More than a decade after AstraZeneca appeared to give up hope of using zibotentan to treat prostate cancer, the endothelin receptor antagonist has received a new lease on life as a combo treatment for chronic kidney disease (CKD) patients.
A combo treatment of 1.5 mg zibotentan and 10 mg of the Big Pharma’s blockbuster CKD and diabetes drug Farxiga was shown to induce a 52% mean reduction in albumin-to-creatinine ratio (UACR)—an indicator of albuminuria—compared to baseline after 12 weeks of treatment.
A combo with a lower, 0.25-mg dose of zibotentan resulted in a similar 47.7% reduction in UACR, AstraZeneca demonstrated in data from a 447-patient phase 2b study presented at the American Society of Nephrology Kidney Week.
When compared to Farxiga alone, the high-dose combo saw a 33.7% greater reduction in UACR, with the lower dose seeing a 27% greater reduction.
High proteinuria—a high level of protein in urine—affects around 10% of patients with CKD and is associated with a higher risk of heart attack and kidney failure, AstraZeneca noted in its Nov. 3 release.
Zibotentan works by improving kidney blood flow and reducing albuminuria and vascular stiffness. However, one issue with endothelin A receptor antagonists that has been identified in other clinical trials has been high rates of fluid retention. While the high-dose cohort in the zibotentan/Farxiga trial also saw an 18.4% rate of these events, the low-dose cohort saw a lower rate of 8.8%, close to the 7.9% rate among the Farxiga monotherapy cohort, AstraZeneca noted.
Today’s results suggest that AstraZeneca’s persistence with zibotentan has paid off after the drug suffered a pair of late-stage trial failures in prostate cancer in 2010 and 2011. Now, the company plans to kick off a phase 3 trial of the combo treatment in CKD before the end of the year.
“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,” Sharon Barr, executive vice president of biopharmaceuticals R&D at AstraZeneca, said in the release.
“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,” Hiddo Heerspink, Ph.D., of the department of clinical pharmacy and pharmacology at the Netherlands’ University of Groningen added in the same release.