Disclosures: Velimir A. Luketic – Grant/Research Support: Intercept, Merck, Idenix, Vertex, Gilead, BMS, Novartis, abbvie, Genfit, Takeda Joseph A. Odin – Advisory Committees or Review Panels: Bristol Meyers Squibb, AbbVie Kris V. Kowdley – Advisory Committees or Review Panels: AbbVie, Gilead, Merck, Novartis, Trio Health, Boeringer Ingelheim, Ikaria, Janssen; Grant/Research Support: AbbVie, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria, Janssen, Merck, Mochida, Vertex Gideon M. Hirschfield – Advisory Committees or Review Panels: Centocor/J&J, Medigene, Intercept, Falk Pharma ; Consulting: Lumena, Intercept

Naga P. Chalasani – Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-rion; Grant/Research Support: PLX3397 mouse Intercept, Lilly, Gilead, Cumberland, Galectin The following people have nothing to disclose: John E. Eaton, Brian D. Juran, Elizabeth J. Atkinson, Erik M. Schlicht, Olaparib Xiao Xie, Mariza de Andrade, Craig Lammert, Ayman A. Koteish, Kapil B. Chopra, Konstantinos Lazaridis Background: Effective medical therapies for PSC are needed. Moderate dose UDCA improves serum biochemistry but does not change the disease course. ATRA can activate FXR (farnesoid X receptor) and RXR (retinoid X receptor) and repress CYP7A1 and bile acid synthesis in human hepatocytes.

In animal models of biliary injury ATRA improved hepatic inflammation and fibrosis when combined with UDCA (He et al. Hepatology 2011; Cai medchemexpress et al. J. Pharm. Exp. Ther. 2014). Aim: To determine if ATRA + UDCA improve serum parameters of cholestasis in PSC patients with alkaline phosphatase (AP) >1.5xULN despite moderate-dose UDCA for ≥6 months. Methods: Patients were enrolled at Yale and Mayo Liver Clinics. ATRA capsules were compounded and dosed at 45 mg/m2/ day divided b.i.d.. Combination therapy was given for 12 weeks followed by a 12-week washout. Baseline labs were compared to the end-of-treatment and to washout. Results: Twenty-one subjects were screened and 19 enrolled. Mean age was 45±11 years, 74% Caucasian and 74% male; 63% had large duct vs. 37% with small-duct PSC, 79% had IBD and median Mayo PSC Risk Score was −0.03±0.7. Mean UDCA

dose was 18±6 mg/kg/day. Fifteen subjects completed 12 weeks of therapy. Mean AP significantly declined (356±209 vs. 318±225 U/L, p=0.046); 20% achieved ≥30% reduction. Interestingly, mean alanine aminotransferase (ALT) also declined (94±55 vs. 56±32 U/L, p=0.007) along with serum bile acid levels (41±52 vs. 28±45 umol/L, p=0.04). Mean LDL (131±60 vs. 155±51 mg/dL, p=0.055) and triglyceride (86±31 vs. 145±45 mg/dL, p=0.003) levels increased while HDL decreased (61±21 vs. 41±11 mg/dL, p=0.01). Mean serum levels of bile acid intermediate 7a-hydroxy-4-cholesten-3-one (C4) significantly decreased (17±19 vs. 9±11 ng/mL, p=0.04) indicating that ATRA inhibited bile acid synthesis. There was no difference in bilirubin or peripheral regulatory T cell frequency.