Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans - 13/11/21
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Abstract |
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.
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Highlights |
• | ACT-1004-1239 is the first-in-class CXCR7 antagonist studied in humans. |
• | Target engagement of ACT-1004-1239 was shown using plasma CXCL12 as biomarker. |
• | CXCL12 plasma concentration approached a plateau based on a PK/PD model. |
• | ACT-1004-1239 showed a favorable safety profile. |
• | A once-daily dosing regimen of ACT-1004-1239 in humans is proposed. |
Abbreviations : ACKR, AE, AI, AUCτ, AUECτ, b.i.d., BMI, Cbmax, CI, Cmax, CNS, CXCL, CXCR, ΔΔQTcF, Emax, EOS, FIH, IC50, LC-MS/MS, MS, o.d., PD, PK, SAEM, t1/2, tmax, VPC
Keywords : CXCR7, CXCL12, ACT-1004-1239, Target engagement, Multiple-ascending dose study, Mice, Humans
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Vol 144
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