First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Pharmacodynamics of DS-7011a, an Anti-TLR7 Antagonistic Monoclonal Antibody for the Treatment of Systemic Lupus Erythematosus.

Autor: Senaldi G; Daiichi Sankyo, Basking Ridge, NJ, USA., Mohan A; Daiichi Sankyo, Basking Ridge, NJ, USA., Zhang L; Daiichi Sankyo, Basking Ridge, NJ, USA., Tanaka J; Daiichi Sankyo, Basking Ridge, NJ, USA., Lin Y; Daiichi Sankyo, Basking Ridge, NJ, USA., Pandya G; Daiichi Sankyo, Basking Ridge, NJ, USA., Grossman S; Daiichi Sankyo, Basking Ridge, NJ, USA., Urbina S; Worldwide Clinical Trials, San Antonio, TX, USA., Reynolds SH; CenExel, Los Alamitos, CA, USA., Hand AH; Worldwide Clinical Trials, San Antonio, TX, USA.
Jazyk: angličtina
Zdroj: Journal of clinical pharmacology [J Clin Pharmacol] 2024 Aug 22. Date of Electronic Publication: 2024 Aug 22.
DOI: 10.1002/jcph.6117
Abstrakt: Toll-like receptor (TLR)7 is a pattern recognition receptor that critically contributes to the pathogenesis of systemic lupus erythematosus (SLE). DS-7011a is an anti-TLR7 monoclonal antibody that prevents TLR7 from signaling. The aim of this first-in-human, double-blind, randomized, and placebo-controlled study was to evaluate the safety, pharmacokinetics, immunogenicity, and pharmacodynamics of single ascending intravenous (IV) and subcutaneous (SC) doses of DS-7011a in healthy subjects (HS) (NCT05203692). On day 1, 80 HS received DS-7011a or placebo 6:2 in 10 cohorts (7 treated IV and 3 SC) of 8 each and were followed for 8 weeks until day 57. Safety was evaluated by recording treatment-emergent adverse events (TEAEs), pharmacokinetics by measuring plasma DS-7011a, immunogenicity by measuring plasma anti-drug antibodies (ADAs), and pharmacodynamics by evaluating the suppression of interleukin-6 production ex vivo in whole blood. DS-7011a was safe and well tolerated across all cohorts. TEAEs were mostly mild in severity and not drug-related. DS-7011a exposure increased with the dose but was not dose proportional, as the elimination of lower doses was accelerated by target-mediated drug disposition. Terminal half-life was about 15-17 days and T max upon SC administration was about 5 days. DS-7011a induced ADAs in about half of HS but with no impact on clinical findings and pharmacokinetics. Pharmacodynamic (PD) response also increased with the dose and at the higher doses was of large extent (>90%), early onset, and lasting duration. DS-7011a showed favorable safety, pharmacokinetics, immunogenicity, and PD properties that support its development for the treatment of SLE.
(© 2024, The American College of Clinical Pharmacology.)
Databáze: MEDLINE
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