Bacon, Bruce

Borg, Brian

Bowlus, Christopher

Choi, Yun-Jung

Doerffel, Yvonne

Forman, Lisa

Freilich, Bradley

Gheorghe, Liana

Goel, Aparna

González, María S

Gordon, Stuart C

Gulamhusein, Aliya

Harrison, Stephen

Huang, Jonathan

Jeong, Sook-Hyang

Kim, Seung U

Lake, John

Levy, Cynthia

Mayo, Marlyn J

McWherter, Charles

Michael, Galambos

Neff, Guy

Odin, Joseph

Stanca, Carmen

Steinberg, Alexandra

Tak, Won Y

Thorburn, Douglas

Tobias, Hillel

Trivedi, Palak

Vierling, John M

Yang, Ke

English

Henry Ford Health System Scholarly Commons

Henry Ford Health Henry Ford Health Scholarly Commons Gastroenterology Meeting Abstracts Gastroenterology 7-1-2021 Efficacy, safety, and tolerability of seladelpar in patients with compensated liver cirrhosis due to primary biliary cholangitis (PBC): a pooled analysis of phase 2 and phase 3 studies Stuart C. Gordon Henry Ford Health, sgordon3@hfhs.org Palak Trivedi Christopher Bowlus Galambos Michael Aparna Goel See next page for additional authors Follow this and additional works at: https://scholarlycommons.henryford.com/gastroenterology_mtgabstracts Recommended Citation Gordon SC, Trivedi P, Bowlus C, Michael G, Goel A, Gulamhusein A, Levy C, Neff G, Stanca C, Thorburn D, Bacon B, Borg B, Doerffel Y, Forman L, Freilich B, Gheorghe L, Gonzalez MS, Harrison S, Huang J, Jeong S-H, Kim SU, Lake J, Odin J, Tak WY, Tobias H, Vierling JM, Yang K, Steinberg A, Choi Y-J, McWherter C, and Mayo MJ. Efficacy, safety, and tolerability of seladelpar in patients with compensated liver cirrhosis due to primary biliary cholangitis (PBC): a pooled analysis of phase 2 and phase 3 studies. J Hepatol 2021; 75:S686-S687. This Conference Proceeding is brought to you for free and open access by the Gastroenterology at Henry Ford Health Scholarly Commons. It has been accepted for inclusion in Gastroenterology Meeting Abstracts by an authorized administrator of Henry Ford Health Scholarly Commons. Authors Stuart C. Gordon, Palak Trivedi, Christopher Bowlus, Galambos Michael, Aparna Goel, Aliya Gulamhusein, Cynthia Levy, Guy Neff, Carmen Stanca, Douglas Thorburn, Bruce Bacon, Brian Borg, Yvonne Doerffel, Lisa Forman, Bradley Freilich, Liana Gheorghe, María S. González, Stephen Harrison, Jonathan Huang, Sook-Hyang Jeong, Seung U. Kim, John Lake, Joseph Odin, Won Y. Tak, Hillel Tobias, John M. Vierling, Ke Yang, Alexandra Steinberg, Yun-Jung Choi, Charles McWherter, and Marlyn J. Mayo This conference proceeding is available at Henry Ford Health Scholarly Commons: https://scholarlycommons.henryford.com/gastroenterology_mtgabstracts/125 PO-1758Circulating Fn14 is associated with pathogenic TH17 polarizationin children with sclerosing cholangitis and inflammatory boweldiseaseSimon Lam1, Immaculeta Osuji2, Annika Yang vom Hofe2,Ruchi Singh2, Cyd Castro Rojas2, Astha Malik2, Jonathan Dillman3,Divya Sharma4, Rebekah Karns2, Rana Herro5, Alexander Miethke2.1Alberta Children’s Hospital, Pediatric Gastroenterology, Hepatology andNutrition, Calgary, Canada; 2Cincinnati Children’s Hospital MedicalCenter, Division of Pediatric Gastroenterology, Hepatology and Nutrition,Cincinnati, United States; 3Cincinnati Children’s HospitalMedical Center,Radiology, Cincinnati, United States; 4University of Cincinnati College ofMedicine, Pathology, Cincinnati, United States; 5Cincinnati Children’sHospital Medical