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Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects

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Abstract

Background

Selonsertib is a first-in-class inhibitor of apoptosis signal-regulating kinase 1 (ASK1) with therapeutic potential for fibrotic diseases. This phase I study evaluated the safety, tolerability, pharmacokinetics (PK), and food effect of selonsertib in healthy subjects.

Methods

This was a double-blinded, randomized, placebo-controlled dose-escalation study. Healthy subjects received 1, 3, 10, 30, or 100 mg of selonsertib or placebo as single or multiple doses once daily for 14 days in the fasted state, or 30 mg or placebo single dose in the fed state. Blood and urine (single-dose cohorts only) samples for selonsertib PK were collected and safety was assessed throughout the study. Ex vivo pharmacodynamic (PD) assessment was performed in blood from a separate cohort of healthy donors using an auranofin-stimulated C-X-C motif chemokine ligand 1 (CXCL1) assay.

Results

Overall, 107 subjects (83 active, 24 placebo) were enrolled and randomized to 11 cohorts. Selonsertib was generally well tolerated; adverse events were generally mild to moderate. Selonsertib was rapidly absorbed with dose-proportional PK of both parent and inactive metabolite GS-607509. There was no food effect on selonsertib PK. Renal excretion was a minor pathway of selonsertib elimination. Selonsertib half maximal effective concentration (EC50) in human whole blood was determined to be 56 ng/mL.

Conclusions

Selonsertib exhibited a favorable PK profile amenable to once-daily dosing without regard to food. PD data suggest pharmacologically relevant exposures were achieved in the dose range evaluated. Study results support further clinical development of selonsertib.

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Acknowledgements

This study was supported by Gilead Sciences. The authors thank the study participants and their families, as well as the investigators and site personnel. Medical writing support was provided by Sunila Reddy, PharmD.

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Authors and Affiliations

  1. Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA

    Cara H. Nelson, Kim Etchevers, Saili Yi, David Breckenridge, Mischa Hepner, Uptal Patel, John Ling & Anita Mathias

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  1. Cara H. Nelson
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  2. Kim Etchevers
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  3. Saili Yi
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  8. Anita Mathias
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Corresponding author

Correspondence to Cara H. Nelson.

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Funding

This study was sponsored by Gilead Sciences, Inc.

Conflicts of interest

Cara Nelson, Kim Etchevers, Saili Yi, David Breckenridge, Mischa Hepner, Uptal Patel, John Ling, and Anita Mathias are employees and shareholders of Gilead Sciences, Inc.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Schulman Associates IRB, IRB# 201303831) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Nelson, C.H., Etchevers, K., Yi, S. et al. Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects. Clin Pharmacokinet 59, 1109–1117 (2020). https://doi.org/10.1007/s40262-020-00878-y

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  • DOI: https://doi.org/10.1007/s40262-020-00878-y

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