P1155 : FXR Agonism with obeticholic acid may attenuate bone mineral density decrease in subjects with primary biliary cirrhosis

POSTERS the receptor of CCL3, CCR5. The observed increased inflammation was concomitant with increased number of mucin-containing goblet cells in the duodenum and ileum, and this was associated with increased expression of a regulator of mucositis Kruppel-like ¨ factor 4. Conclusions: iPLA2b deficiency renders susceptibility for AIH assoicated with increases of hepatic secondary bile acids which could induce intestinal mucosal damage, and hepatic and intestinal damage could in turn lead to an elevation of bile acids in the periphery. Thus, our experimental model demonstrates that AIH in a susceptible host such as with iPLA2b deficiency may lead to enteropathy via bile acid toxicity. P1154 PRE-TREATMENT SERUM VITAMIN D STATUS IS ASSOCIATED WITH SUBSEQUENT RESPONSE TO UDCA IN PBC X. Zhou1 , G. Guo1 , Y. Han1 , Y. Shi1 . 1 Division of Hepatology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China E-mail: [email protected] Background and Aims: Vitamin D is always linked with primary biliary cirrhosis (PBC) for bone complication in the patients. However increasing evidences suggest a non-skeletal role of vitamin D in various autoimmune or liver diseases. We performed this study to investigate the clinical relevance of vitamin D level in PBC, especially the association with therapeutic effects of ursodeoxycholic acid (UDCA). Methods: Consecutive PBC patients were retrospectively studied. 25-hydroxyvitamin D [25(OH)D] levels were determined by pre-treatment frozen serum samples. Response to UDCA was evaluated by Paris-I and Barcelona criteria respectively. Logistic regressions were performed to identify treatment response associated parameters. Results: Of 98 patients, the mean serum 25(OH)D concentration was 17.9±7.6 ng/mL. 25(OH)D levels decreased with increasing histological stage (p = 0.029) and negatively correlated with bilirubin, alkaline phosphatase and Mayo risk score. After one year of UDCA therapy, 31 patients failed to achieve complete response according to Paris-I criteria. Baseline 25(OH)D level was significantly lower in non-responders (14.8±6.4 vs. 19.3±7.6 ng/mL, p = 0.005). In multivariate analysis, vitamin D deficiency at baseline increased the risk of incomplete response, independently from elevated bilirubin and ALP values and advanced stages (OR = 3.93, 95% CI=1.02–15.19, p = 0.047). Similar results were obtained when biochemical response was evaluated by Barcelona criteria. Conclusions: 25(OH)D level is associated with biochemical and histological features in PBC. Pre-treatment vitamin D status independently related to subsequent response to UDCA. Our results suggest adequate 25(OH)D levels may be helpful to improve response to UDCA and supplementation of vitamin D is worth considered, not only for preventing osteoporosis in the patients.

P1155 FXR AGONISM WITH OBETICHOLIC ACID MAY ATTENUATE BONE MINERAL DENSITY DECREASE IN SUBJECTS WITH PRIMARY BILIARY CIRRHOSIS A. Pares1 , R. Pencek2 , Y. Peters2 , T. Marmon2 , L. MacConell2 , L. Adorini2 , D. Shapiro2 , M. Trauner3 , D. Jones4 . 1 Liver Unit, Hospital Clinic, IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain; 2 Intercept Pharmaceuticals, Inc, San Diego, United States; 3 Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; 4 Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom E-mail: [email protected] Background and Aims: Osteoporosis occurs frequently in subjects with primary biliary cirrhosis (PBC). The farnesoid X receptor (FXR) expressed in bone has been shown to positively regulate bone osteogenesis in mice (Cho 2013). Obeticholic acid (OCA), a farnesoid x receptor agonist being developed for the treatment of PBC, produced significant improvements in indices of hepatic damage and function as well as markers of inflammation and cholestasis in the phase 3 POISE trial. This analysis evaluated the effect of OCA compared to placebo on bone mineral density (BMD). Methods: Subjects with PBC ± UDCA (if taking UDCA patients were maintained on a stable dose) with ALP ≥1.67×ULN or bilirubin <2×ULN were randomized to PBO, OCA 5 or 10 mg for 12 months. Subjects on 5 mg were titrated to 10 mg after 6 months (OCA Titration) as clinically indicated. Dual-emission X-ray absorptiometry (DEXA) scan was used to assess BMD in a subset of subjects prior to and following 12 months of OCA or placebo treatment. Results of the femoral neck and lumbar spine (using T-score, Z-score, and BMD) were summarized. Changes from baseline at Month 12 were analyzed using an ANCOVA model with baseline values as a covariate. Osteopenia and osteoporosis were based on WHO thresholds: T score −1.0 to −2.5 and ≤−2.5, respectively. Results: Of 216 subjects enrolled in the trial, 122 had DEXA scans at baseline and Month 12 (85% female; 22% ≥65 years of age; 52% postmenopausal). Baseline ALP was 318±102 U/L and 91% of subjects took concomitant UDCA. At baseline the prevalence of osteopenia and osteoporosis was 7% and 54%, respectively. Placebo subjects had a significant decrease in femoral T-scores (p = 0.03) and a reduction was also detected for 10 mg OCA (p = 0.01). OCAtreated subjects had significantly smaller decreases in femoral T-scores relative to placebo (p < 0.05). No significant differences from baseline or between treatment groups were seen in Lumbar BMD. Results were generally consistent but did not attain statistical significance when assessed based on menopausal status. Conclusions: Individuals with PBC are at increased risk for osteopenia, osteoporosis and bone fractures. This preliminary analysis of BMD in subjects treated with OCA suggests that OCA may attenuate the deterioration in femoral T scores in subjects with PBC and merits further study of the effects of this drug in preventing bone loss and its complications.

Table (abstract P1155). BMD

Lumbar BMD L2–L4 (g/cm2 ) T score Femoral BMD Neck (g/cm2 ) T score

Placebo

Titration OCA

10 mg OCA

BL

End of DB

D

BL

End of DB

D

BL

End of DB

D

0.97 (0.17) −1.16 (1.47)

0.97 (0.18) −1.42 (1.38)

−0.01 (0.01) −0.26 (0.14)

1.02 (0.19) −1.10 (1.51)

1.01 (0.20) −1.10 (1.65)

−0.01 (0.01) −0.01 (0.14)

1.03 (0.17) −0.82 (1.30)

1.00 (0.18) −1.02 (1.30)

−0.01 (0.01) −0.09 (0.14)

0.79 (0.13) −1.15 (1.17)

0.76 (0.13) −1.48 (1.04)

−0.02 (0.01) −0.33 (0.11)†

0.80 (0.12) −1.29 (0.95)

0.81 (0.13) −1.28 (0.95)

−0.01 (0.01) −0.06 (0.11)*

0.87 (0.16) −0.89 (1.04)

0.81 (0.15) −1.06 (0.82)

−0.04 (0.01) −0.07 (0.11)† *

BMD, Bone mineral density. Baseline (BL) and End of Double-blind (DB) values are mean (SD); changes from baseline values are LS mean (SE). *p < 0.05 comparing OCA to placebo using an ANCOVA model; † p < 0.03 end of DB vs BL. S786

Journal of Hepatology 2015 vol. 62 | S263–S864