Netherlands: ZENITH-CKD Trial Findings

A combination of zibotentan and dapagliflozin reduced albuminuria with an acceptable safety and tolerability profile, according to phase IIb ZENITH-CKD trial. Therefore, it could be an option to reduce the progression of chronic kidney disease (CKD) in patients already receiving currently recommended therapy.

"By week 12 of treatment, patients on 1.5 mg zibotentan plus dapagliflozin had a -33.7% difference in urinary albumin-to-creatinine ratio (UACR) versus dapagliflozin (Farxiga) added onto placebo," the researchers reported in The Lancet.

In previous studies, SGLT2 inhibitors and endothelin A receptor antagonists (ERAs) have been shown to reduce albuminuria and glomerular filtration rate (GFR) decline in CKD patients. Prof Hiddo J L Heerspink, University of Groningen, University Medical Center Groningen, Groningen, Netherlands, and colleagues assessed the albuminuria-lowering safety and efficacy of the ERA zibotentan combined with the SGLT2 inhibitor dapagliflozin.

ZENITH-CKD was a randomised, multicentre, double-blind, active-controlled clinical trial, conducted in 170 clinical practice sites in 18 countries. It included adults with an estimated GFR (eGFR) of 20 mL/min per 1·73 m² or greater and a UACR of 150–5000 mg/g. 449 participants were randomly assigned in the ratio of 2:1:2 to 12 weeks of daily treatment with:

• zibotentan 1·5 mg plus dapagliflozin 10 mg (n=179)
• zibotentan 0·25 mg plus dapagliflozin 10 mg (n=91)
• dapagliflozin 10 mg plus placebo (n=177) as an adjunct to angiotensin receptor blockers or angiotensin-converting enzyme inhibitors if tolerated

The primary endpoint of the study was determined as a change from baseline in log-transformed UACR (zibotentan 1·5 mg plus dapagliflozin vs dapagliflozin plus placebo) at week 12. Fluid retention was an event of special interest and defined as an increase in body weight of at least 3% from baseline or a rise of at least 100% in B-type natriuretic peptide (BNP) and either a BNP concentration greater than 200 pg/mL if without atrial fibrillation or BNP greater than 400 pg/mL if with atrial fibrillation.

Based on the study, the researchers reported the following findings:

• Zibotentan 1·5 mg plus dapagliflozin and zibotentan 0·25 mg plus dapagliflozin reduced UACR versus dapagliflozin plus placebo throughout the treatment period of the study.
• At week 12, the difference in UACR versus dapagliflozin plus placebo was –33·7% for zibotentan 1·5 mg plus dapagliflozin and –27·0% for zibotentan 0·25 mg plus dapagliflozin.
• Fluid-retention events were observed in 18% of 179 participants in the zibotentan 1·5 mg plus dapagliflozin group, 9% of 91 in the zibotentan 0·25 mg plus dapagliflozin group, and 8% of 177 in the dapagliflozin plus placebo group.

Zibotentan was described as the most potent and selective endothelin A receptor antagonist developed to date. However, endothelin A receptor antagonists cause oedema and fluid retention, so it was paired with an SGLT2 inhibitor, which has both renoprotective properties and diuretic effects. Other ERAs in development or on the market today include sparsentan and atrasentan.

"The fluid retention profile of a low-dose combination supports further clinical trials," the researchers wrote. "Results of these larger and longer studies in high-risk CKD populations are awaited."