Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Fol
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ORIGINAL RESEARCH ARTICLE
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 Cara H. Nelson1 · Kim Etchevers1 · Saili Yi1 · David Breckenridge1 · Mischa Hepner1 · Uptal Patel1 · John Ling1 · Anita Mathias1
© Springer Nature Switzerland AG 2020
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.
Key Points Selonsertib, a first-in-class apoptosis signal-regulating kinase 1 (ASK1) inhibitor, was safe and well tolerated following single and multiple doses in healthy subjects. Pharmacokinetic (PK) and pharmacodynamic data demonstrate pharmacologically relevant exposures were achieved. The PK and safety profile supports once-daily dosing and continued investigation of selonsertib for the treatment of fibrotic diseases. * Cara H. Nelson [email protected] 1
Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA
1 Introduction Apoptosis signal-regulating kinase 1 (ASK1) is a serine/ threonine signaling kinase that is regulated by its direct interaction with thioredoxin, a redox-responsive protein. Under basal conditions, ASK1 is bound to thioredoxin and is inactive; however, under oxidative stress, thioredoxin is oxidized and dissociates from ASK1, which allows ASK1 to become activated [1]. This in turn activates the mitogenactivated kinases p38 and Jun
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