February 2021 Volume 17, Issue 2, Supplement 3 A SPECIAL MEETING REVIEW EDITION Highlights in Primary Biliary Cholangitis From the EASL 2020 Digital International Liver Congress, the ACG 2020 Virtual Annual Scientific Meeting, and the AASLD 2020 Liver Meeting Digital Experience Special Reporting on: • Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis: A Demographic Subgroup Analysis of 5-Year Results From the POISE Trial • Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis From the POISE Trial Grouped Biochemically by Risk of Disease Progression • Long-Term Efficacy and Safety of Obeticholic Acid in Primary Biliary Cholangitis: Responder Analysis of More Than 5 Years of Treatment in the POISE Trial • ENHANCE: Safety and Efficacy of Seladelpar in Patients With Primary Biliary Cholangitis— A Phase 3, International, Randomized, Placebo-Controlled Study • Real-World Effectiveness of Obeticholic Acid in Patients With Primary Biliary Cholangitis • Results of a Phase 2, Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Efficacy of Saroglitazar Magnesium in Patients With Primary Biliary Cholangitis (EPICS) • Primary Biliary Cholangitis: Patient Characteristics and the Health Care Economic Burden in the United States • Bezafibrate Add-On Therapy Improves Liver Transplantation–Free Survival in Patients With Primary Biliary Cholangitis: A Japanese Nationwide Cohort Study • GLIMMER Trial—A Randomized, Double-Blind, Placebo-Controlled Study of Linerixibat, an Inhibitor of the Ileal Bile Acid Transporter, in the Treatment of Cholestatic Pruritus in Primary Biliary Cholangitis PLUS Meeting Abstract Summaries With Expert Commentary by: Kris V. Kowdley, MD Director, Liver Institute Northwest Clinical Professor, Elson S. Floyd College of Medicine Washington State University Seattle, Washington ON THE WEB: gastroenterologyandhepatology.net Indexed through the National Library of Medicine (PubMed/Medline), PubMed Central (PMC), and EMBASE SPECIAL MEETING REVIEW EDITION HIGHLIGHTS IN PRIMARY BILIARY CHOLANGITIS Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis: A Demographic Subgroup Analysis of 5-Year Results From the POISE Trial rimary biliary cholangitis (PBC) imately 40% of patients do not benefit ated OCA in patients with PBC. In is a chronic autoimmune disease from this approach.6,7 the 12-month double-blind phase, of the liver that damages the Obeticholic acid (OCA) is a mod- patients were randomized to 1 of 3 Pbile ducts, resulting in cholestasis and ified bile acid farnesoid X receptor arms: placebo with or without UDCA fibrosis if left untreated.1,2 Patients agonist that was first approved by the (73 patients), 5 mg of OCA with are also at higher risk for hepato- US Food and Drug Administration allowed adjustment to 10 mg with cellular carcinoma, osteoporosis, (FDA) in May 2016 for use in con- or without UDCA (70 patients), and osteopenia. The disease is rare junction with UDCA.2 OCA acts on or 10 mg of OCA with or without and mainly diagnosed in women in several steps in bile acid homeostasis, UDCA (73 patients). Key inclusion their 40s. Importantly, the incidence ultimately improving the clearance of criteria included a diagnosis of PBC; appears to be steadily increasing in bile acid from the body and decreasing alkaline phosphatase (ALP) of at least the United States, Europe, and Asia.3-5 the amount being made. It also reduces 1.67 times the upper limit of normal Urso deoxycholic acid (UDCA), the inflammation and cholestasis in the (ULN) or total bilirubin greater than standard first-line treatment, alters liver.8 In addition, OCA is antifibrotic. the ULN to less than 2 times the ULN; the course of the disease, but approx- The phase 3 POISE trial evalu- and inadequate response to UDCA or 100 90 80 Year 1 Year 5 Year 6 70 60 50 40 Responders (%) 30 20 10 0 n= 15 11 4 170 114 48 97 60 21 88 65 31 99 63 19 86 62 33 Male Female Age at Age at Age at Age at Study Entry Study Entry Diagnosis Diagnosis ≤55 yrs >55 yrs ≤47.5 yrs >47.5 yrs Figure 1. POISE primary endpoint (ALP <1.67 × ULN, total bilirubin ≤ ULN, and ALP reduction ≥15%) from OCA baseline by demographic subgroup. For patients who received placebo in the double-blind phase, OCA baseline was the last assessment prior to the first OCA dose in OLE. For patients who received OCA in the double-blind phase, OCA baseline was the mean of all available evaluations prior to double-blind treatment. ALP, alkaline phosphatase; OCA, obeticholic acid; OLE, open-label extension; ULN, upper limit of normal. Adapted from Bowlus CL et al. ACG abstract 58. Presented at the American College of Gastroenterology 2020 Virtual Annual Scientific Meeting; October 23-28, 2020.10 2 Gastroenterology & Hepatology