Efficacy and safety of zibotentan and dapagliflozin in patients with chronic kidney disease: study design and baseline characteristics of the ZENITH-CKD trial

Abstract

Background Sodium–glucose co-transporter 2 inhibitors (SGLT2is) are part of the standard of care for patients with chronic kidney disease (CKD), both with and without type 2 diabetes. Endothelin A (ETA) receptor antagonists have also been shown to slow progression of CKD. Differing mechanisms of action of SGLT2 and ETA receptor antagonists may enhance efficacy. We outline a study to evaluate the effect of combination zibotentan/dapagliflozin versus dapagliflozin alone on albuminuria and estimated glomerular filtration rate (eGFR). Methods We conduct a double-blind, active-controlled, Phase 2b study to evaluate the efficacy and safety of ETA receptor antagonist zibotentan and SGLT2i dapagliflozin in a planned 415 adults with CKD (ZENITH-CKD). Participants are being randomized (1:2:2) to zibotentan 0.25 mg/dapagliflozin 10 mg QD, zibotentan 1.5 mg/dapagliflozin 10 mg QD, and dapagliflozin 10 mg QD alone, for 12 weeks followed by a 2-weeks off-treatment wash-out period. The primary endpoint is the change in log-transformed urinary albumin-to-creatinine ratio (UACR) from baseline to Week 12. Other outcomes include change in blood pressure from baseline to Week 12 and change in eGFR the study. The incidence of adverse events will be monitored. Study protocol defined events of special interest include changes in fluid-related measures (weight gain or B-type natriuretic peptide). Results A total of 459 patients were randomized and received treatment in placebo/dapagliflozin (n = 181), zibotentan 0.25 mg/dapagliflozin (n = 94), and zibotentan 1.5 mg/dapagliflozin (n = 184). The mean age was 62.9 years, 30.0% were female and 66.4% were White. At baseline, the mean eGFR of the enrolled population was 47.0 mL/min/1.73 m2 and the geometric mean UACR was 532 mg/g. Conclusion This study evaluates the UACR lowering efficacy and safety of zibotentan with dapagliflozin as a potential new treatment for CKD. The study will provide information about an effective and safe zibotentan dose to be further investigated in a Phase 3 clinical outcome trial. Clinical Trial Registration Number: NCT04724837

Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection

“…An increased production of the potent vasoconstrictor ET-1 contributes to cardiorenal risk in patients with DKD, and therefore is an actual therapeutic target [105]. Based on rodent models of diabetes, ET-1 inhibition has kidney-protective effects through restoring the glomerular endothelium, preventing podocyte loss, and reducing glomerular hypertension and matrix expansion [38].…”

“…Based on rodent models of diabetes, ET-1 inhibition has kidney-protective effects through restoring the glomerular endothelium, preventing podocyte loss, and reducing glomerular hypertension and matrix expansion [38]. ET-1 signals through two receptors: endothelin A (ETA) and endothelin B (ETB) [105]. Selective ETA antagonists are attractive, since the ETB receptor works to clear circulating ET-1 via the lungs, whereas antagonizing the ETA receptor can lower blood pressure, reduce fibrosis, and decrease kidney inflammation [105].…”

“…ET-1 signals through two receptors: endothelin A (ETA) and endothelin B (ETB) [105]. Selective ETA antagonists are attractive, since the ETB receptor works to clear circulating ET-1 via the lungs, whereas antagonizing the ETA receptor can lower blood pressure, reduce fibrosis, and decrease kidney inflammation [105]. ETA-RAs have also shown efficacy for reducing albuminuria and the risk of renal outcomes in patients with DKD, yet they are also associated with fluid retention.…”

Endothelin receptor antagonists in diabetic and non-diabetic chronic kidney disease

“…Part B would include an additional cohort randomized into the aforementioned four treatment arms and two additional arms consisting of zibotentan 0.25 mg and dapagliflozin 10 mg or zibotentan 1.5 mg and dapagliflozin 10 mg. However, an ad hoc safety review closed the randomization in groups receiving high-dose zibotentan (± dapagliflozin) due to the high rate of fluid-retention events, while randomization to the placebo arms was closed due to recent Kidney Disease: Improving Global Outcomes guidelines confirming SGLT2i as the standard of care in the management of CKD [ 47 , 48 ]. The trial design implemented stratified randomization to ensure that the non-diabetic CKD patients comprise 30–50% of patients in the stratum, approximately reflecting real-life incidences and ensuring a sufficient number of patients with this aetiology of CKD.…”

Anti-Anginal Efficacy of Zibotentan in the Coronary Slow-Flow Phenomenon

“…Initially designed for the treatment of prostate cancer [ 26 ], zibotentan is an ET-1 blocker that selectively inhibits the vasoconstricting Et-A receptor but not the Et-B receptor. It is currently being investigated as a potential therapeutic option for chronic kidney disease [ 27 ]. This pilot study assesses the anti-anginal impact of targeted Et-A receptor blockade with zibotentan in patients with CSFP.…”