Treatment with donanemab significantly slowed cognitive and functional decline in adults with early symptomatic Alzheimer disease, according to positive data from a phase 3 study.
Donanemab is an investigational antibody therapy that targets a modified form of deposited amyloid-β peptide called N3pG. The randomized, double-blind, placebo-controlled TRAILBLAZER-ALZ 2 study (ClinicalTrials.gov Identifier: NCT04437511) evaluated the efficacy and safety of donanemab in adults 60 to 85 years of age with early symptomatic Alzheimer disease, which includes mild cognitive impairment or mild dementia, with the presence of confirmed Alzheimer disease neuropathology.
In the primary analysis population (n=1182), which included patients with an intermediate level of tau and clinical symptoms of Alzheimer disease, donanemab was found to slow clinical decline by 35% compared with placebo, based on the change from baseline on the integrated Alzheimer Disease Rating Scale (iADRS; primary endpoint) over 18 months (P <.0001). Donanemab also slowed clinical decline by 36% vs placebo on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; key secondary endpoint) over 18 months (P <.0001).
Additional prespecified secondary analyses showed the following:
- 47% of donanemab-treated patients showed no decline on CDR-SB at 1 year vs 29% of patients who received placebo (P <.001).
- 52% of donanemab-treated patients completed their course of treatment by 1 year and 72% completed it by 18 months as a result of achieving plaque clearance.
- Donanemab-treated patients had 40% less decline in the ability to perform activities of daily living at 18 months, as measured by Alzheimer Disease Cooperative Study – instrumental Activities of Daily Living Inventory (P <.0001).
- Treatment with donanemab was associated with a 39% lower risk of progressing to the next stage of disease vs placebo (CDR-Global Score, hazard ratio, 0.61; P <.001).
Additionally, in the primary analysis combining high tau patients (n=552) with the intermediate tau population, treatment with donanemab resulted in improvements across all clinical endpoints (P <.001), including a 29% and 22% slowing of decline on CDR-SB and iADRS, respectively.
Using amyloid positron emission tomography brain scan, findings showed significant reductions in brain amyloid plaque levels among patients in the donanemab arm as early as 6 months after initiating treatment. In the intermediate tau population, 34% achieved amyloid clearance by 6 months; 71% achieved clearance by 12 months.
“These phase 3 data confirm the benefit observed in our TRAILBLAZER-ALZ study and show that donanemab, if approved, may represent a significant step forward for people with early symptomatic Alzheimer’s disease, and allow them to continue to participate in activities that are meaningful to them,” said Anne White, executive vice president of Eli Lilly and Company and president of Lilly Neuroscience. “We believe our data meets the ‘high level of evidence’ the Centers for Medicare & Medicaid Services (CMS) has described as the trigger for reconsideration of its National Coverage Determination. People with early Alzheimer’s disease need and deserve full coverage and access for approved therapies.”
As for safety, the incidence of amyloid-related imaging abnormalities (ARIA) was found to be consistent with the TRAILBLAZER-ALZ phase 2 study. In the TRAILBLAZER-ALZ 2 study, the incidence of serious ARIA was 1.6% and included 3 deaths.
Full study results will be presented at the Alzheimer’s Association International Conference in July and submitted for publication in a peer-reviewed clinical journal. The Company is planning for regulatory submission this quarter. The Food and Drug Administration previously granted Breakthrough Therapy designation to donanemab for this indication.
- Lilly’s donanemab significantly slowed cognitive and functional decline in phase 3 study of early Alzheimer’s disease. News release. Eli Lilly and Company. Accessed May 3, 2023. https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-significantly-slowed-cognitive-and-functional