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BOSTON -- The investigational agent seladelpar improved markers of disease activity and pruritus in patients with primary biliary cholangitis (PBC) at risk of disease progression, a phase III trial presented here showed.

At 12 months, 61.7% of patients treated with the peroxisome proliferator-activated receptor (PPAR) delta agonist met the study's composite biochemical response endpoint compared with 20% of those who received placebo (P<0.0001), reported Gideon Hirschfield, PhD, of the Toronto Centre for Liver Disease at the University of Toronto, during a late-breaking abstract session at the American Association for the Study of Liver Diseases annual meeting.

As for pruritus, which Hirschfield called "a significant priority for our patients who want, and deserve, a better quality of life," there was a "highly significant, clinically meaningful improvement" with seladelpar.

Among patients with a baseline pruritus numerical rating scale (NRS) score ≥4 (with 0 representing no itch and 10 the "worst imaginable itch"), those in the seladelpar group had a change of -3.2 at 6 months compared with a change of -1.7 in the placebo group. "Furthermore, if you follow these patients on to the end of the 12 months of our placebo-controlled study, the change in pruritus NRS over time ... continues to demonstrate statistical improvement with seladelpar," Hirschfield said.

"These are very exciting results for people living with PBC," he added.

Seladelpar is a first-in-class, oral, selective PPAR delta agonist designed to target multiple cell types and processes in PBC.

The trial's primary endpoint was a composite response of alkaline phosphatase (ALP) <1.67 times the upper limit of normal (ULN), an ALP decrease ≥15%, and total bilirubin <1 times the ULN at month 12.

Hirschfield reported that ALP levels fell by 42.4% (-133.9 U/L) with seladelpar compared with just 4.3% (-16.9 U/L) at 12 months with placebo.

ALP normalization was 25% with seladelpar at 12 months compared with 0% with placebo (P<0.0001). "This is important because studies from the Global PBC [Study] Group have shown that patients who normalize their [ALP] have the best outcomes," Hirschfield said.

Patients treated with seladelpar also had significant declines in alanine aminotransferase, gamma-glutamyl transferase, low-density lipoprotein cholesterol, and triglyceride levels.

Hirschfield also noted that the reductions in pruritus were accompanied by improvements in sleep disturbance. "This is again a very important observation for patients living with PBC," he said, adding that this was evident not only in patients who had baseline NRS scores of ≥4, but in the entire study population.

The was a double-blind, placebo-controlled, global study of 1-year duration that randomized 193 PBC patients in a 2:1 ratio to seladelpar 10 mg or placebo once daily.

Eligible patients had an inadequate response or were intolerant to ursodeoxycholic acid (currently the standard first-line therapy for PBC) and elevated serum biochemistry. In addition, compensated cirrhosis was allowed.

Patients had an average age of 57 years, and more than 90% were women, without about one-third having significant pruritus. Both cohorts had mean baseline ALP levels over 300 U/L.

Regarding safety, the percentage of patients with at least one adverse event (AE) was comparable between the seladelpar and placebo groups (86.7% vs 84.6%, respectively). Serious AEs occurred in 7% and 6.2%, respectively, while AEs leading to study drug discontinuation occurred in 3.1% and 4.6%.

Pruritus was reported as an AE in 4.7% of patients in the seladelpar group compared with 15.4% of those in the placebo group.

"Importantly, there was no difference in liver-related AEs, and no difference in muscle-related AEs," Hirschfield said. "Key to this observation was that 96% of eligible patients completing treatment agreed to enter the ."

Last month, the drug's developer CymaBay Therapeutics announced that based on the statistically significant improvement in PBC-related cholestatic pruritus demonstrated in RESPONSE, the to now reflect treatment of PBC including pruritus in adults without cirrhosis or with compensated cirrhosis.

In an , CymaBay CEO Sujal Shah said the company would likely file for regulatory approval for seladelpar early next year.

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