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Kidney Week

Abstract: FR-OR112

ZENITH-CKD: A Phase 2B Study of Zibotentan in Combination with Dapagliflozin and Dapagliflozin Alone in Patients with CKD

Session Information

Category: CKD (Non-Dialysis)

  • 2302 CKD (Non-Dialysis): Clinical, Outcomes, and Trials

Authors

  • Heerspink, Hiddo Jan L., Universiteit Groningen Faculteit Medische Wetenschappen, Groningen, Groningen, Netherlands
  • Kiyosue, Arihiro, EKI Center Building Clinic, Tokyo, Japan
  • Wheeler, David C., University College London, London, United Kingdom
  • Lin, Min, AstraZeneca, Gothenburg, Sweden
  • Wijkmark, Emma, AstraZeneca, Gothenburg, Sweden
  • Carlson, Glenn F, AstraZeneca, Gothenburg, Sweden
  • Mercier, Anne-Kristina, AstraZeneca, Gothenburg, Sweden
  • Åstrand, Magnus, AstraZeneca, Gothenburg, Sweden
  • Ueckert, Sebastian, AstraZeneca, Gothenburg, Sweden
  • Greasley, Peter J., AstraZeneca, Gothenburg, Sweden
  • Ambery, Philip D., AstraZeneca, Gothenburg, Sweden
Background

Despite treatment of CKD with RAS and SGLT2is, many patients have residual albuminuria which may be associated with rapid CKD progression. The albuminuria-lowering efficacy and safety of zibotentan, a selective ET-A receptor antagonist, were examined when administered concomitantly with an SGLT2i in a phase 2b dose-ranging trial.

Methods

ZENITH-CKD, a randomized, double-blind, active-controlled trial, was conducted in 170 clinical sites in 18 countries. Adults with a urinary albumin-creatinine ratio (UACR) of 150 to 5000 mg/g and eGFR ≥20 mL/min/1.73m2 not on SGLT2i were randomized to 1 of 6 treatment arms. Enrollment to 5 mg zibotentan monotherapy, 5 mg zibotentan/10 mg dapagliflozin, and placebo was discontinued at 62 participants. Enrollment continued across 3 other treatment arms: 0.25 mg/10 mg zibotentan/dapagliflozin, 1.5 mg/10 mg zibotentan/dapagliflozin, dapagliflozin/placebo 10 mg. The primary efficacy endpoint was change from baseline to week 12 in log-transformed UACR, assessed using mixed model repeated measures (in patients who received at least 1 dose of study treatment). Adverse events were recorded as safety endpoints. (NCT04724837)

Results

From April 28, 2021, to January 17, 2023, 447 patients were enrolled and received 0.25 mg/10 mg zibotentan/dapagliflozin (n=91), 1.5 mg/10 mg zibotentan/dapagliflozin (n=179), or 10 mg dapagliflozin/placebo (n=177). Overall, 58.4% of patients had type 2 diabetes, mean baseline eGFR was 46.7 mL/min/1.73m2, and geometric mean UACR was 538.3 mg/g. At week 12, vs dapagliflozin alone, adjusted percentage mean change in UACR was greater in the 0.25 mg/10 mg and 1.5 mg/10 mg zibotentan/dapagliflozin groups (-27.0% [90% CI -38.4%, -13.6%] and -33.7% [90% CI -42.5%, -23.5%]). No increase in BNP, body weight, or total body water was seen for the 0.25 mg/10 mg zibotentan/dapagliflozin group; modest increases were observed in the 1.5 mg/10 mg zibotentan/dapagliflozin group. One SAE of heart failure occurred in the 0.25 mg/10 mg zibotentan/dapagliflozin group and two occurred in the 1.5 mg/10 mg zibotentan/dapagliflozin group.

Conclusion

ZENITH-CKD confirmed 0.25 mg/10 mg zibotentan/dapagliflozin is highly effective in reducing albuminuria, is well tolerated, and could be an attractive option to further delay CKD progression.

Funding

  • Commercial Support – AstraZeneca (NCT04724837)