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Abstract: FR-PO451

Serum Soluble Tumor Necrosis Factor Receptor 1 (sTNFR1) Associates with Decline in Estimated Glomerular Filtration Rate (eGFR) Slope in a Phase 2 Study of Selonsertib in Diabetic Kidney Disease (DKD)

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Tarrant, Jacqueline, Gilead Sciences, Foster City, California, United States
  • Billin, Andrew, Gilead Sciences, Inc., Foster Cuty, California, United States
  • Xiao, Yuanyuan, Gilead Sciences, Foster City, California, United States
  • Peach, Matthew, Gilead Sciences, Inc., Foster Cuty, California, United States
  • Chen, Fang, Gilead Sciences, Foster City, California, United States
  • Patterson, Scott D., Gilead Sciences, Inc., Foster Cuty, California, United States
  • Sundy, John, Gilead Sciences, Inc, Belmont, California, United States
  • Patel, Uptal D., Gilead Sciences, Inc., Foster Cuty, California, United States
  • Pergola, Pablo E., Renal Associates, PA, San Antonio, Texas, United States
  • Chertow, Glenn Matthew, Stanford University School of Medicine, Palo Alto, California, United States
Background

Circulating sTNFR1 is a promising biomarker of DKD severity and risk of progression. We investigated the disease associations and predictive effect of sTNFR1 in a Phase 2 study of selonsertib (SEL), a small molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1), in DKD.

Methods

In this study, 333 patients with moderate-to-advanced DKD (UACR 600 mg/g for stage 3a, UACR 300 mg/g for stage 3b, UACR 150 mg/g for stage 4) were randomized 1:1:1:1 to receive SEL (2, 6, or 18 mg) or matching placebo (PBO) orally once daily for 48 weeks (W48). The analysis population (full analysis set) excluded 2 sites for technical deviations and patients with baseline eGFR 20 mL/min/1.73m2. Serum sTNFR1 was measured at baseline (BL) and W48 by ELISA. Spearman correlation was used to assess association between markers, and a random slope model for differences in chronic eGFR slope (W4-W48) between treatments.

Results

Serum sTNFR1 was inversely correlated with eGFR at BL (N=261; r=-0.74; p<0.001) and at W48 (N=215; r=-0.75; p<0.001), in addition to change of sTNFR1 and change of eGFR at W48 (N=215; r=-0.35; p=0.0016). There was no significant relation between sTNFR1 and UACR at BL (N=261; r=0.12). We found a trend for a relatively lower increase in sTNFR1 from BL to W48 in the 18mg SEL group (median=0.12 ng/mL, Q1-Q3: -0.43 to 0.53 ng/mL; N=49) compared to PBO (median=0.31 ng/mL, Q1-Q3: -0.17 to 0.66 ng/mL; N=49). Applying a BL 4.3 ng/mL sTNFR1 cutpoint retrospectively (identified by Yamanounchi M, et al. Kidney Int 2017), 51% of our overall population were potentially at high risk for progression to end stage renal disease. The subgroup >4.3 ng/mL sTNFR1 had an apparent therapeutic benefit from SEL 18 mg compared to PBO when comparing eGFR chronic slope (W4 to 48) difference (p=0.029), however this was no different from the benefit shown overall (p=0.036).

Conclusion

Serum sTNFR1 was directly correlated with eGFR at BL and change at W48 in patients with moderate-to-advanced DKD. The subgroup with BL sTNFR1>4.3 ng/mL had similar treatment benefit to SEL compared to the overall trial population

Funding

  • Commercial Support