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

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....

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Autores principales:	Christine Huynh, Janneke M. Brussee, Laetitia Pouzol, Marlene Fonseca, Henriette E. Meyer zu Schwabedissen, Jasper Dingemanse, Patricia N. Sidharta
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	CXCR7 CXCL12 ACT-1004-1239 Target engagement Multiple-ascending dose study Mice Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/865066848fe74d97977d8729c1385c53
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spelling	oai:doaj.org-article:865066848fe74d97977d8729c1385c532021-11-14T04:30:21ZTarget engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans0753-332210.1016/j.biopha.2021.112363https://doaj.org/article/865066848fe74d97977d8729c1385c532021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221011471https://doaj.org/toc/0753-3322Antagonism 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.Christine HuynhJanneke M. BrusseeLaetitia PouzolMarlene FonsecaHenriette E. Meyer zu SchwabedissenJasper DingemansePatricia N. SidhartaElsevierarticleCXCR7CXCL12ACT-1004-1239Target engagementMultiple-ascending dose studyMiceTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112363- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CXCR7 CXCL12 ACT-1004-1239 Target engagement Multiple-ascending dose study Mice Therapeutics. Pharmacology RM1-950
spellingShingle	CXCR7 CXCL12 ACT-1004-1239 Target engagement Multiple-ascending dose study Mice Therapeutics. Pharmacology RM1-950 Christine Huynh Janneke M. Brussee Laetitia Pouzol Marlene Fonseca Henriette E. Meyer zu Schwabedissen Jasper Dingemanse Patricia N. Sidharta Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans
description	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.
format	article
author	Christine Huynh Janneke M. Brussee Laetitia Pouzol Marlene Fonseca Henriette E. Meyer zu Schwabedissen Jasper Dingemanse Patricia N. Sidharta
author_facet	Christine Huynh Janneke M. Brussee Laetitia Pouzol Marlene Fonseca Henriette E. Meyer zu Schwabedissen Jasper Dingemanse Patricia N. Sidharta
author_sort	Christine Huynh
title	Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans
title_short	Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans
title_full	Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans
title_fullStr	Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans
title_full_unstemmed	Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans
title_sort	target engagement of the first-in-class cxcr7 antagonist act-1004-1239 following multiple-dose administration in mice and humans
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/865066848fe74d97977d8729c1385c53
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Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans

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