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WASHINGTON -- An investigational drug for primary biliary cholangitis (PBC) that had safety issues at high doses did better at lower doses, with good efficacy and fewer adverse events, a researcher said here.

A proof-of-concept study of the oral drug seladelpar was stopped after high doses were efficacious but also were linked to transient elevations of liver enzymes, according to Gideon Hirschfield, PhD, of the University of Birmingham in England.

Interim analysis of a phase II randomized trial with lower doses, however, showed similar efficacy without the safety issues, Hirschfield told a late-breaker session at the Liver Meeting, the annual conference of the

Indeed, at the lower doses -- 5 and 10 mg/day -- the drug decreased liver enzymes rather than elevating them, Hirschfield said.

The drug activates the peroxisome proliferator-activated receptor (PPAR) delta, which governs several biological processes and is thought to play a role in various chronic diseases, including diabetes, obesity, atherosclerosis, and some cancers.

It's hoped to be useful in PBC, Hirschfield said, because it appears to prompt improvements in bile acid secretion, homeostasis, liver fibrosis, inflammation, and metabolism.

The study findings are "encouraging," given that there are few treatment options for PBC, commented Raymond Chung, MD, of Massachusetts General Hospital in Boston, who was not part of the study but who co-moderated the session at which it was presented.

He added that people with PBC -- especially those who are refractory to current treatments -- are rare.

"What we hope to see -- given the pleotropic effects of this compound on bile acid synthesis, on cholesterol metabolism -- the hope is that this could be applied to other broader liver diseases, like non-alcoholic fatty liver," he told 名媛直播.

In the wake of the earlier trial, Hirschfield said, investigators enrolled 24 patients and randomly assigned them in an open-label fashion to either 5 or 10 mg of the drug. The goal was to see what effect the drug had on alkaline phosphatase, as well as on liver enzymes and total bilirubin.

The study population was at high risk for liver damage owing to PBC -- most were intolerant of the first-line drug for the condition, and all had highly elevated alkaline phosphatase and liver enzymes.

The study called for them to take the drug daily for 12 weeks and then to be rolled into an 18-week extension study with the option for dose adjustment if needed. Hirschfield presented interim outcomes after the first 12 weeks of therapy.

For both doses, he reported, alkaline phosphatase levels dropped sharply over the first 4 weeks, finishing 39% lower than baseline for the low dose and 45% lower for the high dose. There was no statistical difference between the groups.

At 12 weeks, 18% of those taking the low dose and 45% of those on the high dose had alkaline phosphatase below the upper limit of normal, he reported. The drug was also associated with reduced cholestasis, decreases in transaminases, lower LDL-cholesterol, and reduced inflammation, Hirschfield said.

On the tolerability front, the drug was not seen to increase risk of pruritus, one of the most troublesome symptoms of PBC, he said. There were no serious adverse events, he added.

In the light of the findings, Hirschfield said, the study design has been modified: The researchers will add participants to bring the total to 49 in each arm, and lengthen the extension study to 52 weeks.

As well, to see if efficacy can be obtained with even lower doses, the investigators will add a 2-mg arm with 18 patients.

A phase III trial is intended to start next year, he said.

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