Donanemab in Early Symptomatic Alzheimer’s Disease: Efficacy and Safety in TRAILBLAZER‐ALZ 2, a Phase 3 Randomized Clinical Trial

Abstract

Background: In TRAILBLAZER-ALZ, donanemab cleared brain amyloid plaques and significantly slowed disease progression in early symptomatic Alzheimer’s disease (AD). Methods: TRAILBLAZER-ALZ 2 (NCT04437511), a multicenter, randomized, double-blind, placebo-controlled trial, enrolled participants with early symptomatic AD and amyloid and tau pathology by positron-emission tomography. The study randomized participants with low/medium-tau (n=1182) and high-tau (n=552) pathology (missing tau category, n=2). Participants (randomized 1:1) received donanemab (n=860) or placebo (n=876) intravenously every 4 weeks (w) for 72w. Donanemab participants meeting amyloid clearance treatment completion criteria at 24w or 52w were switched to placebo in a blinded procedure. The primary outcomes were change in Integrated AD Rating Scale (iADRS) score from baseline at 76w in either the low/medium-tau or combined (low/medium-tau and high-tau) populations. Statistical testing allocated most power (80% alpha spend) to low/medium-tau population outcomes, with the remainder for combined population outcomes, which included clinical and biomarker assessments. Results: In the low/medium-tau population, change in iADRS score at 76w was -6.02 with donanemab and -9.27 with placebo (difference, 3.25; 95% CI, 1.88 to 4.62; P<0.001), representing a 35.1% slowing of disease progression. Change in Clinical Dementia Rating Scale (CDR) – Sum of Boxes, the key secondary outcome, was 1.20 with donanemab and 1.88 with placebo (difference, -0.67; 95% CI -0.95 to -0.40; P<0.001), representing a 36.0% slowing. Participants receiving donanemab experienced a 38.6% lower risk of progressing to the next disease stage versus placebo over 76w (CDR-Global score, Hazard Ratio=0.61; P<0.001). Amyloid clearance at 24w, 52w and 76w was achieved in 34.2%, 71.3% and 80.1% of donanemab-treated participants, respectively. Plasma P-tau217 was significantly reduced by 39.3% from baseline with donanemab and increased by 8.4% with placebo at 76w (P<0.001). Significant, positive results across all clinical endpoints were also observed in the combined population. The incidence of serious adverse events was 17.4% (donanemab) and 15.8% (placebo), with three deaths among patients treated with donanemab who experienced serious ARIA. Adverse events with donanemab included amyloid-related imaging abnormalities (ARIA)-E (24.0%, 6.1% symptomatic); ARIA-H (31.4%); and infusion-related reactions (8.7%). Conclusion: Donanemab treatment significantly slowed clinical progression at 76w and had a safety profile consistent with earlier studies.