TRAILBLAZER‐ALZ 4: A phase 3 trial comparing donanemab with aducanumab on amyloid plaque clearance in early, symptomatic Alzheimer's disease

Abstract

INTRODUCTION: The phase 3, open‐label TRAILBLAZER‐ALZ 4 study compared the effect of donanemab versus aducanumab on amyloid plaque (AP) clearance in participants with early symptomatic Alzheimer's disease. METHODS: Participants ( n = 148) were randomized 1:1 to receive intravenous donanemab (700 mg every 4 weeks for three doses, then 1400 mg every 4 weeks thereafter) or aducanumab (per label). AP was measured with florbetapir F 18 positron emission tomography. AP clearance was defined as < 24.1 Centiloids. RESULTS: At 6, 12, and 18 months, AP clearance was achieved in 37.9%, 70.0%, and 76.8%, respectively, of donanemab‐treated participants versus 1.6%, 24.6%, and 43.1% of aducanumab‐treated participants ( P < 0.001). Median time to clearance was 359 versus 568 days for donanemab‐ versus aducanumab‐treated participants ( P < 0.001). Amyloid‐related imaging abnormality (ARIA)‐edema/effusion occurred in 23.9% and 34.8% of donanemab‐ and aducanumab‐treated participants, respectively. DISCUSSION: Donanemab treatment resulted in earlier and greater AP clearance compared to aducanumab. ARIA frequencies were consistent with prior studies. Clinical trial registration: No: NCT05108922, TRAILBLAZER‐ALZ 4 Highlights: Here we report the first direct comparator study of two amyloid‐targeting therapies. This was the first investigation of donanemab on biomarker efficacy regardless of tau levels. Donanemab demonstrated superiority over aducanumab in amyloid plaque (AP) clearance. The depth and speed of AP removal did not affect amyloid‐related imaging abnormality risk or incidence.