Exploring zibotentan plus dapagliflozin for cirrhosis

Data from the cirrhosis subpopulation in the ZENITH-CKD trial suggest that a combination of zibotentan and dapagliflozin may positively affect liver health. The authors argue that the mechanistic argument to treat patients with cirrhosis with this combination therapy is strong and should be further evaluated.

Dr Phil Ambery (AstraZeneca, Sweden) and co-investigators aimed to explore the effect of the endothelin A receptor antagonist zibotentan in combination with the SGLT2 inhibitor dapagliflozin on liver cirrhosis among participants included in the phase 2b ZENITH-CKD study. Of the 447 participants enrolled in this trial from 18 countries, 66 had an elevated Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score (>0.675). The participants were divided as follows: zibotentan 0.25 mg plus dapagliflozin, 10 mg (n=10); zibotentan 1.5 mg plus dapagliflozin 10 mg (n=29); placebo plus dapagliflozin 10 mg (n=27).

At week 12, the median NAFLD Fibrosis Score had dropped with only 0.09 points in the high-dose zibotentan arm but with 0.56 points in the low-dose zibotentan arm. In the placebo arm, the median NAFLD Fibrosis Score was reduced with 0.26 points. “I think that the fluid retention associated with zibotentan may masque the effect on the fibrosis score in the high-dose arm,” argued Dr Ambery. “Furthermore, in the phase 2a ZEAL study, investigating the combination of zibotentan and dapagliflozin in patients with liver cirrhosis, we saw a positive signal on the hepatic venous pressure gradient.”

Dr Ambery concluded that early, positive effects on markers of liver health were observed after 12 weeks of treatment with zibotentan and dapagliflozin among patients with chronic kidney disease who had elevated NAFLD Fibrosis scores.

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   1. Ambery P, et al. Reductions in the NFS from the ZENITH CKD trial support exploration of zibotentan dapagliflozin in cirrhosis. LB19, UEG Week 2024, 12–15 October, Vienna, Austria.

Medical writing support was provided by Robert van den Heuvel.
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Posted on 17 October 202417 October 2024