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Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans.
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID 4634830
Author(s) Huynh, Christine; Brussee, Janneke M; Pouzol, Laetitia; Fonseca, Marlene; Meyer Zu Schwabedissen, Henriette E; Dingemanse, Jasper; Sidharta, Patricia N
Author(s) at UniBasel Meyer zu Schwabedissen, Henriette
Huynh, Christine
Year 2021
Title Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans.
Journal Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Volume 144
Pages / Article-Number 112363
Keywords ACT-1004-1239; CXCL12; CXCR7; Humans; Mice; Multiple-ascending dose study; Target engagement

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 (t; max; : 1.75-3.01 h) and the terminal t; 1/2; 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.

ISSN/ISBN 1950-6007
Full Text on edoc
Digital Object Identifier DOI 10.1016/j.biopha.2021.112363
PubMed ID

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