Donanemab puts brakes on Alzheimer’s disease progression

In the treatment of individuals with early symptomatic Alzheimer's disease and amyloid and tau pathology, the immunoglobulin G1 monoclonal antibody donanemab helps slow clinical progression, according to the results of the phase III TRAILBLAZER-ALZ 2 study.

The study included 1,736 participants (mean age 73.0 years, 57.4 percent women, 68.1 percent with low/medium tau pathology, 31.8 percent with high tau pathology) with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging. These participants were randomly assigned to receive either donanemab (n=860) or placebo (n=876) intravenously every 4 weeks for 72 weeks. Those on donanemab were switched to receive placebo in a blinded manner if dose completion criteria were met.

A total of 24 gated outcomes were examined, including change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range 0–144, with lower scores indicating greater impairment; primary outcome) and change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range 0-18, with higher scores indicating greater impairment; secondary outcome).

A total of 1,320 (76 percent) participants completed the trial. Twenty-three of the 24 gated outcomes were statistically significant. At 76 weeks, the least-squares mean (LSM) change in iADRS score was significantly smaller with donanemab than with placebo for participants with low/medium tau (−6.02 vs −9.27; difference, 3.25, 95 percent confidence interval [CI], 1.88-4.62; p<0.001) and for the combined population (−10.2 vs −13.1; difference, 2.92, 95 percent CI, 1.51-4.33; p<0.001).

Likewise, the LSM change in CDR-SB score at 76 weeks was more favourable with donanemab than with placebo for participants with low/medium tau (1.20 vs 1.88; difference, −0.67, 95 percent CI, −0.95 to −0.40; p<0.001) and for the combined population (1.72 vs 2.42; difference, −0.7, 95 percent CI, −0.95 to −0.45; p<0.001).

Amyloid-related imaging abnormalities of oedema or effusion were found in 205 participants (24.0 percent; 52 symptomatic) in the donanemab group and 18 (2.1 percent; 0 symptomatic during study) in the placebo group. Infusion-related reactions were documented in 74 participants (8.7 percent) with donanemab and four (0.5 percent) with placebo. Three deaths in the donanemab group and one in the placebo group were considered treatment-related.