ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

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


  • 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

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.


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.


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).


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


  • Government Support - Non-U.S.