LTA4H inhibitor LYS006: Clinical PK/PD and safety in a randomized phase I clinical trial.
Journal
Clinical and translational science
ISSN: 1752-8062
Titre abrégé: Clin Transl Sci
Pays: United States
ID NLM: 101474067
Informations de publication
Date de publication:
Feb 2024
Feb 2024
Historique:
revised:
13
12
2023
received:
20
07
2023
accepted:
26
12
2023
medline:
26
2
2024
pubmed:
26
2
2024
entrez:
26
2
2024
Statut:
ppublish
Résumé
LYS006 is a novel, highly potent and selective, new-generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil-driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006-treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20 mg b.i.d. and above. Slow re-distribution from target expressing cells resulted in a long terminal half-life and a long-lasting PD effect in ex vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well-tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose-limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil-driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13724Subventions
Organisme : Novartis Pharma AG
Informations de copyright
© 2024 Novartis Biomedical Research. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
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