April 19, 2010 (Vienna, Austria) — A new receptor agonist for regulation of bile acid synthesis significantly reduced alkaline phosphatase (ALP) levels in patients with primary biliary cirrhosis, according to research presented here at the European Association for the Study of the Liver (EASL) 45th Annual Meeting.
INT-747 (6-ethyl chenodeoxycholic acid or CDCA), used along with standard ursodeoxycholic acid (UDCA) treatment, reduced ALP levels by almost 25% in a double-blind, placebo-controlled study, but patients getting higher doses had problems with pruritus.
High ALP levels are associated with an increased risk for mortality in this patient population.
"We believe that this drug shows highly significant effects," said David Shapiro, MD, the chief medical officer of Intercept Pharmaceuticals, San Diego, California, which paid for the study.
Researchers say the findings could be the start of a whole new mode of treatment for the disease — an arena that began drawing the interest of researchers with the discovery of the farnesoid-X receptor (FXR) and the newfound role of bile acids in the health of the liver.
INT-747 is derived from the primary human bile acid CDCA, the natural ligand for the FXR. It is about 100 times more potent as an FXR agonist. In animal models, it has demonstrated choleretic and antifibrotic properties and has been shown to reduce portal hypertension.
Dr. Shapiro explained that the drug might fill a big need for primary biliary cirrhosis (PBC) patients.
"Ursodeoxycholic acid is the only drug approved for the treatment of PBC," he said. "And I think we’d all agree that this therapy has had a major impact on the disease. However, a substantial proportion of patients have an inadequate response, and there is a need for better therapies."
Study Design and Results
The study was conducted across 33 centers in 8 countries. Patients were an average of 55 years old, 95% of patients were female, and 96% were white.
All patients had definite (65%) or probable (35%) PBC. They also had consistently high ALP levels, greater than or equal to 1.5 to 10 times the upper limit of normal.
A total of 165 patients were randomized to INT-747, 10 mg, 25 mg, or 50 mg, or placebo, once daily for 12 weeks, given in combination with their existing UDCA treatment.
Those in the 10-mg group (38 patients) had an average reduction of 23.7% in ALP level. Those in the 25-mg group (47 patients) had an average reduction of 24.7%. In the 50-mg group, the reduction averaged 21.0% (P < .0001 in all cases compared with placebo).
Phosphoglycerate kinase levels decreased an average of 48% in the 10-mg group, 63% in the 25-mg group, and 57% in the 50-mg group (P < .0001 in all cases compared with placebo.)
Adverse Events Common
Pruritus was the most common adverse event, occurring in 50% of placebo patients, 47% of patients in the 10-mg group, 85% of patients in the 25-mg group, and 80% of patients in the 50-mg group. The more severe cases occurred in patients receiving the highest dose.
"In placebo, most of the patients had mild and a few moderate cases of pruritus, whereas with the top dose it was mainly severe or moderate," Dr. Shapiro told Medscape Gastroenterology. "Further, the onset of pruritus was related to the dose of the drug."
Serious adverse events were reported in 7 patients. Three of them were hepatic — gastrointestinal bleed from prior varices, PBC flare, and jaundice — and all occurred in the 50-mg group.
Session moderator Gustav Paumgartner, MD, of the University of Munich, Germany, said the next step should be to evaluate lower doses.
"There was no [dose-]response relationship, so it tells me that with regard to the desired effect, they were above the required dose," he explained. "Therefore, they can go down with the dose. And when they go down with the dose, I will expect that the adverse effects with regard to pruritus will be less."
The findings are a good sign for future treatment, Dr. Paumgartner said.
"It's absolutely novel; it is a rationally designed drug," he said. "Even if this will not be the decisive drug...it will move the field into a new direction. So, to me, it’s very exciting."
This study received commercial support from Intercept Pharmaceuticals. Dr. Shapiro is chief medical officer with Intercept. Dr. Paumgartner has disclosed no relevant financial relationships.
European Association for the Study of the Liver (EASL) 45th Annual Meeting. Presented April 15, 2010.
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Cite this: Farnesoid-X Agonist Shows Promise in Primary Biliary Cirrhosis Patients - Medscape - Apr 19, 2010.