Kris V Kowdley1, Raj Vuppalanchi2, Cynthia Levy3, Annarosa Floreani4, Pietro Andreone5, Nicholas F LaRusso6, Roshan Shrestha7, James Trotter8, David Goldberg9, Simon Rushbrook10, Gideon M Hirschfield11, Thomas Schiano12, Yuying Jin13, Richard Pencek13, Leigh MacConell13, David Shapiro13, Christopher L Bowlus14. 1. Liver Institute Northwest, Seattle, WA, USA. Electronic address: kkowdley@liverinstitutenw.org. 2. Indiana University School of Medicine, Indianapolis, IN, USA. 3. Division of Hepatology, University of Miami Miller School of Medicine, Miami, FL, USA. 4. Università di Padova, Padova, Italy. 5. SMECHIMAI Department, Università di Modena e Reggio-Emilia, Modena, Italy. 6. Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA. 7. Department of Transplantation, Piedmont Transplant Institute, Atlanta, GA, USA. 8. Division of Transplant Hepatology, Baylor University, Dallas, TX, USA. 9. Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 10. Faculty of Medicine and Health Sciences, Norwich Medical School, Norwich, UK. 11. Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada. 12. Recanati/Miller Transplantation Institute/Division of Liver Diseases, The Mount Sinai Medical Center, New York, NY, USA. 13. Intercept Pharmaceuticals, Inc., San Diego, CA, USA. 14. Division of Gastroenterology and Hepatology, University of California, Davis, Sacramento, CA, USA.
Abstract
BACKGROUND & AIMS:Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC. METHODS:AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5-3.0 mg, or OCA 5-10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety. RESULTS: The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5-3.0 mg (n = 25), and OCA 5-10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5-10 mg vs. placebo (least-square [LS] mean difference = -83.4 [SE = 40.3] U/L; 95% CI -164.28 to -2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5-3.0 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L; 95% CI -162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5-3.0 mg 60%; OCA 5-10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged. CONCLUSIONS: Treatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event. REGISTRATION: ClinicalTrials.gov: NCT02177136; EudraCT: 2014-002205-38. LAY SUMMARY:Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies.
RCT Entities:
BACKGROUND & AIMS:Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC. METHODS: AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5-3.0 mg, or OCA 5-10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety. RESULTS: The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5-3.0 mg (n = 25), and OCA 5-10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5-10 mg vs. placebo (least-square [LS] mean difference = -83.4 [SE = 40.3] U/L; 95% CI -164.28 to -2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5-3.0 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L; 95% CI -162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5-3.0 mg 60%; OCA 5-10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged. CONCLUSIONS: Treatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event. REGISTRATION: ClinicalTrials.gov: NCT02177136; EudraCT: 2014-002205-38. LAY SUMMARY:Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies.
Authors: Aldo J Montano-Loza; Jessica R Allegretti; Angela Cheung; Maryam Ebadi; David Jones; Nanda Kerkar; Cynthia Levy; Sumera Rizvi; John M Vierling; Fernando Alvarez; Wayne Bai; Susan Gilmour; Aliya Gulamhusein; Orlee Guttman; Bettina E Hansen; Sonya MacParland; Andrew Mason; Fernanda Onofrio; Pere Santamaria; Ashley Stueck; Mark Swain; Catherine Vincent; Amanda Ricciuto; Gideon Hirschfield Journal: Can Liver J Date: 2021-11-11