Donanemab in Early Alzheimer's Disease.

By Mark A. Mintun, A. Lo, C. Duggan Evans, A. Wessels, P. Ardayfio, S. Andersen, S. Shcherbinin, J. Sparks, J. Sims, M. Brys and 3 more. New England Journal of Medicine, 2021

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BACKGROUND A hallmark of Alzheimer's disease is the accumulation of amyloid-β (Aβ) peptide. Donanemab, an antibody that targets a modified form of deposited Aβ, is being investigated for the treatment of early Alzheimer's disease. METHODS We conducted a phase 2 trial of donanemab in patients with early symptomatic Alzheimer's disease who had tau and amyloid deposition on positron-emission tomography (PET). Patients were randomly assigned in a 1:1 ratio to receive donanemab (700 mg for the first three doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks. The primary outcome was the change from baseline in the score on the Integrated Alzheimer's Disease Rating Scale (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks. Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog13), the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET. RESULTS A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The baseline iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was -6.86 with donanemab and -10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P = 0.04). The results for most secondary outcomes showed no substantial difference. At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo. Amyloid-related cerebral edema or effusions (mostly asymptomatic) occurred with donanemab. CONCLUSIONS In patients with early Alzheimer's disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed. Longer and larger trials are necessary to study the efficacy and safety of donanemab in Alzheimer's disease. (Funded by Eli Lilly; TRAILBLAZER-ALZ ClinicalTrials.gov number, NCT03367403.).

Subfields: Physiology, Psychiatry and Mental health, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/5e92ac79f8fd89b1dfe1dda97966ff30b8defd50

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Citations in the corpus

Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future (2023, result): “com/news-releases/news-releasedetails/lilly-shares-positive-donanemab-data-first-active-comparator) announced the result of the first active comparator study (TRAILBLAZER-ALZ 4), which showed that donanemab, another monoclonal antibody targeting deposited plaques had outperformed aducanumab-avwa tre”
Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease (2022, background): “Localized superficial siderosis 14 (3) 52 (10) 73 (13) 10 (2) 51 (9) 89 (16)”
Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup (2024, positive): “149,150,161,229 Consistent results across both successful and failed immunotherapy trials show that the amount of amyloid PET reduction is associated with the degreeofclinicalbenefit.”