Computer Science editorial
Open AccessOA2023
Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial
In the TRAILBLAZER-ALZ 2 trial, donanemab significantly slowed cognitive and functional decline in participants with early symptomatic Alzheimer disease and amyloid/tau pathology, but was associated with amyloid-related imaging abnormalities and infusion reactions.
J. Sims; Jennifer A. Zimmer; C. Evans; Ming-ning Lu; P. Ardayfio; J. Sparks; A. Wessels; S. Shcherbinin; Hong Wang; Emel Serap Monkul Nery; E. Collins; P. Solomon; S. Salloway; L. G. Apostolova; O. Hansson; C. Ritchie; Dawn A. Brooks; M. Mintun; D. Skovronskyยท Journal of the American Medical Association (JAMA)ยท 2023ยท DOI 10.1001/jama.2023.13239
The core problem
Alzheimer disease (AD) is a progressive neurodegenerative disorder with limited efficacious treatments. The accumulation of amyloid-beta plaques in the brain is a hallmark of AD, and therapies aimed at clearing these plaques are a major focus of research. Donanemab is a monoclonal antibody designed to target and clear brain amyloid plaque. The TRAILBLAZER-ALZ 2 trial was conducted to assess the efficacy and adverse events of donanemab in participants with early symptomatic AD (mild cognitive impairment or mild dementia) who had confirmed amyloid pathology and low/medium or high tau pathology.
Innovation
This was a multicenter, randomized, double-blind, placebo-controlled, 18-month phase 3 trial conducted at 277 medical research centers/hospitals across 8 countries. A total of 1736 participants with early symptomatic AD and amyloid and tau pathology (as determined by positron emission tomography) were enrolled between June 2020 and November 2021. Participants were randomized 1:1 to receive either donanemab (n=860) or placebo (n=876) intravenously every 4 weeks for 72 weeks. In the donanemab group, participants were switched to placebo in a blinded manner once they met dose completion criteria. The primary outcome was the change in the integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range 0-144; lower scores indicate greater impairment). Key secondary outcome included the change in the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score (range 0-18; higher scores indicate greater impairment). Statistical testing allocated ฮฑ of .04 to the low/medium tau population and .01 to the combined population. The trial is registered with ClinicalTrials.gov (NCT04437511).
Introduction
Alzheimer disease (AD) is a progressive neurodegenerative disorder with limited efficacious treatments. The accumulation of amyloid-beta plaques in the brain is a hallmark of AD, and therapies aimed at clearing these plaques are a major focus of research. Donanemab is a monoclonal antibody designed to target and clear brain amyloid plaque. The TRAILBLAZER-ALZ 2 trial was conducted to assess the efficacy and adverse events of donanemab in participants with early symptomatic AD (mild cognitive impairment or mild dementia) who had confirmed amyloid pathology and low/medium or high tau pathology.
Why it matters
The TRAILBLAZER-ALZ 2 trial met its primary and most secondary endpoints, demonstrating that donanemab significantly slowed clinical progression in participants with early symptomatic AD and amyloid/tau pathology. The benefits were observed in both the low/medium tau population and the combined population, though the effect sizes were modest. The difference in iADRS of 3.25 points (low/medium tau) and 2.92 points (combined) at 76 weeks represents a slowing of decline by approximately 35% and 22%, respectively, relative to placebo. Similarly, the CDR-SB difference of -0.67 and -0.7 points corresponds to a 36% and 29% slowing. These results are clinically meaningful but not curative. The safety profile was consistent with other anti-amyloid antibodies, with ARIA being the most notable adverse event. The higher incidence of ARIA in the donanemab group (24.0% vs 2.1%) underscores the need for careful monitoring. The trial's limitations include the lack of diversity (majority white participants) and the relatively short duration. Nonetheless, donanemab represents a significant advance in the treatment of early AD, and ongoing studies will further elucidate its long-term efficacy and safety.
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