AstraZeneca: Zibotentan/dapagliflozin combination shows albuminuria reduction

Combination of zibotentan with dapagliflozin showed statistically significant and clinically meaningful reductions in urinary albumin-to-creatinine ratio, used to assess albuminuria, at 12 weeks compared with dapagliflozin alone. After 12 weeks of treatment, the Phase IIb ZENITH-CKD trial showed that 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 -52.5% for high-dose and -47.7% for low-dose combination. These results were presented today at the American Society of Nephrology Kidney Week 2023 and simultaneously published in The Lancet. Previous studies showed endothelin A receptor antagonists are associated with high rates of fluid retention.2 The results from ZENITH-CKD showed low-dose zibotentan/dapagliflozin, but not high-dose, had comparable fluid retention events to dapagliflozin alone, with 18.4%, 8.8% and 7.9% of patients experiencing events in high-dose combination, low-dose combination and dapagliflozin groups, respectively. This novel investigational therapy leverages zibotentan, a highly selective ETA receptor antagonist that works by improving kidney blood flow and reducing albuminuria and vascular stiffness,10-13 and dapagliflozin, a selective sodium-glucose cotransporter 2 inhibitor proven to help delay the worsening of CKD in patients at risk of progression.14 Dapagliflozin works by driving fluid out of the extravascular space,15 potentially leading to a further reduction in the risk of fluid retention. These results support progress to Phase III, which aims to start in Q4 2023.