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Effects of Selonsertib in Patients with Diabetic Kidney Disease.

Authors
  • Chertow, Glenn M1
  • Pergola, Pablo E2
  • Chen, Fang3
  • Kirby, Brian J3
  • Sundy, John S3
  • Patel, Uptal D3
  • 1 Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California; [email protected]
  • 2 Renal Associates PA, San Antonio, Texas; and.
  • 3 Gilead Sciences, Inc., Foster City, California.
Type
Published Article
Journal
Journal of the American Society of Nephrology
Publisher
American Society of Nephrology
Publication Date
Oct 01, 2019
Volume
30
Issue
10
Pages
1980–1990
Identifiers
DOI: 10.1681/ASN.2018121231
PMID: 31506292
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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. Although the trial did not meet its primary endpoint, exploratory post hoc analyses suggest that selonsertib may slow diabetic kidney disease progression. Copyright © 2019 by the American Society of Nephrology.

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