A phase III study has enrolled 217 patients with primary biliary cirrhosis who had either failed to get an adequate response with UDCA ( Ursodeoxycholic acid ), or had been unable to tolerate it.
Patients were randomised to placebo or one of two doses of Obeticholic acid ( 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: 55.8 years, female: 91%, Caucasian: 94%.
Pruritus, generally mild to moderate, was the most frequently reported adverse event associated with Obeticholic acid 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 Obeticholic acid 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 severe adverse effects in the OCA treatment groups, none were considered drug-related and there were no apparent patterns in the severe adverse reactions.
Primary biliary cirrhosis 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.
In addition to these new phase III data, there are three other presentations on OCA, which further support the potential role of this new drug in treating primary biliary cirrhosis.
Two 12-week, double-blind, placebo-controlled phase 2 trials of OCA in primary biliary cirrhosis patients with persistently high ALP ( greater than or equal to 1.5-10x ULN ) and bilirubin less than 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. ( Xagena )
Source: European Association for the Study of the Liver ( EASL ), 2014