GS-9674/GS-0976 versus Selonsertib
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Study Design
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.
Study 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.
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 PKof GS-0976was not affected byeither SEL or GS-9674.
Study 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.
References
Nelson CH, Kirby BJ, Lu N, McColgan B, Djedjos CS, Myers RP. Pharmacokinetics of selonsertib, gs-9674, and/or gs-0976 in combination in healthy adults . International Liver Congress. Amsterdam, Netherlands. 2017; April 2017.
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