OP02 The first new monotherapy therapeutic PBC study in a decade? An international study evaluating the farnesoid X receptor agonist obeticholic acid in PBC: Abstract OP02 Table 1

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. Abstract OP02 Table 1 Mean±SEM ? % AP ? AP ? U/l % ? GGT % ? ALT Pbo (n=23) +0.4±3.2 +11.7±13.1 −3±5 −4±9 OCA 10 mg (n=20) −44.5±5.5*** −233.5±47.5*** −73±4*** −37±8** OCA 50 mg (n=16) −37.6±5.3*** −161.3±32.4*** −65±6*** −35±7** ** p<0.01, ***p<0.0001