Combination Zibotentan/Dapagliflozin Reduces Albuminuria in CKD

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Results of the ZENITH-CKD trial provide evidence of the safety and efficacy profile of combination zibotentan plus dapagliflozin in patients with chronic kidney disease.

Data from the ZENITH-CKD trial demonstrated use of zibotentan/dapagliflozin combination was associated with a statistically significant reduction in albuminuria among patients with chronic kidney disease (CKD) and proteinuria.

Results of the study, which were presented at the American Society of Nephrology Kidney Week 2023, provide evidence of a 52.5% reduction with high-dose and 47.7% reduction with low-dose combination compared to baseline, with those receiving the low-dose form of the combination agent experiencing comparable fluid retention events to dapagliflozin alone. In a press release, AstraZeneca announced plans to further examine the agent in a phase 3 trial expected to begin before 2024.1,2

“Elevated levels of albuminuria are associated with an increased risk of kidney function loss over time and by reducing the level, we can lower the risk of progression to kidney failure. Today’s encouraging data from the ZENITH-CKD trial show therapeutic potential to help patients who remain at risk due to residual albuminuria by harnessing the beneficial aspects of an ETA receptor antagonist with an SGLT2 inhibitor,” said Hiddo Heerspink, PhD, of the Department of Clinical Pharmacy and Pharmacology at the University of Groningen and University Medical Center Groningen.2

A randomized, double-blind phase 2b trial conducted at 170 sites in 18 countries, ZENITH-CKD was launched with the intent of evaluating the efficacy, safety, and tolerability of zibotentan/dapagliflozin in patients with CKD. For inclusion in the trial, patients were required to be between 18 to 90 years of age, have an eGFR of 20 mL/min/1.73m2 or greater, and a UACR of 150 to 5000 mg/g.1

Per trial protocol, patients were randomized in a 2:1:2 ration to receive zibotentan 1.5 mg plus dapagliflozin 10 mg, zibotentan 0.25 mg plus dapagliflozin 10 mg, or dapagliflozin 10 mg plus placebo, as an adjunct therapy to ACEi/ARBs for 12 weeks.1

The trial’s primary endpoint was change from baseline in log-transformed UACR at week 12. Fluid retention events were also assessed as an event of interest as part of the trial. For the purpose of analysis, this was defined as an increase in bodyweight of at least 3% from baseline or an increase of at least 100% in 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.1

In total, 1492 patients were assessed for eligibility from April 28, 2021, to January 17, 2023. Of these, 449 underwent randomization and 447 received at least 1 study dose. This cohort had a mean age of 62.8 years (Standard Deviation [SD], 12.1], 31% were female, and 68% were White. Investigators noted the cohort had a mean eGFR of 46.7 (SD, 22.4) mL/min/1.73m2 and median of UACR 565.5 (IQR, 243.0 to 1212.6) mg/g.1

Upon analysis, results suggested the difference in UACR at week 12 relative to dapagliflozin plus placebo was –33.7% (90% Confidence Interval [CI], –42.5 to –23.5; P <.0001) for zibotentan 1.5 mg plus dapagliflozin and –27.0% (90% CI, –38.4 to –13.6; P=.0022) for zibotentan 0.25 mg plus dapagliflozin. When assessing fluid retention events in the trial, investigators highlighted these events were observed in 18% of the zibotentan 1.5 mg plus dapagliflozin group, 9% of the zibotentan 0.25 mg plus dapagliflozin group, and 8% of the dapagliflozin plus placebo group.1

“Despite current treatment options, residual proteinuria persists in a sizeable portion of patients and is associated with a high risk of kidney failure. The evidence published today supports advancement of zibotentan/dapagliflozin into a Phase III clinical trial to further assess its potential as a first-in-class treatment for residual proteinuria in CKD,” said Sharon Barr, executive vice president of BioPharmaceuticals Research and Development at AstraZeneca.2