Participants were able to stop treatment after achieving amyloid plaque clearance and experience lasting results.
Donanemab significantly slowed cognitive and functional decline in patients with amyloid-positive early symptomatic Alzheimer disease (AD), regardless of the baseline level of tau—a biomarker for disease progression, according to the final results of the pivotal TRAILBLAZER-ALZ 2 study.
"If approved, we believe donanemab can provide clinically meaningful benefits for people with this disease and the possibility of completing their course of treatment as early as 6 months once their amyloid plaque is cleared,” said Eli Lilly and Company president Anne White, in a press release.
TRAILBLAZER-ALZ 2 (NCT04437511) is a phase 3, double-blind, placebo-controlled study that evaluated the safety and efficacy of donanemab in 1736 global participants aged 60 to 85 years with confirmed early symptomatic AD neuropathy. Donanemab is a disease-modifying therapy for amyloid-positive early symptomatic AD, whether that is mild cognitive impairment or mild dementia. It works by clearing deposited amyloid plaque that leads to cognitive decline.
At 18 months, donanemab reduced 84% of amyloid plaque compared to 1% with placebo in patients across all disease (tau) stages. Patients could stop treatment once achieving the pre-defined criteria for amyloid plaque clearance and continue to benefit from the treatment over time, according to the study.
Investigators used the integrated Alzheimer's Disease Rating Scale (iADRS) and the Clinical Dementia Rating-Sum of Boxes (CDR-SB) to measure patient cognition and function over 18 months. They stratified patients by disease progression (tau stage), which were low-medium tau or high tau (lower to higher disease progression).
According to the iADRS and CDR-SB tests, patients with low-medium tau levels experienced a 35% and 36% reduction in the rate of cognitive and functional decline, respectively. All amyloid-positive early symptomatic AD patients experienced a 22% and 26% reduction in cognitive decline, respectively.
Earlier AD diagnosis and treatment with donanemab may also provide more clinical benefit, added Liana Apostolova, MD, a professor in neurology, radiology, medical and molecular genetics at the Indiana University School of Medicine, and investigator at the Alzheimer’s Disease Center.
Approximately 47% of patients with low-medium tau had no disease progression at 1 year (29% in placebo), and their risk of disease progression went down 39%. In addition, the iADRS and CDR-SB scales show that patients with the earliest stage of AD—mild cognitive impairment—experienced 60% and 46% slower decline with donanemab, respectively.
“The results of this study reinforce the importance of diagnosing and treating disease sooner than we do today," said Mark Mintun, MD, group vice president Neuroscience Research & Development at Lilly, and president of Avid Radiopharmaceuticals, in the press release.
A post-hoc subgroup analysis showed that patients aged younger than 75 years with low-medium tau experienced more benefits than those older than 75 years of age. Donanemab slowed cognitive and functional decline by 48% (iADRS) and 45% (CDR-SB) in patients younger than 75 years of age compared to 25% (iADRS) and 29% (CDR-SB) in patients aged 75 years and older.
The data were shared at the 2023 Alzheimer's Association International Conference and published in JAMA. It has already been submitted to the FDA for approval, with regulatory action expected at the end of 2023.
White concluded, “we must continue to remove any barriers in access to amyloid-targeting therapies and diagnostics in an already complex health care ecosystem for AD."
Results from Lilly's Landmark Phase 3 Trial of Donanemab Presented at Alzheimer's Association Conference and Published in JAMA. Lilly. News Release. July 17, 2023. Accessed on July 18, 2023. https://investor.lilly.com/news-releases/news-release-details/results-lillys-landmark-phase-3-trial-donanemab-presented