Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans

Biomed Pharmacother. 2021 Dec:144:112363. doi: 10.1016/j.biopha.2021.112363. Epub 2021 Oct 28.


Antagonism of the chemokine receptor CXCR7 has shown promising effects in diverse disease areas through modulation of its ligands, CXCL11 and CXCL12. Preclinical data of the first-in-class CXCR7 antagonist, ACT-1004-1239, showed efficacy in animal models of multiple sclerosis and acute lung injury. In healthy humans, single-dose administration of ACT-1004-1239 revealed a favorable clinical profile. Here, we report the target engagement of ACT-1004-1239 in healthy mice and humans after multiple doses using CXCL11 and CXCL12 as biomarkers. In addition, safety/tolerability, concentration-QTc relationship, and pharmacokinetics (PK) were assessed in a randomized, double-blind, placebo-controlled Phase 1 clinical study. Multiple-dose ACT-1004-1239 dose-dependently increased CXCL12 plasma concentration across the investigated dose range in mice and humans (mice: 1-100 mg/kg b.i.d.; humans: 30-200 mg o.d.) when compared to vehicle/placebo demonstrating target engagement. Mouse and human PK/PD models predicted that CXCL12 concentration approached a plateau within these dose ranges. In humans, ACT-1004-1239 was rapidly absorbed (tmax: 1.75-3.01 h) and the terminal t1/2 was approximately 19 h. Steady-state conditions were reached by Day 3 with an accumulation index of 1.2. Female subjects had overall higher exposure compared to males. Multiple-dose ACT-1004-1239 was well tolerated up to 200 mg once daily in humans. There was no evidence of ACT-1004-1239-mediated QTc interval prolongation. Overall, multiple oral doses of ACT-1004-1239 showed target engagement with CXCR7 in healthy mice and humans, therefore, assessment of CXCL12 as translational tool for further investigations in patients is warranted. Favorable safety/tolerability and PK profiles allow for further clinical development.

Keywords: ACT-1004-1239; CXCL12; CXCR7; Humans; Mice; Multiple-ascending dose study; Target engagement.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Animals
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Healthy Volunteers
  • Humans
  • Long QT Syndrome / chemically induced
  • Male
  • Mice
  • Mice, Inbred DBA
  • Oxazoles / administration & dosage
  • Oxazoles / pharmacology*
  • Piperidines / administration & dosage
  • Piperidines / pharmacology*
  • Receptors, CXCR / antagonists & inhibitors*
  • Sex Characteristics


  • ACKR3 protein, human
  • ACT-1004-1239
  • Cmkor1 protein, mouse
  • Oxazoles
  • Piperidines
  • Receptors, CXCR