Obeticholic acid reduced alkaline phosphatase level, total bilirubin level, and other biomarkers of cholestasis, hepatocellular injury, inflammation, and apoptosis in patients with primary biliary cholangitis participating in a phase III clinical trial, which was reported online August 17 in the New England Journal of Medicine.
A study to assess the drug’s effects on clinical outcomes is currently enrolling patients (NCT02308111), said Frederik Nevens, MD, PhD, of University Hospitals Leuven (Belgium) and his associates.
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Dr. Frederik Nevens
They assessed treatment with obeticholic acid, a selective farnesoid X receptor agonist, in a manufacturer-sponsored double-blind randomized trial involving 217 patients treated at 59 sites in 13 countries. Participants were assigned to receive a once-daily oral placebo (73 patients), obeticholic acid at an initial dose of 5 mg with escalation to 10 mg if possible (71 patients), or a daily 10-mg dose of obeticholic acid (73 patients). All were also given standard ursodiol (13-15 mg per kg) at the same time, with the expectation that many would have to discontinue that drug due to adverse events. The study participants were treated for 1 year, when the double-blind phase of the study was completed and all were offered entry into a 5-year open-label phase.
The primary composite endpoint was 1) an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% below baseline level, and 2) a total bilirubin level at or below the upper limit of the normal range. After 1 year of treatment, 46% of the 5-mg group and 47% of the 10-mg group achieved this endpoint, compared with only 10% of the placebo group. The response to treatment was rapid, with patients in the active-treatment groups showing significantly lower alkaline phosphatase and bilirubin levels than the placebo group within 2 weeks of starting therapy.
In addition, the percentage of patients who showed at least a 15% reduction in alkaline phosphatase level was significantly higher with 5-10 mg active treatment (77%) and with 10 mg active treatment (77%) than with placebo (29%). And total bilirubin level progressively decreased in both active treatment groups but progressively increased in the placebo group, Dr. Nevens and his associates said (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMoa1509840). Obeticholic acid also reduced levels of IgM and interleukin-12, as well as levels of gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, and conjugated bilirubin. It did not induce significant symptom relief as measured by a disease-specific quality of life questionnaire, and it didn’t reduce liver fibrosis as measured by noninvasive techniques.
In the open-label extension phase of the study, treatment efficacy was similar.
The most common adverse event was pruritus, which is also characteristic of the disease itself. The incidence was higher in both active-treatment groups (56% with 5-10-mg therapy and 68% with 10-mg therapy) than in the placebo group (38%). One patient (1%) in the 5-10-mg group and seven patients (10%) in the 10-mg group discontinued treatment because of pruritus, compared with no patients in the placebo group.
The treatment’s beneficial effects persisted for 2 years, but that is a relatively short follow-up for a chronic disease that will require lifelong therapy. Future research must address longer-term benefits as well as adverse events, the investigators said.