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Kidney Week

Abstract: TH-PO1203

Soluble Tumor Necrosis Factor Receptor 1 (sTNFR1) Is Prognostic for ESRD over 48 Weeks in a Randomized Clinical Trial in Moderate to Advanced Diabetic Kidney Disease (DKD)

Session Information

Category: Diabetic Kidney Disease

Authors

  • Tarrant, Jacqueline, Gilead Sciences, Inc., Foster City, California, United States
  • Vestergaard, Lene, Gilead Sciences, Inc., Foster City, California, United States
  • Elboudwarej, Emon, Gilead Sciences, Inc., Foster City, California, United States
  • Tian, Yuan, Gilead Sciences, Inc., Foster City, California, United States
  • Chen, Fang, Gilead Sciences, Inc., Foster City, California, United States
  • Patterson, Scott D., Gilead Sciences, Inc., Foster City, California, United States
  • Patel, Uptal D., Gilead Sciences, Inc., Foster City, California, United States
  • Pergola, Pablo E., Renal Associates, P.A., San Antonio, Texas, United States
  • Chertow, Glenn Matthew, Stanford University School of Medicine, Palo Alto, California, United States
  • Skupien, Jan, Jagiellonian University Medical College, Krakow, Poland
  • Krolewski, Andrzej S., Joslin Diabetes Center, Boston, Massachusetts, United States
Background

Serum sTNFR1 associates with progression to ESRD in natural history studies of DKD. A predefined sTNFR1 cutpoint has been proposed as a potential patient selection criterion for clinical trials. We conducted a pre-planned retrospective analysis of the prognostic power of sTNFR1 over 48 weeks (48W) in a Phase 2 trial of selonsertib (SEL) in patients with DKD at high risk of progression based on estimated glomerular filtration rate (eGFR) and albuminuria.

Methods

The Phase 2 SEL trial comprised 333 patients randomized 1:1:1:1 to receive SEL (2, 6, or 18 mg) or matching placebo for 48W. Serum sTNFR1 and UACR cut-points previously described in Joslin type 1 DKD (T1DKD n=279) and T2DKD (n=221) cohorts (Yamanouchi M, et al. Kidney Int 2017;92:258) were applied to evaluate risk of the composite endpoint: ESRD, 40% decrease in eGFR, or nonrenal death. Cox proportional hazards models compared event rates by sTNFR1. Results were then evaluated in propensity score matched patients by age, sex and race.

Results

The proportion of the Phase 2 SEL trial patients categorized as high risk based on sTNFR1 >4.3 ng/mL was higher than the Joslin cohorts combined (60% vs 33%, p<0.001 as was the high risk subgroup with UACR > 1900mg/g and sTNFR1 >2.9≤4.3ng/mL (8% vs 6%, p<0.01. In the SEL trial, we observed 32 events, with annualized event rates of 15% vs 3% in patients above or below sTNFR1 4.3 ng/mL, respectively (p=0.002). Comparable event rates were observed in the subpopulation of matched SEL trial and Joslin T2DKD patients (n=121 pairs, 21% vs 4% and 21% vs 8%, respectively). Further, each standard deviation increase of sTNFR1 was associated with a higher risk of the composite endpoint in the full SEL trial (HR 1.64, 95% CI 1.12-2.41) and full Joslin T2DKD cohort (HR 1.76, 95% CI 1.31-2.38).

Conclusion

We validated a predefined cutpoint of serum sTNFR1 associated with a higher event rate in a DKD trial population already selected for high risk based on eGFR and albuminuria criteria. sTNFR1 may improve the efficiency of DKD trial design as a patient stratification or selection biomarker.

Funding

  • Commercial Support