Clinical AstraZeneca’s zibotentan granted new life in CKD trial

AstraZeneca’s zibotentan granted new life in CKD trial


In a surprising turn of events, AstraZeneca’s once-forgotten drug, zibotentan, has found a new purpose in the world of medicine. More than a decade after it failed in late-stage trials for prostate cancer treatment, this endothelin receptor antagonist has been given a fresh lease on life as a potential treatment for chronic kidney disease (CKD). The breakthrough comes in the form of combination therapy with Farxiga, AstraZeneca’s blockbuster CKD and diabetes drug, presenting new hope for patients suffering from CKD-related complications.

During the American Society of Nephrology Kidney Week, a Phase 2b trial highlighted the impressive prospects of this combined therapy. Patients receiving a combo of 1.5 mg zibotentan and 10 mg of Farxiga experienced a substantial 52% mean reduction in their albumin-to-creatinine ratio (UACR) after just 12 weeks of treatment. UACR is a crucial indicator of albuminuria, a common issue in CKD patients.

Interestingly, even a lower dosage of 0.25 mg zibotentan in combination with Farxiga led to a remarkable 47.7% reduction in UACR, demonstrating the drug’s effectiveness in managing albuminuria. In comparison to using Farxiga alone, the high-dose combination therapy achieved a 33.7% greater reduction in UACR, while the lower dose achieved a 27% greater reduction.

Chronic kidney disease, a widespread health issue affecting millions worldwide, is often accompanied by the complication of high proteinuria, characterized by an excessive amount of protein in the urine. Approximately 10% of CKD patients suffer from high proteinuria, which is associated with an elevated risk of heart attacks and kidney failure. In this context, AstraZeneca’s new approach to managing albuminuria through zibotentan has the potential to change lives and prevent severe complications in CKD patients.

The mode of action for Zibotentan entails enhancing renal blood circulation while decreasing albuminuria and vascular rigidity. However, previous clinical trials involving endothelin A receptor antagonists have revealed a common issue: high rates of fluid retention. Despite this, the recent study has provided a glimmer of hope, as the high-dose combination therapy saw an 18.4% rate of fluid retention events, notably lower than previous expectations. The low-dose combination therapy fared even better, with an 8.8% rate, closely resembling the 7.9% rate observed in the Farxiga monotherapy cohort.

These promising results have ignited new enthusiasm at AstraZeneca, which has persistently pursued the potential of zibotentan, despite its past setbacks. Following failed late-stage trials for prostate cancer treatment in 2010 and 2011, the company now has plans to initiate a Phase 3 trial for the combination therapy in CKD by the end of the year. Sharon Barr, Executive Vice President of Biopharmaceuticals R&D at AstraZeneca, expressed her optimism, stating that “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.”

Hiddo Heerspink, Ph.D., of the University of Groningen, emphasized the significance of these findings by pointing out that elevated levels of albuminuria are linked to a higher risk of kidney function deterioration over time. Reducing these levels through the zibotentan/Farxiga combination therapy could help lower the risk of progression to kidney failure.

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