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Effects of Selonsertib in Patients with Diabetic Kidney Disease.

Publication ,  Journal Article
Chertow, GM; Pergola, PE; Chen, F; Kirby, BJ; Sundy, JS; Patel, UD; GS-US-223-1015 Investigators,
Published in: J Am Soc Nephrol
October 2019

BACKGROUND: Apoptosis signal-regulating kinase 1 (ASK1) activation in glomerular and tubular cells resulting from oxidative stress may drive kidney disease progression. Findings in animal models identified selonsertib, a selective ASK1 inhibitor, as a potential therapeutic agent. METHODS: In a phase 2 trial evaluating selonsertib's safety and efficacy in adults with type 2 diabetes and treatment-refractory moderate-to-advanced diabetic kidney disease, we randomly assigned 333 adults in a 1:1:1:1 allocation to selonsertib (oral daily doses of 2, 6, or 18 mg) or placebo. Primary outcome was change from baseline eGFR at 48 weeks. RESULTS: Selonsertib appeared safe, with no dose-dependent adverse effects over 48 weeks. Although mean eGFR for selonsertib and placebo groups did not differ significantly at 48 weeks, acute effects related to inhibition of creatinine secretion by selonsertib confounded eGFR differences at 48 weeks. Because of this unanticipated effect, we used piecewise linear regression, finding two dose-dependent effects: an acute and more pronounced eGFR decline from 0 to 4 weeks (creatinine secretion effect) and an attenuated eGFR decline between 4 and 48 weeks (therapeutic effect) with higher doses of selonsertib. A post hoc analysis (excluding data for 20 patients from two sites with Good Clinical Practice compliance-related issues) found that between 4 and 48 weeks, rate of eGFR decline was reduced 71% for the 18-mg group relative to placebo (difference 3.11±1.53 ml/min per 1.73 m2 annualized over 1 year; 95% confidence interval, 0.10-6.13; nominal P=0.043). Effects on urine albumin-to-creatinine ratio did not differ between selonsertib and placebo. CONCLUSIONS: Although the trial did not meet its primary endpoint, exploratory post hoc analyses suggest that selonsertib may slow diabetic kidney disease progression.

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Published In

J Am Soc Nephrol

DOI

EISSN

1533-3450

Publication Date

October 2019

Volume

30

Issue

10

Start / End Page

1980 / 1990

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Treatment Outcome
  • Pyridines
  • Protein Kinase Inhibitors
  • Middle Aged
  • Male
  • Imidazoles
  • Humans
  • Glomerular Filtration Rate
  • Female
 

Citation

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Chicago
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Chertow, G. M., Pergola, P. E., Chen, F., Kirby, B. J., Sundy, J. S., Patel, U. D., & GS-US-223-1015 Investigators, . (2019). Effects of Selonsertib in Patients with Diabetic Kidney Disease. J Am Soc Nephrol, 30(10), 1980–1990. https://doi.org/10.1681/ASN.2018121231
Chertow, Glenn M., Pablo E. Pergola, Fang Chen, Brian J. Kirby, John S. Sundy, Uptal D. Patel, and Uptal D. GS-US-223-1015 Investigators. “Effects of Selonsertib in Patients with Diabetic Kidney Disease.J Am Soc Nephrol 30, no. 10 (October 2019): 1980–90. https://doi.org/10.1681/ASN.2018121231.
Chertow GM, Pergola PE, Chen F, Kirby BJ, Sundy JS, Patel UD, et al. Effects of Selonsertib in Patients with Diabetic Kidney Disease. J Am Soc Nephrol. 2019 Oct;30(10):1980–90.
Chertow, Glenn M., et al. “Effects of Selonsertib in Patients with Diabetic Kidney Disease.J Am Soc Nephrol, vol. 30, no. 10, Oct. 2019, pp. 1980–90. Pubmed, doi:10.1681/ASN.2018121231.
Chertow GM, Pergola PE, Chen F, Kirby BJ, Sundy JS, Patel UD, GS-US-223-1015 Investigators. Effects of Selonsertib in Patients with Diabetic Kidney Disease. J Am Soc Nephrol. 2019 Oct;30(10):1980–1990.

Published In

J Am Soc Nephrol

DOI

EISSN

1533-3450

Publication Date

October 2019

Volume

30

Issue

10

Start / End Page

1980 / 1990

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Treatment Outcome
  • Pyridines
  • Protein Kinase Inhibitors
  • Middle Aged
  • Male
  • Imidazoles
  • Humans
  • Glomerular Filtration Rate
  • Female