OP02 The first new monotherapy therapeutic PBC study in a decade? An international study evaluating the farnesoid X receptor agonist obeticholic acid in PBC. (6th September 2011) - Jones, D
Abstract : Introduction: Obeticholic Acid (OCA), 6-ethyl chenodeoxycholic acid (CDCA) or INT-747, is a novel derivative of the primary human bile acid CDCA, the natural ligand for the farnesoid-X receptor. OCA has ∼100x more FXR agonist potency than CDCA and in preclinical studies shows choleretic and anti-fibrotic properties. A prior primary biliary cirrhosis (PBC) study showed that OCA 10–50 mg, achieved highly statistically significant reductions in alkaline phosphatase (AP), GGT and ALT when added to ursodeoxycholic acid. Aim: To undertake an international, double blind, placebo (Pbo) controlled, parallel group, dose response study evaluating the effects of OCA in PBC. Method: Double blind, placebo (Pbo) controlled, parallel group, dose response study to explore effects on AP, other liver enzymes and safety in patients with PBC and persistently high AP levels (≥1.5–10× the upper limit of normal (ULN)) who had not been taking UDCA for at least 6 months. 59 patients received placebo, OCA 10 mg or 50 mg once daily for 12 weeks. All patients had definite (54%) or probable (46%) PBC; mean age was 55±1 years; female: 85%, Caucasian: 95%. Key pre-treatment values (mean±SEM): AP: 433±31 (female ULN: 117) U/l; GGT: 527±48 (female ULN: 50) U/l; ALT: 81±6 (ULN: 67) U/l; AST: 68±4 (ULN: 50) U/l. Results Efficacy: End of study changes (from pre-treatment). The 10 mg group showed an AP decrease from 3.9× ULN pre-treatment to 1.9× ULN at the end of the study. Results - Safety: Pruritus was the most common Adverse Experience (AE): Pbo: 30%, 10 mg: 70%, 50 mg: 94%; pruritic severity and discontinuation rate (Pbo: 0%, 10 mg: 15%, 50 mg: 38%) increased with dose. Other AEs were not clearly more commonly seen with OCA therapy. There was one serious AE in a placebo patient. Conclusion: OCA is the first rationally developed drug for cholestatic liver disease and shows substantial efficacy as a treatment for PBC as a single agent. Based on these data, a direct comparison with UDCA seems merited.