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Kidney Week

Abstract: FR-OR089

Evaluation of the Endothelin A Receptor Antagonist Zibotentan in Systemic Sclerosis-Associated CKD

Session Information

  • Lupus and Then Some
    November 08, 2019 | Location: Ballroom C, Walter E. Washington Convention Center
    Abstract Time: 06:06 PM - 06:18 PM

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Stern, Edward, University College London, London, LOndon, United Kingdom
  • Host, Lauren V., University College London, London, LOndon, United Kingdom
  • Escott, Katherine J., AstraZeneca, Royston, United Kingdom
  • Gilmour, Peter S., AstraZeneca, Royston, United Kingdom
  • Wanjiku, Ivy, Royal Free Hospital, London, United Kingdom
  • Ochiel, Rachel, Royal Free Hospital, London, United Kingdom
  • Burns, Aine, Royal Free Hospital, London, United Kingdom
  • Unwin, Robert J., University College London, London, LOndon, United Kingdom
  • Ong, Voon, University College London, London, LOndon, United Kingdom
  • Denton, Christopher Paul, University College London, London, LOndon, United Kingdom
Background

Systemic sclerosis (SSc) causes scleroderma renal crisis (SRC) and chronic kidney disease (SSc-CKD). A previous open label trial of bosentan suggested possible benefit for CKD following SRC. We report the results of a placebo-controlled trial of zibotentan, a highly selective endothelin A receptor antagonist, in SSc-CKD.

Methods

ZEBRA-1 was a double-blind randomised placebo-controlled trial in SSc-CKD (eGFR 45-60 ml/min) comparing oral zibotentan 10 mg/day and placebo over 26 weeks with final assessment at 52 weeks (Clinical Trials NCT02047708). eGFR and candidate urinary molecular markers of SSc-CKD were measured at each time point and safety was a key secondary endpoint.

Results

16 patients consented with 3 screen failures due to ineligible eGFR on re-testing. 7 patients received placebo and 6 zibotentan. Baseline renal function was well-matched between groups—median eGFR in placebo 51 (44-58); zibotentan 50.5 (49-59). Renal function remained equal at 26 weeks—placebo 53 (37-58); zibotentan 54 (50-58)—but significantly improved in the active treatment group at 52 weeks—placebo 50 (36-55) zibotentan 60.5 (50-74), p=0.0082 (Figure 1).
Our previous work identified high urinary MCP-1 as a marker of SSc-CKD. In ZEBRA-1 levels declined on zibotentan but not on placebo. Median baseline MCP-1:creatinine (pg/mg/L) was 7.1 (5.2-21.9) in placebo and 5.4 (3.1-28.9) for zibotentan, increased to 8.8 (6.3-33.5) at 26 weeks on placebo and reduced to 4.4 (2.9-11.2) on zibotentan. At 52 weeks MCP-1:creatinine for placebo was 7.5 (6.4-15.8) and was significantly lower at 4.5 (4.1-6.0; p=0.0095) for zibotentan.
There were 46 reported adverse events (26 placebo and 20 zibotentan) with 6 serious adverse events (3 in each arm).

Conclusion

This is the first placebo-controlled clinical trial in renal SSc. Zibotentan treatment was safe and associated with improved eGFR and reduced urinary MCP-1 at 52 weeks compared to placebo. These prelimanary results suggest potential benefit from targeting endothelin A in SSc-associated CKD.

Figure 1. Impact of zibotentan or placebo on eGFR at baseline, 26 and 52 weeks

Funding

  • Government Support - Non-U.S.