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Studies with Zenith-CKD showed significant albuminuria reduction.
The combination of zibotentan/dapagliflozin (AstraZeneca) produced a significant decrease in albuminuria in patients with chronic kidney disease (CKD) and proteinuria during its Phase IIb Zenith-CKD trial. According to AstraZeneca, the trial showed a 52.5% reduction with the high-dose combination and 47.7% reduction with the low-dose combination compared to baseline, and an acceptable tolerability profile.1
“Despite current treatment options, residual proteinuria persists in a sizeable portion of patients and is associated with a high risk of kidney failure,” said Sharon Barr, EVP, BioPharmaceuticals R&D, AstraZeneca, in a press release. “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.”
Patients with CKD experience a gradual loss of kidney function, which affects the ability to filter wastes and excess fluids from the blood that exit the body in urine. In patients with advanced CKD, dangerous levels of fluid, electrolytes, and waste, can build up in the body.2
Patients with early-stage CKD may experience few signs or symptoms and potentially may not realize they have the disease until it reaches the advanced stage. CKD treatment typically focuses on inhibiting the progression of kidney damage; however, controlling the cause may not prevent damage progression. CKD can lead to death as it progresses to end-stage kidney failure, which is requires dialysis or transplantation to prevent mortality.2
The National Kidney Foundation estimates that 37 million US adults have CKD, with millions of other individuals carrying an elevated risk. Progression can be inhibited by early detection to help prevent the disease from causing kidney failure. Whereas heart disease is the main cause of death for patients with CKD, its main causes are diabetes and high blood pressure, which is responsible for two-thirds of chronic kidney disease cases.
Other causes of CKD include glomerulonephritis, inherited diseases such as polycystic kidney disease, kidney and urinary tract abnormalities before birth, and autoimmune diseases, including lupus nephritis.3
As reported by the ZENITH-CKD trial, after 12 weeks of treatment, the UACR difference of zibotentan/dapagliflozin versus dapagliflozin alone (n=177) was –33.7% (90% CI –42.5 to –23.5; p<0.001) for high dose (1.5 mg zibotentan / 10 mg dapagliflozin; n=179) and –27.0% (90% CI –38.4 to –13.6; p=0.002) for low dose (0.25 mg / 10 mg; n=91). The percentage mean change from baseline in UACR was –52.5% (90% CI –59.0 to –44.9) for high-dose and –47.7% (90% CI –55.7 to –38.2) for low-dose combination.1
“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,” said Hiddo Heerspink, Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. “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.”
1. Zibotentan/dapagliflozin combination demonstrated significant albuminuria reduction in patients with chronic kidney disease and proteinuria in ZENITH-CKD Phase IIb trial. AstraZeneca. November 3, 2023. Accessed November 6, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/zibotentan-dapagliflozin-combination-demonstrated-significant-albuminuria-reduction-in-patients-with-chronic-kidney-disease-and-proteinuria-in-zenith-ckd-phase-IIb-trial.html
2. Mayo Clinic. Chronic kidney disease: Symptoms and causes. Available at: https://www.mayoclinic.org/diseases-conditions/chronic-kidney-disease/symptoms-causes/syc-20354521. Accessed November 7, 2023.
3. National Kidney Foundation. About Chronic Kidney Disease. Available at: https://www.kidney.org/atoz/content/about-chronic-kidney-disease. Accessed November 7, 2023.