Clinical Meaningfulness of Donanemab in Early Symptomatic Alzheimer Disease: Data From the Randomized Phase 3 TRAILBLAZER-ALZ 2 Trial.

BACKGROUND AND OBJECTIVES: Understanding the meaningfulness of clinical trial outcomes is essential for people living with Alzheimer disease (AD) and their clinicians to make evidence-based shared treatment decisions in real-world clinical care. Donanemab, a monoclonal antibody targeting the insoluble form of β-amyloid found in plaques, significantly slows cognitive and functional decline of AD in participants with mild cognitive impairment (MCI) or mild AD-related dementia. This analysis reviews the efficacy of donanemab across various clinical outcome assessments, using both published data and new complementary analyses to provide context on its potential benefits for patients and caregivers. METHODS: We present findings from prespecified and post hoc analyses from the TRAILBLAZER-ALZ 2 trial. Clinical outcomes assessed were Integrated AD Rating Scale (iADRS), comprising the 13-item AD Assessment Scale-Cognitive Subscale (ADAS-Cog13) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL); Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB) for clinical severity and individual cognitive and functional domains; CDR-Global for clinical severity stage progression; meaningful within-patient change (MWPC); and ADCS-Activities of Daily Living dependence score. RESULTS: Donanemab reduced the risk of progression from MCI to mild AD by 33% (hazard ratio [HR] = 0.67; 95% CI 0.52-0.87; p = 0.003) and from mild to moderate AD by 50% (HR = 0.50; 95% CI 0.33-0.78; p = 0.002). In addition, donanemab reduced MWPC risk over 76 weeks by 38% for CDR-SB (HR = 0.62; 95% CI 0.52-0.75; p < 0.001) and 30% for iADRS (HR = 0.70; 95% CI 0.58-0.84; p < 0.001). Donanemab-treated participants exhibited significant slowing of clinical progression across multiple ADAS-Cog13 and ADCS-iADL items and all CDR-SB cognitive and functional domains. Donanemab also slowed progression of dependence least-squares mean change difference, -0.14 [95% CI -0.24 to -0.04; p = 0.007]), representing 23% slowing of progression (95% CI 6.17%-40.32%), and reduced risk of progression to requiring in-home support by 27% (HR = 0.74; 95% CI 0.59-0.91; p = 0.005). DISCUSSION: These results add to the evidence and further support clinically meaningful donanemab-mediated effects on cognition and function for patients and their caregivers and may aid communication of realistic treatment expectations and informed decision-making. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT04437511. Submitted: June 17, 2020; First patient enrolled: June 19, 2020. clinicaltrials.gov/study/NCT04437511 EudraCT Number 2020-000077-25. Start date of recruitment: June 19, 2020. clinicaltrialsregister.eu/ctr-search/trial/2020-000077-25/results.