A Multipurpose First-in-Human Study With the Novel CXCR7 Antagonist ACT-1004-1239 Using CXCL12 Plasma Concentrations
Christine Huynh1,2, Andrea Henrich1, Daniel S Strasser1
1Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Abstract:
The C-X-C chemokine receptor 7 (CXCR7) has evolved as a promising, druggable target mainly in the immunology and oncology fields modulating plasma concentrations of its ligands CXCL11 and CXCL12 through receptor-mediated internalization. This "scavenging" activity creates concentration gradients of these ligands between blood vessels and tissues that drive directional cell migration. This randomized, double-blind, placebo-controlled first-in-human study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT-1004-1239, a first-in-class drug candidate small-molecule CXCR7 antagonist. Food effect and absolute bioavailability assessments were also integrated in this multipurpose study. Healthy male subjects received single ascending oral doses of ACT-1004-1239 (n = 36) or placebo (n = 12). At each of six dose levels (1-200 mg), repeated blood sampling was done over 144 hours for pharmacokinetic/pharmacodynamic assessments using CXCL11 and CXCL12 as biomarkers of target engagement. ACT-1004-1239 was safe and well tolerated up to the highest tested dose of 200 mg. CXCL12 plasma concentrations dose-dependently increased and more than doubled compared with baseline, indicating target engagement, whereas CXCL11 concentrations remained unchanged. An indirect-response pharmacokinetic/pharmacodynamic model well described the relationship between ACT-1004-1239 and CXCL12 concentrations across the full dose range, supporting once-daily dosing for future clinical studies. At doses ≥ 10 mg, time to reach maximum plasma concentration ranged from 1.3 to 3.0 hours and terminal elimination half-life from 17.8 to 23.6 hours. The exposure increase across the dose range was essentially dose-proportional and no relevant food effect on pharmacokinetics was determined. The absolute bioavailability was 53.0% based on radioactivity data after oral vs. intravenous 14 C-radiolabeled microtracer administration of ACT-1004-1239. Overall, these comprehensive data support further clinical development of ACT-1004-1239.
Insights
The novel drug ACT-1004-1239, a C-X-C chemokine receptor 7 (CXCR7) antagonist, demonstrated safety and well-tolerated profiles in healthy individuals. This study confirmed target engagement by showing increased CXCL12 plasma concentrations, supporting further clinical development.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- C-X-C chemokine receptor 7 (CXCR7) modulates CXCL11 and CXCL12 ligand concentrations via receptor-mediated internalization.
- This "scavenging" activity is crucial for creating cell migration gradients between blood vessels and tissues.
Purpose of the Study:
- To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT-1004-1239, a novel small-molecule CXCR7 antagonist.
- To evaluate food effects and absolute bioavailability of ACT-1004-1239.
- To establish target engagement using CXCL11 and CXCL12 as biomarkers.
Main Methods:
- A randomized, double-blind, placebo-controlled, first-in-human study involving healthy male subjects.
- Single ascending oral doses of ACT-1004-1239 (1-200 mg) or placebo administered to 48 subjects (36 active, 12 placebo).
- Pharmacokinetic/pharmacodynamic assessments over 144 hours, including analysis of CXCL11 and CXCL12 plasma concentrations.
Main Results:
- ACT-1004-1239 was safe and well-tolerated up to 200 mg.
- A dose-dependent increase in CXCL12 plasma concentrations (more than doubling baseline) indicated target engagement; CXCL11 levels remained unchanged.
- Pharmacokinetic analysis supported once-daily dosing, with dose-proportional exposure, a half-life of 17.8–23.6 hours, and 53.0% absolute bioavailability.
Conclusions:
- ACT-1004-1239 is a safe and well-tolerated first-in-class CXCR7 antagonist.
- The drug effectively engages the CXCR7 target, as evidenced by increased CXCL12 levels.
- Comprehensive pharmacokinetic and pharmacodynamic data support the further clinical development of ACT-1004-1239.