Center, Immunobiology, Cincinnati, United StatesEmail: simon.lam@albertahealthservices.caBackground and aims: Sclerosing cholangitis (SC) including primarysclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis(ASC) are highly associated with inflammatory bowel disease (IBD),most commonly ulcerative colitis (UC), and SC-IBD may represent aunique IBD phenotype.We previously reported Th17.1 polarization inliver tissue, using both liver RNAs-seq and multi-parameterimmunofluorescence, to segregate with SC-IBD. In the presentstudy, we aim to discover biomarkers that selectively segregatewith SC-IBD.Method: Circulating plasma proteins were assayed by Slow Off-rateModified Aptamer (SOMAscan) technology on children in 2 separatecohorts of SC-IBD and healthy controls (HC) (A: SC-IBD = 17, meanage = 15.4 years, male = 10, UC = 8; HC = 13, mean age = 17.8 years,male = 7; B: SC-IBD = 11, mean age = 16.1 years, male = 9, UC = 8; HC =8, mean age = 14.1 years, male = 3). Significantly differentiallyexpressed proteins determined by Wilcoxon Rank Sum test andcorrected using a false discovery rate of <5% in cohort A werevalidated in cohort B using logistic regression. Spearman rank ordercorrelation was used to correlate significant circulating plasmaproteins and liver biochemistries.Results: Of 1305 circulating plasma proteins assayed, 215 proteinswere nominally significant between SC-IBD and HC in cohortA. Pathways related to TH1 and TH2 cell differentiation, TNF, and IL-17 signaling pathways were upregulated in childrenwith SC-IBD. Tenof these 215 proteins were validated in cohort B with increasedconcentrations of CXCL8, TIMP1, FGF23, FCGR3B, PIGR, SCARB2,TNFRSF1A and Fn14, while ACY1 and CTSD were the only proteinswith decreased concentrations in SC-IBD compared toHC. SC-IBD hada 3.7-fold increase in Fn14 compared to HC, highest among allvalidated proteins (Table 1). Concentrations of circulating Fn14correlated with AST (rs = 0.40, p = 0.03) and GGT (rs = 0.37, p = 0.04).Table 1:Mean concentrationsϮ of significantly differentiallyexpressedcirculating plasma proteins in children with SC-IBD compared to HCassayed by SOMAscanProtein HC SC-IBDFold Change(SC-IBD/HC)Correctedp valueFn14 377 1398 3.71 <0.001SCARB2 441 872 1.98 <0.001PIGR 12040 18706 1.55 <0.001TNFRSF1A 1423 1962 1.38 <0.001CXCL8 2407 3229 1.34 <0.001TIMP1 482 500 1.04 <0.001FCGR3B 2225 2265 1.02 <0.001ACY1 16734 16609 0.99 <0.001CTSD 1462 1421 0.97 <0.001ϮConcentrations of proteins expressed as relative fluorescent units (RFU)calibrated to a standard curveConclusion: Large scale plasma proteomic analysis discoveredcirculating Fn14 to segregate with pediatric SC-IBD and to correlatewith biomarkers of SC liver disease. Fn14 was previously shown topromote TH17 polarization in autoimmune conditions like rheuma-toid arthritis. The role of Fn14 in driving hepatic TH17.1 requiresfurther investigations.PO-1809Efficacy, safety, and tolerability of seladelpar in patients withcompensated liver cirrhosis due to primary biliary cholangitis(PBC): a pooled analysis of phase 2 and phase 3 studiesStuart C. Gordon1, Palak Trivedi2, Christopher Bowlus3,Galambos Michael4, Aparna Goel5, Aliya Gulamhusein6,Cynthia Levy7, Guy Neff8, Carmen Stanca9, Douglas Thorburn10,Bruce Bacon11, Brian Borg12, Yvonne Doerffel13, Lisa Forman14,Bradley Freilich15, Liana Gheorghe16, María Saraí González17,Stephen Harrison18, Jonathan Huang19, Sook-Hyang Jeong20,Seung Up Kim21, John Lake22, Joseph Odin23, Won Young Tak24,Hillel Tobias25, John M. Vierling26, Ke Yang27,Alexandra (Sasha) Steinberg27, Yun-Jung Choi27,Charles McWherter27, Marlyn J. Mayo28. 