Kidney Week

Abstract: SA-PO155

Pharmacokinetic-Pharmacodynamic Relationships for the Effect of Selonsertib on eGFR in a Phase 2 Study in Subjects with Diabetic Kidney Disease

Session Information

• Diabetic Kidney Disease: Clinical - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 602 Diabetic Kidney Disease: Clinical

Authors

• Kirby, Brian J., Gilead Sciences, Inc., Foster City, California, United States

Brian J. Kirby,

• Nelson, Cara H., Gilead Sciences, Inc., Foster City, California, United States

Cara H. Nelson,

• Billin, Andrew, Gilead Sciences, Inc., Foster City, California, United States

Andrew Billin,

• Chen, Fang, Gilead Sciences, Inc., Foster City, California, United States

Fang Chen,

• Patel, Uptal D., Gilead Sciences, Inc., Foster City, California, United States

Uptal D. Patel,

• Mathias, Anita, Gilead Sciences, Inc., Foster City, California, United States

Anita Mathias,

Background

Selonsertib (SEL) is a first-in-class, small molecule apoptosis signal-regulating kinase 1 (ASK1) inhibitor in clinical development for the treatment of diabetic kidney disease (DKD) and nonalcoholic steatohepatitis. In a Phase 2 dose ranging study in subjects with Stage 3a to 4 DKD, SEL was safe and well tolerated, showed a dose- dependent acute reduction in eGFR (baseline to WK4, as a result of inhibition of renal creatinine secretion), and at the 18 mg dose resulted in 75% reduction in the slope of chronic eGFR decline (WK4 to WK48) compared to placebo. This analysis characterizes the pharmacokinetic-pharmacodynamic (PK/PD) relationships observed in this study.

Methods

Subjects were administered 2, 6, or 18 mg SEL, or placebo once daily for 48 WKs. Serum creatinine based eGFR was assessed at baseline and throughout treatment. Samples were collected for plasma exposure of SEL (AUC_tau by population PK) and phosphorylation status of p38 (%P-p38: downstream marker of ASK1 inhibition) in blood. PK/PD relationships for SEL exposure, %P-p38 and eGFR were characterized.

Results

260 subjects with measureable SEL AUC_tau,%P-p38, and eGFR estimates were included in this analysis. SEL PK/PD relationships (figure) depict the acute and chronic changes in eGFR versus SEL exposure or dose (A) and %P-p38 (B), respectively. Mean exposure from SEL 18 mg provided near maximal %P-p38 inhibition (74% of E_max), and resided on the flat portion of the exposure-response curve for effect on chronic eGFR slope.

Conclusion

These PK/PD analyses provide further understanding of the relationships between SEL, ASK1 pathway inhibition, acute change and chronic slope of eGFR, supporting further clinical evaluation of the safety and efficacy of SEL 18 mg in subjects with DKD.

Funding

• Commercial Support – Gilead Sciences Inc.