AstraZeneca said that the combination of zibotentan with dapagliflozin has reduced urinary albumin-to-creatinine ratio (UACR) in patients with chronic kidney disease (CKD) and proteinuria in the ZENITH-CKD phase 2b trial.

Zibotentan is a highly selective ETA receptor antagonist that improves kidney blood flow and reduces albuminuria and vascular stiffness.

Dapagliflozin is said to be a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. It is designed to support the delay of worsening of CKD in patients at risk of progression.

The results showed statistically significant and clinically meaningful reductions in UACR, used to assess albuminuria, at 12 weeks compared with dapagliflozin alone.

The UACR difference of zibotentan/dapagliflozin versus dapagliflozin alone was –33.7% for high dose and –27.0% for low dose.

The percentage mean change from baseline in UACR was noted at –52.5% for high-dose and –47.7% for low-dose combination.

According to earlier studies, Endothelin A (ETA) receptor antagonists were found linked to increased rates of fluid retention.

In the ZENITH-CKD trial, the patients who received low-dose zibotentan/ dapagliflozin experienced fluid retention events that were comparable to those caused by dapagliflozin alone.

These patients included 18.4%, 8.8%, and 7.9% of those who received the high-dose combination, low-dose combination, and dapagliflozin, respectively.

AstraZeneca BioPharmaceuticals R&D EVP Sharon Barr said: “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 3 clinical trial to further assess its potential as a first-in-class treatment for residual proteinuria in CKD.”

The Phase 2b ZENITH-CKD study is a randomised, double-blind study conducted across 18 countries.

It has a goal to assess the efficacy, safety and tolerability of zibotentan/ dapagliflozin in 447 patients with CKD by randomising them into three treatment arms.

Key endpoints were defined as the change from baseline in UACR at week 12 and fluid retention across the clinical trial.

Based on these positive results, the pharmaceutical company plans to move forward to Phase 3, which is scheduled to begin in Q4 2023.