1978 Donanemab in early symptomatic Alzheimer’s Disease: Efficacy and safety in TRAILBLAZER-ALZ 2, Phase 3 Randomized Clinical Trial

Abstract Introduction In TRAILBLAZER-ALZ donanemab (DONA) cleared brain amyloid plaques, significantly slowing disease progression in early symptomatic Alzheimer’s disease (ESAD). Methods: TRAILBLAZER-ALZ2 enrolled participants with ESAD and amyloid and tau pathology by positron-emission tomography, randomizing (multicenter) those with low/medium-tau (n=1182) and high-tau (n=552) (missing tau n=2). Participants (randomized double-blind,1:1) received DONA (n=860)/placebo (n=876) IV every 4w for 72w. DONA participants meeting amyloid clearance treatment completion criteria at 24/52w had blinded switched to placebo. Primary outcomes Integrated AD Rating Scale(iADRS) change from baseline at 76w in low/medium-tau or combined (low/medium- and high-tau) populations. Statistical testing allocated most power (80% α spend) to low/medium-tau population outcomes, with the remainder for combined population outcomes, including clinical and biomarker assessments. Results In the low/medium-tau population iADRS change at 76w: −6.02 (DONA) and −9.27 (placebo) (difference 3.25; 95%CI, 1.88-4.62; P<0.001), 35.1% slowing of disease progression. Change in Clinical Dementia Rating Scale (CDR)–Sum of Boxes: 1.20 (DONA) and 1.88 (placebo) (difference −0.67; 95% CI −0.95 to −0.40; P<0.001), 36.0% slowing. Participants receiving DONA experienced 38.6% less risk of progressing to next disease stage vs placebo over 76w (CDR-Global score, HR=0.61; P<0.001). Amyloid clearance at 24/52/76w: achieved in 34.2%/71.3%/80.1% DONA-treated participants. Significant, positive results were observed in the combined population. Serious AEs: 17.4% (DONA), and 15.8% (placebo), with 3 deaths among DONA patients who experienced serious amyloid-related imaging abnormalities (ARIA). AEs with DONA included ARIA-E (24.0%, 6.1% symptomatic); ARIA-H (31.4%); infusion-related reactions (8.7%). Conclusion DONA treatment significantly slowed clinical progression at 76w with a safety profile consistent with earlier studies. Presented: AAIC2023.