Affiliation:
1. Eli Lilly and Company Bracknell UK
2. Former Employee of Eli Lilly and Company Indianapolis Indiana USA
3. Eli Lilly and Company Singapore Singapore
4. Eli Lilly and Company Indianapolis Indiana USA
Abstract
Donanemab is an amyloid‐targeting therapy that resulted in robust amyloid plaque reduction and slowed Alzheimer's disease (AD) progression compared with placebo in the phase II TRAILBLAZER‐ALZ study (NCT03367403). The objectives of the current analyses are to characterize (i) the population pharmacokinetics of donanemab, (ii) the relationship between donanemab exposure and amyloid plaque reduction (response), and (iii) the relationship between donanemab exposure and amyloid‐related imaging abnormalities with edema or effusions (ARIA‐E). Model development included data from participants with mild cognitive impairment or mild to moderate dementia due to AD from the phase Ib study on donanemab (NCT02624778) and participants with early symptomatic AD from the TRAILBLAZER‐ALZ study. The analysis showed donanemab has a terminal elimination half‐life of 11.8 days. Body weight and antidrug antibody titer impact donanemab exposure but not the pharmacodynamic response. Maintaining a donanemab serum concentration above 4.43 μg/mL (95% confidence interval: 0.956, 10.4) is associated with amyloid plaque reduction. The time to achieve amyloid plaque clearance (amyloid plaque level < 24.1 Centiloids) varied depending on the baseline amyloid level, where higher baseline levels were associated with fewer participants achieving amyloid clearance. The majority of participants achieved amyloid clearance by 52 weeks on treatment. Apolipoprotein ε4 carriers, irrespective of donanemab serum exposure, were 4 times more likely than noncarriers to have an ARIA‐E event by 24 weeks.
Subject
Pharmacology (medical),Pharmacology
Reference20 articles.
1. Donanemab in Early Alzheimer’s Disease
2. Donanemab (LY3002813) phase 1b study in Alzheimer's disease: rapid and sustained reduction of brain amyloid measured by florbetapir F18 imaging;Lowe S.L.;J. Prev. Alzheimers Dis.,2021
3. Donanemab (LY3002813) dose‐escalation study in Alzheimer's disease;Lowe S.L.;Alzheimers Dement.,2021
4. A Plaque-Specific Antibody Clears Existing β-amyloid Plaques in Alzheimer's Disease Mice
Cited by
28 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献