title: Biomarker-guided clinical development of the first-in-class anti-inflammatory FPR2/ALX agonist ACT-389949.
abstract: 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 A4receptor (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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Translational Science, Drug Discovery Biology, Actelion Pharmaceuticals Ltd, 4123, Allschwil, Switzerland.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Stalder
authors.affiliation: Clinical Pharmacology, Actelion Pharmaceuticals Ltd, 4123, Allschwil, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Lott
authors.affiliation: Translational Science, Drug Discovery Biology, Actelion Pharmaceuticals Ltd, 4123, Allschwil, Switzerland.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Strasser
authors.affiliation: Clinical Pharmacology, Actelion Pharmaceuticals Ltd, 4123, Allschwil, Switzerland.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Cruz
authors.affiliation: Clinical Pharmacology, Actelion Pharmaceuticals Ltd, 4123, Allschwil, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Krause
authors.affiliation: Translational Science, Drug Discovery Biology, Actelion Pharmaceuticals Ltd, 4123, Allschwil, Switzerland.
authors.forename: Peter M A
authors.initials: PM
authors.lastname: Groenen
authors.affiliation: Clinical Pharmacology, Actelion Pharmaceuticals Ltd, 4123, Allschwil, Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015415:Biomarkers; D054443:Cell Migration Assays; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D008070:Lipopolysaccharides; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010080:Oxazoles / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000378:metabolism*; D014230:Triazoles / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C000625805:ACT-389949; D015415:Biomarkers; D016207:Cytokines; C105101:FPR2 protein, human; D008070:Lipopolysaccharides; D010080:Oxazoles; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D014230:Triazoles
keywords: FACS; FPR2/ALX; LPS challenge; biomarker; cytokines; dose finding; first in class; flow cytometry; inflammation; sputum