Clinical benefits were evident in patients with early symptomatic Alzheimer disease after 76 weeks of treatment with the amyloid-targeting monoclonal antibody donanemab, according to findings of the phase 3 TRAILBLAZER-ALZ 2 trial. Clinical progression was slowed in those with low/medium tau and combined low/medium and high tau pathology, the authors conclude. Three deaths in the donanemab arm were considered treatment related.
At 277 medical research centers/hospitals in 8 countries, participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology were randomized to donanemab or placebo intravenously every 4 weeks for 72 weeks. Positron emission tomography imaging measured pathology from June 2020 to Nov. 2021. The primary outcome was the change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). Primary, secondary, and exploratory gated outcomes included the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment).
“Among 1,736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1,182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1,320 (76%) completed the trial,” the researchers report. “Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and −10.2 (95% CI, −11.22 to −9.16) with donanemab and −13.1 (95% CI, −14.10 to −12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, −0.67 [95% CI, −0.95 to −0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, −0.7 [95% CI, −0.95 to −0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related.”
Editorials: Four related editorials are published with this study, covering the agent’s clinical benefits, safety, reimbursement, and place in therapy. “Treatment with donanemab was associated with significant safety risks,” editorialists write in the safety editorial. “Three deaths were determined to be drug related among participants who developed serious amyloid-related imaging abnormalities or brain bleeding and swelling. Donanemab decreased whole-brain volume and increased ventricular volume. In the treatment group, amyloid-related imaging abnormalities were seen in about 37% vs 15% in the placebo group and were seen in 40.6% of APOE ε4 homozygotes. Microhemorrhage occurred in 26.8% in the donanemab group vs 12.5% in the placebo group.”