Results from an international Phase III study presented today at the International Liver CongressTM 2014 have shown obeticholic acid (OCA) given to patients suffering from Primary Biliary Cirrhosis (PBC) who previously had an inadequate response to, or have been unable to tolerate ursodeoxycholic acid (UDCA), produced meaningful biochemical and clinical improvements. UDCA is the only therapy currently approved to treat PBC.
Obeticholic acid at both a 10 mg dose and a 5 mg dose titrated to 10 mg, met the trial's primary composite endpoint of achieving a serum alkaline phosphatase (ALP) activity of less than 1.67 times the upper limit of normal (ULN), a total bilirubin within normal limits, and at least a 15% decrease in ALP.
The proportion of patients meeting the primary endpoint was: 47% in the 10 mg OCA group and 46% in the 5-10 mg OCA group vs. only 10% in the placebo group (both dose groups p<0.0001). In addition, both OCA dose groups met secondary endpoints of improvements in other liver function parameters, including gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT) and total bilirubin.
Presenting these results, EASL's Scientific Committee Member Dr. Frank Lammert, Professor of Internal Medicine at the Saarland University Medical Center, Homburg, Germany pointed out: "These trial results indicate that a statistically greater number of OCA-treated patients achieved the response criteria as defined by Global Primary Biliary Cirrhosis Study Group. We know that these endpoints have, in turn, been shown in previous studies to strongly correlate with clinical benefits and an improved long-term prognosis, with a reduced risk of liver transplantation and death."
"While UDCA has been the standard PBC therapy for the past 20 years, a significant percentage of patients fail to get an adequate response with this treatment, or are unable to tolerate it. We therefore need new therapies to prevent PBC from progressing to cirrhosis and liver failure, and this study suggests that OCA has the potential to be a much needed advance for these patients," Dr. Frank Lammert added.
PBC is a chronic disease that primarily occurs in women. It is characterised by the destruction of bile ducts in the liver, which in turn leads to liver scarring. Long-term damage from PBC over the years can result in cirrhosis and liver failure. PBC affects around 30 people per million, with an estimated prevalence of 12,000 - 15,000 in the UK. It has been reported that PBC is more prevalent in some geographic areas, such as Northern Europe and Northern America.
OCA is a new bile acid analogue (6alpha-ethyl-chenodeoxycholic acid) and first-in-class agonist of the nuclear receptor (FXR), which represents the central bile acid sensor in humans. It is being studied in PBC, as well as non-alcoholic steatohepatitis (NASH) and other liver and intestinal diseases.
Study methodology and adverse event data
This Phase III study enrolled 217 patients with primary biliary cirrhosis who had either failed to get an adequate response with UDCA, or had been unable to tolerate it. Patients were randomised to placebo or one of two doses of OCA, with the lower dose titrated to the higher strength after six months based on clinical response. Patients who were able to tolerate UDCA were allowed to continue on it; the median UDCA dose was 15.3mg/kg; 7% of patients were UDCA-intolerant. All three treatment groups were well matched. Mean age: 55.8yrs, female: 91%, Caucasian: 94%.
Pruritus, generally mild to moderate, was the most frequently reported adverse event associated with OCA treatment (placebo: 38%, OCA 10 mg: 68%, OCA 5-10 mg titration: 56%).
However, only a few patients withdrew due to pruritus: none in the placebo group, seven (10%) of the patients in the 10 mg OCA group, and only one (1%) of the patients in the OCA 5-10 mg titration group.
Apart from pruritus, the incidence of adverse events was generally similar across both OCA and placebo groups (placebo: 90%, OCA 10 mg: 86%, OCA 5-10 mg titration group: 89%). Overall, serious adverse events (SAEs) occurred in (10%) of the patients and, although there were more SAEs in the OCA treatment groups, none were considered drug-related and there were no apparent patterns in the SAEs.
PBC patients typically have significantly elevated HDL cholesterol levels; modest decreases in HDL were observed in both OCA dose groups, similar to those seen in the prior PBC clinical trials. In addition, slight decreases in triglycerides, but no changes in LDL cholesterol were observed in the OCA dose groups.
Other new data further support role of obeticholic acid in PBC
In addition to these new Phase III data, there are three other presentations on OCA at this year's International Liver CongressTM, which further support the potential role of this new drug in treating PBC.
Two 12-week, double-blind, placebo-controlled Phase 2 trials of OCA in PBC patients with persistently high ALP (≥1.5-10x ULN) and bilirubin <2x ULN, showed OCA resulted in a highly significant improvement in the biochemical response criteria which are associated with improved transplant-free survival versus placebo, in both the OCA monotherapy and UDCA-combination therapy studies.
Having previously demonstrated the efficacy of 10mg and 50mg doses of OCA, given as monotherapy, in achieving highly significant reductions in ALP and other biochemical markers, compared with placebo, an open label, long-term study extension has shown that OCA treatment resulted in a durable improvement in ALP and other liver chemistry. UDCA was added in 11 of the patients. Pruritus, while prevalent appeared to diminish in incidence and severity with continued therapy.
In an experimental rat model of cholestasis, FXR-agonism was shown to restore ileal permeability and decrease bacterial translocation (which is known to drive infectious complications of cirrhosis), potentially showing a crucial protective role for FXR in the gut-liver axis.