Volume 17, Issue 2, Supplement 3 February 2021 HIGHLIGHTS IN PRIMARY BILIARY CHOLANGITIS inability to tolerate it.9 The primary age at study entry (≤55 years vs >55 long-term OCA treatment is associated POISE endpoint was ALP of less than years), age when diagnosed with PBC with durable improvements or stabili- 1.67 times the ULN, a reduction of at (≤47.5 years vs >47.5 years), and sex zation in markers of disease severity in least 15% in ALP from baseline, and (male vs female). PBC patients, regardless of age or sex. normal total bilirubin (≤ ULN) at 12 A total of 193 of the 198 patients months. who completed the double-blind phase References 1. Hirschfield GM, Beuers U, Corpechot C, et al; Euro- The primary endpoint was met by of the study enrolled in the open-label pean Association for the Study of the Liver. EASL Clin- 46% of patients in the 5-mg to 10-mg extension. Of these, 116 completed 5 ical Practice Guidelines: the diagnosis and management OCA arm and by 47% of patients years of OCA treatment, including 52 of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-172. in the 10-mg OCA arm, compared who received OCA in the double-blind 2. Galoosian A, Hanlon C, Zhang J, Holt EW, Yimam with 10% of patients in the placebo phase and thus received a total of 6 years KK. Clinical updates in primary biliary cholangitis: arm. In addition, PBC patients who of OCA treatment. Figure 1 shows the trends, epidemiology, diagnostics, and new therapeutic approaches. J Clin Transl Hepatol. 2020;8(1):49-60. received OCA for 12 months experi- POISE primary endpoint from OCA 3. Lu M, Li J, Haller IV, et al. Factors associated with enced significantly decreased levels of baseline by demographic subgroup prevalence and treatment of primary biliary cholangi- ALP, alanine aminotransferase (ALT), for years 1, 5, and 6. Total bilirubin tis in United States health systems. Clin Gastroenterol Hepatol. 2018;16(8):1333-1341.e6. aspartate aminotransferase (AST), and remained stabilized and the improve- 4. Kim KA, Ki M, Choi HY, Kim BH, Jang ES, Jeong gamma-glutamyl transferase (GGT), ments in ALP were maintained across SH. Population-based epidemiology of primary biliary compared with those on placebo, as all subgroups after 6 years of treatment cirrhosis in South Korea. Aliment Pharmacol Ther. 9 2016;43(1):154-162. well as stabilization of total bilirubin. with OCA. Likewise, all of the sub- 5. Lleo A, Jepsen P, Morenghi E, et al. Evolving trends Following the 12-month dou- groups sustained the improvements in in female to male incidence and male mortality of pri- ble-blind phase of the POISE trial, both ALT and GGT that they achieved mary biliary cholangitis. Sci Rep. 2016;6:25906. 6. Younossi ZM, Bernstein D, Shiffman ML, et al. patients were eligible to enter an during the early phase of the study. In Diagnosis and management of primary biliary cholan- open-label extension. All patients were general, both ALT and AST were higher gitis. Am J Gastroenterol. 2019;114(1):48-63. treated with OCA 5 mg for 3 months, in the 2 younger-age subgroups. The 7. Bahar R, Wong KA, Liu CH, Bowlus CL. Update on new drugs and those in development for the treatment after which the dose could be titrated most common side effect was mild to of primary biliary cholangitis. Gastroenterol Hepatol (N based on tolerability. moderate pruritus, which occurred at Y). 2018;14(3):154-163. At the American College of Gas- similar rates in all demographic sub- 8. Santiago P, Scheinberg AR, Levy C. Cholestatic liver diseases: new targets, new therapies. Therap Adv Gastro- troenterology 2020 Virtual Annual groups. enterol. 2018;11:1756284818787400. Scientific Meeting, Dr Christopher L. OCA led to sustained improve- 9. Nevens F, Andreone P, Mazzella G, et al; POISE Bowlus presented results from an analy- ments in ALP, ALT, AST, and GGT as Study Group. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. sis of the long-term efficacy and safety well as stabilization of total bilirubin 2016;375(7):631-643. of OCA in demographic subgroups of through 5 years across demographic 10. Bowlus CL, Trauner M, Nevens F, et al. Long-term patients who had been treated for 5 or subgroups. Adverse events were con- efficacy and safety of obeticholic acid in patients with 10 primary biliary cholangitis: a demographic subgroup more years in the POISE trial. This sistent with OCA’s established safety analysis of 5-year results from the POISE trial [ACG analysis pooled double-blind placebo profile, and there were no new safety abstract 58]. Presented at the American College of Gas- and double-blind OCA patients, and observations during long-term treat- troenterology 2020 Virtual Annual Scientific Meeting; October 23-28, 2020.