LONDON – Obeticholic acid significantly reduced key liver enzyme and bilirubin levels in patients with primary biliary cirrhosis in a phase III trial.
Results of POISE [PBC OCA International Study of Efficacy] showed that at the final 1-year assessment, 46% of patients treated with an initial 5-mg daily dose of OCA, and 47% of those treated with a 10-mg daily dose, achieved the primary endpoint of an alkaline phosphatase (ALP) level less than 1.67 times the upper limit of normal (ULN) with bilirubin levels less than the ULN and a 15% or greater reduction ALP. In comparison, just 10% of placebo-treated patients achieved this endpoint, which has been linked to a reduction in the need for liver transplantation and death.
Significant reductions (P less than .001) in levels of other key liver enzymes – gamma glutamyl transferase, alanine aminotransferase, and aspartate aminotransferase – were also seen with active versus placebo treatment.
Study investigator Frederik Nevens said in an interview that OCA represents the first new treatment for PBC in 2 decades and it could even be "aspirin for hepatologists" if data from translational research are borne out in clinical trials.
Indeed, Dr. Nevens, of University Hospital Gasthuisberg in Leuven, Belgium, said that because OCA targets the farnesoid-X receptor, which is a nuclear receptor involved in multiple metabolic and other pathways, it could have widespread clinical applications.
"It has an effect on fibrosis, probably, it has an effect on portal hypertension, and it has an effect on cholestasis," he said. Furthermore, it reduces bacterial translocation from the gut, which has implications for the prevention of liver infections, and there is also the suggestion that it might be of benefit in patients with diabetes, Crohn’s disease, and malignancies.
"Certainly it also has a beneficial effect on NASH [nonalcoholic steatohepatitis], and NASH is one of the most common [liver] problems these days," Dr. Nevens observed. Recently, the phase II FLINT trial conducted with OCA in patients with NASH was halted because of positive interim results.
PBC affects mostly women, at rate of about 1 in 1,000 women over 40 years of age in the United States, and is the fifth most common reason for liver transplantation in the country, Dr. Nevens said. Currently, ursodeoxycholic acid is the only approved treatment, although fewer than 50% of patients respond adequately to the drug.
The POISE data clearly have shown a potential benefit for OCA in patients with PBC, the researcher said at the meeting, sponsored by the European Association for the Study of the Liver. Data from a phase II trial had already shown that OCA with or without the standard treatment (ursodeoxycholic acid) at a dose of 10-50 mg produced significant improvement in cholestasis but the main side effect was pruritus. While itching is a characteristic of PBC itself, a key aim of the phase III trial was to reduce the prevalence of this side effect.
Significantly lowering and titrating the dose reduced the occurrence and impact of pruritus, Dr. Nevens reported during a late-breaking trials session. Nevertheless, the side effect was seen in more than two-thirds of patients given the 10-mg dose and 56% of those given the 5-mg dose, which was titrated up to 10 mg over a 6-month period, compared with 38% of placebo-treated patients. The bile acid sequestrant cholestyramine was permitted as a means to alleviate itching and was used in 26%, 19%, and 11% of patients, respectively.
"Titration from 5 to 10 mg based on clinical response improved tolerance, minimized dropouts due to pruritus, and showed comparable efficacy to 10 mg OCA," Dr. Nevens said. "The long-term safety and efficacy is currently being evaluated in an open-label extension study," he added, noting almost all patients (95%) completing the phase III trial had opted to continue therapy in the extension study.
Further confirmation of OCA’s benefits are needed, but the problem with doing a trial to prove that mortality is reduced as a result of long-term treatment is that it would not be ethical to treat patients with placebo for 10 years, Dr. Nevens pointed out. Reduction in ALP and bilirubin levels, as used in POISE, was a good surrogate marker for outcome, he said. The Global PBC Study Group found that ALP less than 1.67 times the ULN and normal predicted the likelihood of transplant-free survival with a hazard ratio of 3.53.
Intercept Pharmaceuticals sponsored the study. Dr. Nevens was an investigator for the POISE trial but did not receive any grants or speaker fees from the company.