November 3, 2023 — Combination of zibotentan with dapagliflozin showed statistically significant and clinically meaningful reductions in urinary albumin-to-creatinine ratio (UACR), 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 (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.
These results were presented today at the American Society of Nephrology (ASN) Kidney Week 2023 and simultaneously published in The Lancet.1
Previous studies showed endothelin A (ETA) 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% (33/179), 8.8% (8/91) and 7.9% (14/177) of patients experiencing events in high-dose combination, low-dose combination and dapagliflozin groups, respectively.
Hiddo Heerspink, Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands, said: “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.”
Sharon Barr, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, 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 III clinical trial to further assess its potential as a first-in-class treatment for residual proteinuria in CKD.”
Nearly 850 million people worldwide—or more than 1 in 10 people—are affected by chronic kidney disease (CKD).3,4 High proteinuria affects approximately 10% of patients with CKD5 and is independently associated with higher cardiovascular mortality risk and progression to kidney failure,6-9 remaining a serious unmet need in this patient population.
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 (SGLT2) 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.16
These results support progress to Phase III, which aims to start in Q4 2023.
Proteinuria and albuminuria
Proteinuria describes levels of protein in the urine, which can include albumin, the most abundant circulating protein found in plasma.17 Proteinuria is associated with an increased risk of kidney function loss over time, leading to CKD.8 Clinical research has demonstrated that the level of proteinuria reduction positively correlates with long-term kidney protection; so, the larger the initial reduction in proteinuria in the first few months of treatment, the lower the risk of kidney failure during treatment.7,8 However, a number of patients carry residual proteinuria while on current SoC treatment and remain at risk for kidney disease progression.7
The Phase IIb ZENITH-CKD clinical trial is a randomised, double-blind study conducted across 18 countries to evaluate the efficacy, safety and tolerability of zibotentan/dapagliflozin in 447 patients with CKD, classified as an estimated glomerular filtration rate (eGFR) of ≥20 mL/min/1.73m2 and a urine albumin-to-creatinine ratio (UACR) between 150 and 5000 mg/g. The efficacy analysis reports data on patients who were randomised to three treatment arms evaluating 1) high-dose combination of zibotentan (1.5 mg) and dapagliflozin (10 mg), 2) low-dose combination of zibotentan (0.25 mg) and dapagliflozin (10 mg) and 3) dapagliflozin (10 mg) alone, taken daily over 12 weeks. Key endpoints include change from baseline in UACR at week 12 and fluid retention throughout the trial.
AstraZeneca in CVRM
Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s main disease areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys, liver and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection by slowing or stopping disease progression, and ultimately paving the way towards regenerative therapies. The Company’s ambition is to improve and save the lives of millions of people by better understanding the interconnections between CVRM diseases and targeting the mechanisms that drive them, so we can detect, diagnose and treat people earlier and more effectively.
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines in Oncology, Rare Disease and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca.
1. Heerspink HJL, et al. Zibotentan in combination with dapagliflozin compared to dapagliflozin alone in patients with chronic kidney disease: A randomised active-controlled clinical trial. Lancet. 2023. (In press).
2. Heerspink HJL, et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet. 2019;393(10184):1937-1947.
3. Jager KJ, et al. A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases. Kidney Int. 2019;96(5):1048-1050.
4. Kovesdy CP. Epidemiology of chronic kidney disease: an update 2022. Kidney Int Suppl (2011). 2022;12(1):7-11.
5. Murton M, et al. Burden of Chronic Kidney Disease by KDIGO Categories of Glomerular Filtration Rate and Albuminuria: A Systematic Review. Adv Ther. 2021;38(1):180-200.
6. Said S, et al. The link between chronic kidney disease and cardiovascular disease. J Nephropathol. 2014;3(3):99-104.
7. Oshima M, et al. Early change in albuminuria with canagliflozin predicts kidney and cardiovascular outcomes: A posthoc analysis from the CREDENCE Trial. J Am Soc Nephrol. 2020;31(12):2925-2936.
8. Heerspink HJL, et al. Albuminuria is an appropriate therapeutic target in patients with CKD: The pro view. Clin J Am Soc Nephrol. 2015;10(6):1079-88.
9. Gansevoort RT, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013;382(9889):339-52.
10. Davenport AP, et al. Endothelin. Pharmacol Rev. 2016;68(2):357-418.
11. Morris CD, et al. Specific inhibition of the endothelin A receptor with ZD4054: clinical and pre-clinical evidence. Br J Cancer. 2005;92(12):2148-52.
12. Kohan DE, et al. Endothelin and endothelin antagonists in chronic kidney disease. Kidney Int. 2014;86(5):896-904.
13. Raina R, et al. The role of endothelin and endothelin antagonists in chronic kidney disease. Kidney Dis (Basel). 2020;6(1):22-34.
14. FARXIGA® (dapagliflozin) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2023.
15. Amiguet M, et al. Dapagliflozin and short-term changes on circulating antigen carbohydrate 125 in heart failure with reduced ejection fraction. Sci Rep. 2023;13(1):10591.
16. Veenit V, et al. The sodium glucose co-transporter 2 inhibitor dapagliflozin ameliorates the fluid-retaining effect of the endothelin A receptor antagonist zibotentan. Nephrol Dial Transplant. 2023;38(10):2289-2297.
17. National Kidney Foundation. Albuminuria (proteinuria). https://www.kidney.org/atoz/content/albuminuria. (Accessed October 18 2023)
Posted: November 2023
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