Pharmacokinetics of selonsertib, GS-9674, and/or GS-0976 in combination in healthy subjects
Author(s): ,
Cara H Nelson
Affiliations:
,Gilead sciences, Inc,Foster City,United States
,
Brian J Kirby
Affiliations:
,GILEAD SCIENCES, INC,Foster City,United States
,
Na Lu
Affiliations:
,GILEAD SCIENCES, INC,Foster City,United States
,
Bryan McColgan
Affiliations:
,GILEAD SCIENCES, INC,Foster City,United States
,
C. Stephen Djedjos
Affiliations:
,GILEAD SCIENCES, INC,Foster City,United States
,
Robert P Myers
Affiliations:
,GILEAD SCIENCES, INC,Foster City,United States
,
Jennifer Cuvin
Affiliations:
,GILEAD SCIENCES, INC,Foster City,United States
,
Ann Qin
Affiliations:
,GILEAD SCIENCES, INC,Foster City,United States
Anita Mathias
Affiliations:
,GILEAD SCIENCES, INC,Foster City,United States
EASL LiverTree™. Nelson C. Apr 20, 2017; 168796
Topic: Experimental
Cara Nelson
Cara Nelson

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Abstract
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THU-344

Topic: Fatty liver disease: Clinical aspects

Background and aims
Selonsertib (SEL, formerly GS-4997) is a selective apoptosis signal-regulating kinase 1 (ASK1) inhibitor. GS-9674 is a selective farnesoid X receptor (FXR) agonist. GS-0976 is an allosteric inhibitor of acetyl-CoA carboxylase (ACC) isoforms 1 and 2. These compounds are currently in clinical development as monotherapies for the treatment of nonalcoholic steatohepatitis (NASH). Based on their distinct mechanisms of action, combinations of SEL, GS-9674, and GS-0976 may provide additional therapeutic benefit in NASH as compared to their use as monotherapy. This Phase 1 study was conducted to evaluate potential pharmacokinetic (PK) drug-drug interactions (DDIs) between each of the possible combinations of these agents to support dosing in combination Phase 2 clinical studies.

Methods
This was an open-label, multiple dose study in healthy subjects. Each subject received 1 of 3 monotherapies for 7 days (18 mg SEL QD, 100 mg GS-9674 QD, or 20 mg GS-0976 QD; N = 10, 18, and 26 per combination, respectively) and 2 of the 3 agents in combination for the following 7 days. Safety was assessed by routine clinical and laboratory monitoring. Intensive PK sampling up to 96 hours postdose occurred on Days 7 and 14. Geometric mean ratios (GMR) and 90% confidence intervals (CI) were estimated for AUCtau and Cmax for each analyte.

Results
108 subjects were enrolled and received at least one dose of study drug in these three cohorts. Three subjects discontinued prematurely; two for personal reasons and one for Grade 3 creatinine kinase elevation in the context of strenuous activity. All other AEs were Grade 1 in severity and most laboratory abnormalities were Grade 1 or 2. The GMR and 90% CIs for AUCtau and Cmax for each study drugs in combination are shown in the figure below with the gray-shaded region representing 0.7 to 1.43 bounds. SEL coadministration caused a slight increase in GS-9674 Cmax (~26%) with no significant change in AUCtau while GS-0976 had no effect on GS-9764 exposure. Neither GS-9674 nor GS-0976 had a meaningful effect on SEL PK. Similarly, the PK of GS-0976 was not affected by either SEL or GS-9674.

Conclusions
Combinations of SEL, GS-9674, and/or GS-0976 were well-tolerated at the doses evaluated in this short-term study of healthy subjects. The minimal and non-clinically relevant changes in PK observed support combination studies of SEL, GS-9674, and/or GS-0976 without dose modifications in Phase 2 clinical studies in patients with NASH, which may be confirmed in additional studies.

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