Kidney Week

Abstract: TH-PO1148

Effects of Selonsertib in Patients with Diabetic Kidney Disease (DKD)

Session Information

• Late-Breaking Clinical Trials Posters
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• No subcategory defined

Authors

• Chertow, Glenn Matthew, Stanford University School of Medicine, Palo Alto, California, United States

Glenn Matthew Chertow,

• Pergola, Pablo E., Renal Associates, PA, San Antonio, Texas, United States

Pablo E. Pergola,

• Chen, Fang, Gilead Sciences, Inc., Foster City, California, United States

Fang Chen,

• Kirby, Brian J., Gilead Sciences, Inc., Foster City, California, United States

Brian J. Kirby,

• Sundy, John, Gilead Sciences, Inc., Foster City, California, United States

John Sundy,

• Patel, Uptal D., Gilead Sciences, Inc., Foster City, California, United States

Uptal D. Patel,

Group or Team Name

• GS-US-223-1015 Investigators

Background

Increased oxidative stress in the kidney and the resulting activation of apoptosis signal-regulating kinase 1 (ASK1) in glomerular and tubular cells has been implicated in progression of acute and chronic kidney diseases. This Phase 2 trial evaluated the safety and efficacy of selonsertib (SEL), a potent and selective ASK1 inhibitor, in 334 pts with treatment-refractory moderate to advanced DKD.

Methods

Pts were randomized to receive SEL (2, 6, or 18 mg oral daily) or PBO. Primary outcome was change from baseline eGFR with SEL compared with PBO at 48 wks.

Results

SEL appeared safe with no dose-dependent adverse effects over 48 wks. Although there was no significant difference in SEL group mean (±SE) eGFR compared with PBO (0.38±1.21, 0.84±1.22, and -0.87±1.23 mL/min/1.73m² in the 2-, 6-, and 18-mg groups, respectively; p>0.4 for all pairwise comparisons; n=333 dosed; full analysis set [FAS]), differences in eGFR at 48 wks were confounded by acute effects related to SEL’s inhibition of creatinine secretion. To account for this unanticipated effect, we used piecewise linear regression and found two dose-dependent effects: an acute, more pronounced decline in eGFR from 0-4 wks (creatinine secretion effect) and an attenuated decline in eGFR between 4-48 wks (therapeutic effect) seen with higher doses of SEL. Between 4-48 wks, rate of eGFR decline was reduced 71% for the 18-mg group relative to PBO (difference 3.11±1.53 mL/min/1.73m² annualized over 1 year, 95% CI, 0.10-6.13; nominal p=0.043; n=313; FAS excluding data from 2 sites with GCP compliance findings).

Conclusion

Although the trial did not meet its primary pre-specified endpoint, post-hoc analyses indicate that SEL appears to slow the progression of DKD (ClinicalTrials.gov: NCT02177786).

Figure 1 Adjusted Mean (95% CI) Change in eGFR (MDRD)

Funding

• Commercial Support – Gilead Sciences, Inc.