1Henry Ford Health System,Detroit, United States; 2University Hospital Birmingham, Birmingham,United Kingdom; 3University of California Davis Medical Center,Sacramento, United States; 4Digestive Healthcare of Georgia, Atlanta,United States; 5Stanford Hospital, Stanford, United States; 6TorontoGeneral Hospital, Toronto, Canada; 7University of Miami, Miami, UnitedStates; 8Covenant Research, Sarasota, United States; 9NYU LangoneHealth, New York, United States; 10Royal Free Hospital, London, UnitedKingdom; 11Saint Louis University School of Medicine, St. Louis, UnitedStates; 12Jackson Liver and GI Specialists, Jackson, United States;13Charite, Berlin, Germany; 14University of Colorado, Aurora, UnitedStates; 15Kansas City Research Institute, Kansas City, United States;16Fundeni Clinical Institute, Bucharest, Romania; 17Consultorio de laDoctora Maria Sarai Gonzalez Huezo, Metepec, Mexico; 18PinnacleClinical Research, San Antonio, United States; 19University of Rochester,Rochester, United States; 20Seoul National University Bundang Hospital,Bundang-Gu, Seongnam-Si, Korea, Rep. of South; 21Severance HospitalYonsei University Health System, Seodaemun-Gu, Korea, Rep. of South;22University of Minnesota, Minneapolis, United States; 23Mount SinaiHospital, New York, United States; 24Kyungpook National UniversityHospital, Daegu, Korea, Rep. of South; 25Concorde Medical Group,New York, United States; 26Baylor College of Medicine, Houston, UnitedStates; 27CymaBay Therapeutics, Newark, United States; 28University ofTexas Southwestern, Dallas, United StatesEmail: ychoi@cymabay.comBackground and aims: Patients with PBC and compensated cirrhosiscan progress to decompensation with its associated complications,liver transplantation or death. PBC patients with an incompleteresponse or intolerance to UDCA have an unmet need to slow diseaseprogression. Seladelpar, a selective PPAR delta agonist, has shownpotent anti-cholestatic and anti-pruritic activity in PBC studies. Wenow report a pooled analysis from two studies assessing the efficacy,safety, and tolerability of seladelpar in PBC patients with compen-sated cirrhosis.Method: Eligible PBC patients with an inadequate response orintolerance to UDCA (ALP ≥1.67 × ULN) were enrolled into an open-label phase 2 study (EudraCT 2016-002996-91) or a placebo (Pbo)-controlled phase 3 study (EudraCT 2018-001171-20). Cirrhosis wasdiagnosed using liver biopsy, imaging tests, or liver elastography.Patients received oral Pbo, seladelpar 5 mg or 10 mg once daily +UDCA if tolerated. Efficacy analyses at 3 months included compositeresponse (ALp <1.67 × ULN, ALP decrease of ≥15% and total bilirubin[TB] ≤ULN), ALP % change, ALP ≤ULN, and changes in liver function.Safety was assessed for 3 months.Results: Of 384 enrolled patients, 53 had compensated cirrhosis(Child-Pugh A: Pbo [n = 7], 5 mg [n = 22], and 10 mg [n = 24]).Baseline characteristics included: 92% female, mean age 58 yrs, 94%POSTER PRESENTATIONSS686 Journal of Hepatology 2021 vol. 75(2) | S294–S803Downloaded for Anonymous User (n/a) at Henry Ford Hospital / Henry Ford Health System (CS North