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Kidney Week

Abstract: TH-PO925

The Acute Effect of Selonsertib on eGFR Is a Result of Creatinine Transport Inhibition, Not Alteration of Renal Function

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Weber, Elijah J., Gilead Sciences, Inc., Foster City, California, United States
  • Nelson, Cara H., Gilead Sciences, Inc., Foster City, California, United States
  • Kirby, Brian J., Gilead Sciences, Inc., Foster City, California, United States
  • Weng, Winnie, Gilead Sciences, Inc., Foster City, California, United States
  • Chen, Fang, Gilead Sciences, Inc., Foster City, California, United States
  • Patel, Uptal D., Gilead Sciences, Inc., Foster City, California, United States
  • Mathias, Anita, Gilead Sciences, Inc., Foster City, California, United States
Background

Selonsertib (SEL) is a first-in-class small molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1) in clinical development for the treatment of diabetic kidney disease (DKD). As small, dose-dependent, and reversible increases in serum creatinine were observed across clinical studies, an analysis of in vitro and clinical data was conducted to identify and confirm the mechanism by which SEL decreases estimated GFR (eGFR) without changing measured GFR (mGFR).

Methods

In vitro studies assessed the potential for SEL and its inactive metabolite, GS-607509, to inhibit renal transporters (OCT2, MATE1, and MATE2K) and determined their IC50 values. Clinical studies in healthy subjects included a multiple ascending dose (MAD) study (SEL 1 to 100 mg or placebo, QD) to assess the effects of SEL on eGFR. Additionally, a mechanistic study (SEL 18 mg or placebo, QD) evaluated the effect of SEL on renal function using iohexol to measure GFR before, during, and after treatment for 2 weeks. Meta-analyses of clinical studies were conducted to quantify the magnitude and consistency of the acute effect across patient populations.

Results

Based on the 2017 FDA drug interaction guidance, SEL and GS-607509 demonstrate low potential for inhibition of OCT2 (Cmax,u/IC50 > 0.1). SEL, but not GS-607509, is a potential inhibitor of MATE1 and MATE2K (Cmax,u/IC50 of > 0.02). In the MAD study, a dose-dependent reduction in eGFR was observed and was reversible upon washout of SEL (A). Results from the mechanistic study showed no change in mGFR for subjects taking SEL or placebo (B). Regardless of baseline eGFR, meta-analyses showed at the 18 mg dose, a consistent acute percent decrease (median 7.3%) in eGFR across patient populations.

Conclusion

The totality of data from in vitro and clinical studies indicate that the acute effect of SEL on eGFR is dose-dependent, reversible, and a result of inhibition of renal creatinine transporters without altering mGFR. Clinical trials evaluating the efficacy of SEL on slowing the loss of kidney function will need to account for these acute effects.

Funding

  • Commercial Support