Biomarker‐guided clinical development of the first‐in‐class anti‐inflammatory FPR2/ALX agonist ACT‐389949

• Published in: British journal of clinical pharmacology Vol. 83; no. 3; pp. 476 - 486
• Main Authors: Stalder, Anna K., Lott, Dominik, Strasser, Daniel S., Cruz, Hans G., Krause, Andreas, Groenen, Peter M.A., Dingemanse, Jasper
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.03.2017
• Subjects: Adolescent; Adult; Animals; biomarker; Biomarkers; Cell Migration Assays; Clinical Trials; cytokines; Cytokines - blood; Disease Models, Animal; dose finding; Dose-Response Relationship, Drug; Double-Blind Method; FACS; first in class; flow cytometry; FPR2/ALX; Humans; inflammation; Inflammation - chemically induced; Lipopolysaccharides; LPS challenge; Male; Middle Aged; Neutrophils - drug effects; Neutrophils - metabolism; Oxazoles - adverse effects; Oxazoles - pharmacokinetics; Oxazoles - pharmacology; Receptors, Formyl Peptide - metabolism; Receptors, Lipoxin - metabolism; sputum; Triazoles - adverse effects; Triazoles - pharmacokinetics; Triazoles - pharmacology; Young Adult; dose finding; FPR2/ALX; inflammation; LPS challenge; cytokines; flow cytometry; sputum; FACS; biomarker; first in class
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13149

Aims The main objectives of these two phase I studies were to investigate safety and tolerability as well as the pharmacokinetic/pharmacodynamic profile of the novel potent and selective formyl peptide receptor type 2 (FPR2)/Lipoxin A4 receptor (ALX) agonist ACT‐389949. A challenge model was used to assess the drug's anti‐inflammatory potential, with the aim of selecting a dosing regimen for future patient studies. Methods Two double‐blind, randomized phase I studies investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of ACT‐389949 at different doses and dosing regimens. Drug exposure was correlated with target engagement markers such as receptor internalization and cytokine measurements. The effect of FPR2/ALX agonism on neutrophil migration was studied in a lipopolysaccharide (LPS) inhalation model. Results ACT‐389949 was well tolerated. Maximum concentrations were reached around 2 h after dosing, with a mean terminal half‐life of 29.3 h [95% confidence interval (CI) 25.5, 33.7]. After multiple‐dose administration, exposure increased by 111% (95% CI 89, 136), indicating drug accumulation. Administration of ACT‐389949 resulted in a dose‐dependent, long‐lasting internalization of FPR2/ALX into leukocytes. Pro‐ and anti‐inflammatory cytokines were dose‐dependently but transiently upregulated only after the first dose. No pharmacological effect on neutrophil count was observed in the LPS challenge test performed at steady state. Conclusions FPR2/ALX agonism with ACT‐389949 was shown to be safe and well tolerated in healthy subjects. Receptor internalization and downstream mediators pointed towards a desensitization of the system, which may explain the lack of effect on neutrophil recruitment in the LPS challenge model.