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PRESENTATION TYPE: Oral or Poster CURRENT CATEGORY: Human Cholestatic and Autoimmune Liver Diseases CURRENT DESCRIPTORS: IO1. PBC/PSC and Other Cholestatic Disease TITLE: Durable Response in the Markers of Cholestasis through 18 Months of Open-Label Long Term Safety Extension Study of Obeticholic Acid in Primary Biliary Cirrhosis AUTHORS (FIRST NAME, LAST NAME): Michael Trauner1, Frederik Nevens2, Pietro Andreone3, Giuseppe Mazzella3, Simone I. Strasser4, Christopher L. Bowlus5, Pietro Invernizzi6, Joost Drenth7, Paul J. Pockros8, Jaroslaw Regula9, Annarosa Floreani10, Simon Hohenester11, Velimir A. Luketic12, Mitchell L. Shiffman13, Karel J. van Erpecum14, Victor Vargas15, Catherine Vincent16, Bettina E. Hansen17, Roya Hooshmand-Rad18, Shawn Sheeron18, David Shapiro18 Institutional Author(s): INSTITUTIONS (ALL): 1.Medical University of Vienna, Vienna, Austria. 2.UZ Leuven, Leuven, Belgium. 3.Universitaria di Bologna, Bologna, Italy. 4.Royal Prince Alfred Hospital, Sydney, NSW, Australia. 5.University of California-Davis, Sacramento, CA, United States. 6.Humanitas Clinical and Research Center, Rozzano, Italy. 7.UMC St. Radboud, Nijmegen, Netherlands. 8.Scripps Clinic, La Jolla, CA, United States. 9.Cancer Centre, Warsaw, Poland. 10.Università di Padova, Padova, Italy. 11.LMU University of Munich, Munich, Germany. 12.McGuire DVAMC, Richmond, VA, United States. 13.Liver Institute of Virginia, Newport News, VA, United States. 14.UMC Utrecht, Utrecht, Netherlands. 15.Hospital Vall d’Hebron, Barcelona, Spain. 16.Centre Hospitalier Universitaire de l’Université de Montréal-St. Luc, Montréal, QC, Canada. 17.Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. 18.Intercept Pharmaceuticals, Inc., San Diego, CA, United States. Character Count: 2100 Background: Obeticholic Acid (OCA) is a selective and potent farnesoid X receptor (FXR) agonist developed for treatment of primary biliary cirrhosis (PBC). 216 patients were randomized and dosed in a double-blind, placebo-controlled phase 3 PBC trial (POISE); 198 patients completed the trial and 193 (97%) patients enrolled in an open- label long term safety extension (LTSE). The LTSE aim is to assess the continued durability of OCA on the markers of cholestasis and safety. Methods: Inclusion criteria: PBC diagnosis, ALP ≥1.67x ULN and/or total bilirubin >ULN to <2x ULN, stable UDCA dose or unable to tolerate UDCA. During the double blind (DB) phase, patients were randomized to: daily Placebo (PBO), 5 to 10mg OCA titration group (titration after 6 months based on response and tolerability), or 10mg OCA. In the LTSE, all patients were initially treated with 5 mg OCA regardless of DB treatment with the option to increase OCA dose up to 10 mg after 3 months. LTSE demographics: mean age 56 y; female: 91%; Caucasian 94%; mean UDCA dose 16 mg/kg. Results: In the DB period, all OCA groups had significant reductions in ALP, GGT, ALT and AST (Table 1). In OCA Titration and 10mg groups, this response was durable for 30 months. For PBO, bilirubin increased during the DB period, but decreased following the initiation of OCA. OCA Titration and 10mg groups sustained no increase in bilirubin in the DB or LTSE. Overall OCA was safe and well-tolerated; pruritus was the most common AE associated with OCA. Patients on OCA in the DB period showed a decrease in crude incidence of pruritus in the LTSE, from 53-67% (12 months DB treatment) to 19-36% (18 months LTSE treatment). PBO subjects who initiated OCA in the LTSE saw an increase in pruritus consistent with initiation of OCA. Unrelated to OCA, 1 patient died as a result of sepsis secondary to endocarditis after a prosthetic aortic valve replacement. Conclusion: OCA treatment produced a sustained improvement in hepatic biochemistry through 30 months of treatment. Pruritus was the most common AE, but its incidence appeared to lessen with longer treatment.   Table 1: Laboratory changes through the double-blind and LTSE study period Original Treatment Group Placebo OCA Titration 10 mg OCA Number of Patients 51 50 54 ALP (U/L) DB Baseline 310.3 (96.8) 207.5 (104.3) 307.7 (97.8) ∆ DB 12 mo -12.1 (80.4) -106.1 (87.0)*** -122.0 (74.9)*** ∆ LTSE 18 mo -97.8 (69.6)*** -111.3 (90.3)*** -106.8 (91.4)*** Bilirubin (µmol/L) DB Baseline 11.0 (6.4) 10.6 (6.0) 10.9 (7.1) ∆ DB 12 mo 1.5 (4.3)* -0.6 (3.5) -1.2 (4.7) ∆ LTSE 18 mo 1.9 (14.0) -0.3 (3.9) -1.3 (4.5) GGT (U/L) DB Baseline 329.4 (506.6) 267.0 (177.8) 277.0 (229.3) ∆ DB 12 mo -16.0 (190.6) -149.4 (157.1)*** -188.3 (166.8)*** ∆ LTSE 18 mo -176.7 (406.4)** -161.7 (156.0)*** -143.3 (157.0)*** ALT (U/L) DB Baseline 55.7 (31.5) 65.4 (42.5) 57.0 (43.3) ∆ DB 12 mo -5.3 (19.6) -23.8 (22.7)*** -25.0 (28.3)*** ∆ LTSE 18 mo -22.1 (25.0)*** -25.8 (27.1)*** -17.5 (57.5)* AST (U/L) DB Baseline 47.3 (18.2) 54.1 (27.6) 51.1 (34.4) ∆ DB 12 mo 1.9 (35.0) -12.9 (15.1)*** -14.3 (20.5)*** ∆ LTSE 18 mo -10.4 (15.2)*** -13.1 (17.9)*** -12.7 (32.4)** P-values for Change vs. DB Baseline measurement: *p<0.05, **p<0.01, ***p<0.0001. Values are Mean (SD). P-value for the within treatment comparisons are obtained using a paired t-test. All patients represented received ≤10 mg OCA.