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

Author names: M Mintun1; C Ritchie2; P Solomon3; JR Sims1; S Salloway4; O Hansson5; LG Apostolova6; JA Zimmer1; CD Evans1; M Lu1; P Ardayfio1; JD Sparks1; AM Wessels1; S Shcherbinin1; H Wang1; ESM Nery1; EC Collins1; EB Dennehy1; DA Brooks1; DM Skovronsky1; TRAILBLAZER-ALZ 2 Investigators; A Farquharson (Non-author presenter)1

Author provenances: 1. Eli Lilly and Company, USA; 2. Scottish Brain Sciences, UK; 3. Boston Center for Memory and Boston University Alzheimer's Disease Center, USA; 4. Departments of Neurology and Psychiatry, Alpert Medical School of Brown University, USA; Butler Hospital, USA; 5. Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sweden; Memory Clinic, Skåne University Hospital, Sweden; 6. Department of Neurology, Indiana University School of Medicine, USA

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<.001), 35.1% slowing of disease progression. change in clinical dementia rating scale (cdr)–sum 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 progressing next 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.