated using mixed models for repeated measures.

At baseline, mean amyloid values were 143.4 CL in the highest decile and 87.5 CL in the lowest decile compared with the overall trial mean of 102.9 CL. 

Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (coefficient of determination [R²], 0.73) and CDR-SB score (R², 0.87) and with decreased p-tau217 (R², 0.86), p-tau181 (R², 0.88), and GFAP (R², 0.87) scores but not NfL scores (R², 0.03).

Notably, nearly all (99.6%) participants in the lowest three deciles of amyloid posttreatment received donanemab, and all (100%) donanemab-treated participants in the lowest three deciles achieved amyloid clearance (< 24.1 CL) by 76 weeks.

Participants in the lowest deciles of amyloid had the least cognitive decline, whereas those with higher posttreatment amyloid (mostly on placebo) worsened more rapidly. Patients who achieved amyloid clearance experienced the slowest disease progression.

‘Major’ Clinical Implications

“This is the first published analysis within one antiamyloid agent, as opposed to comparisons across drugs, that clearly shows that full clearance with treatment increases the likelihood of a clinical benefit,” study investigator David Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News.