Safety, Tolerability, and Pharmacokinetics of Zagotenemab in Participants with Symptomatic Alzheimer's Disease: A Phase I Clinical Trial.
Aggregated tau
Alzheimer’s disease
antibody
safety pharmacokinetics
zagotenemab
Journal
Journal of Alzheimer's disease reports
ISSN: 2542-4823
Titre abrégé: J Alzheimers Dis Rep
Pays: Netherlands
ID NLM: 101705500
Informations de publication
Date de publication:
2023
2023
Historique:
received:
13
02
2023
accepted:
16
08
2023
medline:
18
10
2023
pubmed:
18
10
2023
entrez:
18
10
2023
Statut:
epublish
Résumé
Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer's disease (AD). The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD. This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks. A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration. No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed.Clinicaltrials.gov: NCT03019536.
Sections du résumé
Background
UNASSIGNED
Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer's disease (AD).
Objective
UNASSIGNED
The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD.
Methods
UNASSIGNED
This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks.
Results
UNASSIGNED
A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration.
Conclusions
UNASSIGNED
No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed.Clinicaltrials.gov: NCT03019536.
Identifiants
pubmed: 37849628
doi: 10.3233/ADR-230012
pii: ADR230012
pmc: PMC10578324
doi:
Banques de données
ClinicalTrials.gov
['NCT03019536']
Types de publication
Journal Article
Langues
eng
Pagination
1015-1024Informations de copyright
© 2023 – The authors. Published by IOS Press.
Déclaration de conflit d'intérêts
Sergey Shcherbinin, Louise Chinchen, Scott W. Andersen, Elizabeth S. LaBell, David G. S. Perahia, Paula M. Hauck, and Stephen L. Lowe are full-time employees and minor stockholders of Eli Lilly and Company. Brian A. Willis, previous employee and minor stockholder of Eli Lilly and Company, is currently at Eisai Inc. Albert C. Lo is a previous employee and minor stockholder of Eli Lilly and Company. Jeffrey L. Dage, previous employee and minor stockholder of Eli Lilly and Company, is currently at Indiana University School of Medicine and has received speaker fees and in kind support for his research from Eli Lilly.
Références
Neurology. 2010 Jun 15;74(24):1954-60
pubmed: 20548041
Alzheimers Dement (N Y). 2018 Nov 09;4:652-660
pubmed: 30511011
Brain. 2023 Jun 1;146(6):2275-2284
pubmed: 36730056
J Nucl Med. 2018 Jun;59(6):937-943
pubmed: 29284675
JAMA Neurol. 2020 Jul 1;77(7):829-839
pubmed: 32338734
JAMA Neurol. 2022 Jan 1;79(1):13-21
pubmed: 34807243
Bioanalysis. 2010 Dec;2(12):1961-9
pubmed: 21110740
J Immunol Methods. 2007 Oct 31;327(1-2):10-7
pubmed: 17716682
MAbs. 2016 Jul;8(5):854-60
pubmed: 27030142
J Biol Chem. 2013 Jan 18;288(3):1856-70
pubmed: 23188818
Alzheimers Dement. 2016 Dec;12(12):1226-1234
pubmed: 27436677
Nat Commun. 2020 May 26;11(1):2612
pubmed: 32457389
JAMA Neurol. 2022 Aug 1;79(8):758-767
pubmed: 35696185
Life Sci. 2020 Sep 1;256:117996
pubmed: 32585249
Neurol Neuroimmunol Neuroinflamm. 2014 Aug 21;1(2):e18
pubmed: 25340070
Alzheimers Dement. 2018 Aug;14(8):989-997
pubmed: 29626426
Front Cell Dev Biol. 2021 Jul 28;9:707268
pubmed: 34395435