TRAILBLAZER‐ALZ 4: Directly comparing donanemab to aducanumab on amyloid lowering in early, symptomatic Alzheimer’s disease ‐ Results from 12‐months

Abstract

AbstractBackgroundTRAILBLAZER‐ALZ 4 demonstrated superiority of donanemab versus aducanumab at the 6‐month primary endpoint of the percentage of participants achieving amyloid plaque clearance (<24.1 Centiloids [CL]) in patients with early symptomatic AD (Salloway et al. CTAD 2022).MethodsParticipants (n = 148) were randomized 1:1 to receive donanemab (titration: 700mg IV Q4W [first 3 doses], then 1400mg IV Q4W [subsequent doses]) or aducanumab (titration per USPI: 1mg/kg IV Q4W [first 2 doses], 3mg/kg IV Q4W [next 2 doses], 6mg/kg IV Q4W [next 2 doses] and 10mg/kg IV Q4W [subsequent doses]). The study is ongoing with a total duration of 18 months.ResultsBaseline demographics and characteristics were well‐balanced across treatment arms (donanemab [N = 71], aducanumab [N = 69]). Twenty‐seven donanemab‐treated and 28 aducanumab‐treated participants had low/medium (intermediate) tau levels based on screening tau PET scans. In all participants at 12 months, 70.2%±6.3% (least square [LS] mean ± standard error [SE]) donanemab‐treated vs. 21.9%±5.9% aducanumab‐treated participants achieved amyloid plaque clearance (p<0.001) assessed by florbetapir F18 PET scans. In the low/medium tau subpopulation, 80.0%±9.9% donanemab‐treated vs. 9.6%±5.4% aducanumab‐treated participants achieved amyloid clearance (p<0.001). The percent change (LS mean ± SE) in brain amyloid levels were ‐82.8%±3.1% (baseline [LS mean ± standard deviation]: 97.59±28.20 CL) and ‐57.0%±3.1% (baseline: 102.71±35.30 CL) in donanemab and aducanumab arms, respectively (p<0.001). In the low/medium tau subpopulation, percent change in brain amyloid levels were ‐82.7%±4.6% (baseline: 104.97±25.68 CL) and ‐57.0%±4.5% (baseline: 102.99±27.87 CL) in donanemab and aducanumab arms, respectively (p<0.001). Adverse events occurred in 78.9% of donanemab‐treated and 82.6% of aducanumab‐treated participants, respectively. Amyloid‐related imaging abnormalities occurred in 29.6% (1.4% serious [n = 1]) and 40.6% (2.9% serious [n = 2]) of participants in the donanemab and aducanumab arms, respectively, with higher rates in ApoE4 carriers.ConclusionsTRAILBLAZER‐ALZ 4 provides the first active comparator data on amyloid plaque clearance in patients with early symptomatic AD and demonstrates the higher brain amyloid reduction of donanemab vs. aducanumab at 12 months when drug titration has been completed and the treatment regime has stabilized.