America) from ClinicalKey.com by Elsevier on August 25, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.on UDCA, ALP 287 U/L, TB 0.92 mg/dL, ALT 50 U/L, AST 49 U/L, GGT228 U/L, albumin 3.96 g/dL, and platelets 197 × 103/µL. After 3months, 39 patients were treated. The composite end point wasmet in 50% (9/18) of 5 mg and 63% (10/16) of 10 mg groups comparedto none in Pbo (0/5). Reductions in ALP in the 5 mg (-31%,− 82 U/L)and 10 mg groups (−41%, −114 U/L) were greater than Pbo (−2.6%,−8.7 U/L). ALP was normalized in 3 patients in each seladelpar group(17–19%) but none in Pbo. Changes in ALT were −15%, −6%, and −32%in Pbo, 5 and 10 mg groups, respectively. Total bilirubin, platelets,albumin, and INR remained stable. One patient in 10 mgdiscontinueddue to AE (pruritus). Three patients had an SAE: 2 on 5 mg (febrileneutropenia, procedural pain) and 1 on 10 mg (angina pectoris), allunrelated to study drug. Efficacy, tolerability, and safety in patientswith compensated cirrhosis were comparable to that of non-cirrhoticpatients.Figure:Conclusion: Seladelpar appeared safe and was well tolerated andmay provide an effective treatment option for patients withcompensated liver cirrhosis due to PBC.PO-1811Odevixibat effects on cholestasis-related parameters: Analysis ofpooled data from the PEDFIC 1 and PEDFIC 2 studies in childrenwith progressive familial intrahepatic cholestasisRichard Thompson1, Reha Artan2, Ulrich Baumann3,Piotr Czubkowski4, Buket Dalgıç5, Ozlem Durmaz6,Emmanuel Gonzales7, Tassos Grammatikopoulos1,8, Girish Gupte9,Patrick Horn10, Alain Lachaux11, Patrick McKiernan12, Hasan Ozen13,Sanjay Rajwal14, Bertrand Roquelaure15, Ekkehard Sturm16,Henkjan Verkade17, Qifeng Yu10, Lise Kjems10. 1Institute of LiverStudies, King’s College London; 2Akdeniz University; 3Hannover MedicalSchool; 4The Children’s Memorial Health Institute; 5Gazi UniversityFaculty of Medicine; 6Istanbul University; 7Hôpital Bicêtre, AP-HP,Université Paris-Saclay, Hépatinov, Inserm U 1193; 8King’s CollegeHospital NHS Trust, Pediatric Liver, GI and Nutrition Centre;9Birmingham Women’s and Children’s NHS Foundation Trust; 10AlbireoPharma, Inc.; 11Hospices Civils de Lyon, Hôpital Femme-Mer̀e-Enfant;12UPMC Children’s Hospital of Pittsburgh; 13Hacettepe UniversityFaculty of Medicine; 14Leeds Teaching Hospitals NHS Trust, LeedsChildren’s Hospital; 15CHU, Hospital de la Timone; 16UniversityChildren’s Hospital Tübingen; 17University of Groningen, BeatrixChildren’s Hospital/University Medical Center GroningenEmail: lise.kjems@albireopharma.comBackground and aims: Odevixibat, an ileal bile acid transporterinhibitor, is in development to treat cholestatic liver diseases. In thephase 3 PEDFIC 1 (P1) and PEDFIC 2 (P2) studies, odevixibattreatment reduced serum bile acids (sBAs) and improved pruritusin patients with progressive familial intrahepatic cholestasis (PFIC).Using pooled data from these studies, we analysed changes inparameters of cholestasis, pruritus, and hepatic laboratory markersand compared patients who responded to odevixibat treatment (Rs)with non-responders (NRs).Method: P1was a 24-week, randomized, placebo-controlled study inchildren with PFIC1 or PFIC2, and P2 is an ongoing, 72-weekextension study in patients with any type of PFIC. In this pooledanalysis, spanning 48 weeks, 77 patients have received odevixibat(PFIC1, n = 20; PFIC2, n = 