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

• High-Impact Clinical Trials
  November 03, 2023 | Location: Hall A, Pennsylvania Convention Center
  Abstract Time: 11:30 AM - 11:45 AM

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

Hiddo Jan L. Heerspink,

• Kiyosue, Arihiro, EKI Center Building Clinic, Tokyo, Japan

Arihiro Kiyosue,

• Wheeler, David C., University College London, London, United Kingdom

David C. Wheeler,

• Lin, Min, AstraZeneca, Gothenburg, Sweden

Min Lin,

• Wijkmark, Emma, AstraZeneca, Gothenburg, Sweden

Emma Wijkmark,

• Carlson, Glenn F, AstraZeneca, Gothenburg, Sweden

Glenn F Carlson,

• Mercier, Anne-Kristina, AstraZeneca, Gothenburg, Sweden

Anne-Kristina Mercier,

• Åstrand, Magnus, AstraZeneca, Gothenburg, Sweden

Magnus Åstrand,

• Ueckert, Sebastian, AstraZeneca, Gothenburg, Sweden

Sebastian Ueckert,

• Greasley, Peter J., AstraZeneca, Gothenburg, Sweden

Peter J. Greasley,

• Ambery, Philip D., AstraZeneca, Gothenburg, Sweden

Philip D. Ambery,

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)