51; PFIC3, n = 5; MYO5B deficiency, n = 1;overall median exposure: 37 weeks). Two responder definitions wereexamined: 1) sBA response (ie, sBAs <65 or <102 μmol/L for PFIC1 andPFIC2, respectively) and 2) sBA response or pruritus response (ie, a≥1-point drop from baseline in PRUCISION score).Results: Rates of sBA Rs and sBA or pruritus Rs were 31% and 57%,respectively, at weeks 0–24, 48% and 60% at weeks 25–36, and 59%and 65% at weeks 37–48. Among all odevixibat-treated patients,mean change from baseline (CFB) to week 48 in alanine amino-transferase (ALT) and total bilirubin was −82 U/L and −18 μmol/L,respectively. In general, Rs had greater mean CFB (ie, improvements)vs NRs in these hepatic laboratory parameters with long-termodevixibat treatment (Table) that started as early as week 4 andincreased over time.Table:Liver EnzymeLevelssBA Response sBA or Pruritus ResponseYes No Yes Non(%a)Mean(SE) mMean(SE)n(%a)Mean(SE) mMean(SE)ALT, U/LBaseline 24(39)124(33)38 82(12)48(63)104(18)28 69(11)CFB→wk 4 23(39)−28(37)36 21(16)43(61)−2(24)27 9 (4)CFB→wk 24 19(40)−67(42)28 −10(11)31(62)−56(27)19 5 (8)CFB→wk 48 15(63)−112(57)9 −32(22)18(75)−108(48)6 −5(15)Total bilirubin,μmol/LBaseline 24(39)27 (7) 38 74(12)48(63)42 (6) 28 67(16)CFB→wk 4 23(39)−8 (4) 36 −10(9)43(61)−6 (4) 27 −14(11)CFB→wk 24 19(40)−23(8)28 −19(10)31(62)−19(7)19 −23(13)CFB→wk 48 15(63)−25(11)9 −6(14)18(75)−25(9)6 1 (20)aResponder rate ([n/(n +m)] × 100).Conclusion: Patients with PFIC who responded to odevixibattreatment had sustained improvements in cholestasis-related para-meters that were not observed to the same extent in treatment non-responders.PO-1828Geneticmutation and cystic fibrosis-associated liver disease at thetime of diagnosis in children: A correlational studyAlejandra Marisela Sabillon-Mendoza1, Rubén Peña Velez1,Flora Zarate1, Jaime Ramirez1. 1Instituto Nacional de Pediatría,Gastroenterología y Nutrición, Ciudad de México, MexicoEmail: alesabillon@yahoo.comBackground and aims: It is estimated that 10 to 15% of patients withcystic fibrosis have liver disease (CFLD), this negatively impacts theevolution of the disease, it has been reported that dysfunction of thetransmembrane conductance regulator (CFTR) has a direct effect onthe cholangiocyte function, finally the spectrum of complicationsranges from cholestasis, progressive fibrosis, biliary obstruction tofocal biliary cirrhosis. Around 2000 mutations in CFTR have beendetermined and classified according to their functional defect,however, none of them have been associated with CFLD, acceptingthat this is due to the interaction of environmental factors,POSTER PRESENTATIONSS687Journal of Hepatology 2021 vol. 75(2) | S294–S803Downloaded for Anonymous User (n/a) at Henry Ford Hospital / Henry Ford Health System (CS North America) from ClinicalKey.com by Elsevier on August 25, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

Efficacy, safety, and tolerability of seladelpar in patients with compensated liver cirrhosis due to primary biliary cholangitis (PBC): a pooled analysis of phase 2 and phase 3 studies

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Efficacy, safety, and tolerability of seladelpar in patients with compensated liver cirrhosis due to primary biliary cholangitis (PBC): a pooled analysis of phase 2 and phase 3 studies

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