Long-Term Maintenance of Response and Improved Liver Health With Maralixibat in Patients With Progressive Familial Intrahepatic Cholestasis (PFIC): 2-Year Data From the MARCH-ON Study

E. SOKAL (1), A. MIETHKE (2), A. MOUKARZEL (3), G. PORTA (4), J. ESQUER (5), P. CZUBKOWSKI (6), F. ORDONEZ (7), M. CANDUSSO (8), A. AQUL (9), R. SQUIRES (10), D. D'AGOSTINO (11), U. BAUMANN (12), L. D'ANTIGA (13), N. KASI (14), N. LABORDE (15), C. ARIKAN (16), C. LIN (17), S. GILMOUR (18), N. MITTAL (19), F. CHIOU (20), S. HORSLEN (21), W. HUBER (22), T. NUNES (23), A. LASCAU (23), L. LONGPRE (23), D. MOGUL (23), M. BAEK (24), P. VIG (23), V. HUPERTZ (25), R. GONZALEZ-PERALTA (26), U. EKONG (27), J. HARTLEY (28), N. LAVERDURE (29), N. OVCHINSKY (30), R. THOMPSON (31) / [1] UCLouvain, Cliniques Universitaires St Luc, , Belgium, Pediatric Hepatology, [2] Cincinnati Chilren's Hospital, , United States (the), Pediatric Hepatology, [3] Hôtel Dieu de France Saint Joseph, , Lebanon, Pediatric Gastroenterology, [4] Hospital Sírio-Libanês, , Brazil, Hospital Sírio-Libanês, [5] Nois de México, , Mexico, Pediatric Hepatology, [6] The Children's Memorial Health Institute, Warsaw, Poland, Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, [7] Foundation-La Cardio, Bogota, Colombia, Cardioinfantil, [8] Ospedale Pediatrico, Lazio, Italy, Bambino Gesù Irccs, [9] University of Texas Southwestern, Dallas, United States (the), Pediatric Hepatology, [10] UPMC, Pittsburgh, United States (the), Children’s Hospital of Pittsburgh, [11] Hospital Italiano de Buenos Aires, Buenos Aires, Argentina, Pediatric Gastro-hepatology, [12] Hannover Medical School, Hannover, Germany, Pediatric Gastroenterology and Hepatology, , [13] Hospital Papa Giovanni XXIII, Bergamo, Italy, Paediatric Hepatology, Gastroenterology and Transplantation, [14] Medical University of South Carolina, Charleston, United States (the), Pediatric Gastroenterology, [15] Hôpital des Enfants, Toulouse, France, Pediatric Gastroenterology, [16] Koc University School of Medicine, Istanbul, Turkey, Pediatric Gastroenterology Hepatology and Nutrition, [17] Children's Hospital Los Angeles, Los Angeles, United States (the), Hepatology at the Division of Gastroenterology, [18] University of Alberta, Alberta, Canada, Pediatrics, [19] University of Texas Health Science Center, San Antonio, United States (the), Pediatric Gastroenterology, Hepatology & Nutrition, [20] KK Women's and Children's Hospital, Singapore, Singapore, Paediatric Gastroenterology, [21] UPMC, Pittsburgh, United States (the), Pediatric Hepatology, [22] Medical University of Vienna, Vienna, Austria, Pediatric Hepatology, [23] Mirum Pharmaceuticals, Inc., Foster City, United States (the), Medical, [24] Mirum Pharmaceuticals, Inc., Foster City, United States (the), Biostats, [25] Cleveland Clinic Children's, Cleveland, United States (the), Pediatric Hepatology and Liver Transplantation, [26] AdventHealth for Children and AdventHealth Transplant Institute, Orlando, United States (the), Pediatric Gastroenterology, Hepatology, and Liver Transplant, [27] MedStar Georgetown University Hospital, Washington, United States (the), MedStar Georgetown Transplant Institute, [28] Birmingham Women and Children's Hospital,, Birmingham, United Kingdom (the), Paediatric Hepatology, [29] Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France, Pediatric Hepato Gastroenterology and Nutrition Unit, [30] New York University Grossman School of Medicine, New York, United States (the), Pediatric Hepatology, [31] King's College Hospital London, London, United Kingdom (the), Institute of Liver Studies + Introduction Progressive familial intrahepatic cholestasis (PFIC) is a group of genetic disorders resulting in disrupted bile composition, cholestasis, and pruritus. Maralixibat (MRX) is a minimally absorbed ilea I bile acid transporter inhibitor which prevents enterohepatic bile acid recirculation. In the 26-week placebo-controlled MARCH Phase 3 study, MRX at 570 μg/kg BID demonstrated significant improvements in pruritus, serum bile acids (sBA), total bilirubin (TB) and growth in patients across the broadest range of PFIC types studied to date. Aim We report on long-term maintenance of effect of up to 2 years of treatment with MRX in MARCH-ON, an open-label, long-term extension study of MARCH. Methods Long-term maintenance of response was assessed for patients who were originally randomised to receive MRX in MARCH and continued with treatment in MARCH-ON (MRX-MRX group: n=33; BSEP [n=14], FIC1 [n=7], MDR3 [4], TJP2 [6], MYOSB [2]), and for patients who received placebo (PBO) in the MARCH study and switched to open-label MRX in MARCH-ON (PBO-MRX group: n=27; BSEP [n=14], FIC1 [n=6], MDR3 [n=5], TJP2 [n=1], MYO5B [n=1]). Assessments included: pruritus, sBA, TB, growth z-scores, and incidence of treatment-emergent adverse events (TEAEs). Baseline (BL) was defined as the start of MRX for each group. Results For the MRX-MRX group, the median (min, max) time on MRX was 638 days (108, 1023). 13 of 33 patients reached Week 104 at time of analysis. Significant improvements observed in the first 26 weeks of the MARCH study were sustained through Week 104 in MARCH-ON for pruritus (-2.03, p<0.0001), sBA (-166 μmol/L, p=0.003), TB (-1.6 mg/dL, p=0.02), and growth (height z-score: +0.40, p=0.046; weight z-score: +0.52, p=0.01 ). In the PBO-MRX group, the median time on MRX was 475 days (72, 720). 18 of 27 patients reached Week 52 of MRX treatment at time of analysis. Significant improvements through Week 52 for pruritus (-1.1, p=0.0001), sBA (-71 μmol/L, p=0.03), and growth (height z-score: +0.37, p=0.01; weight z-score: +0.32, p=0.03) were in line with observations from the initial MARCH MRX group. Additionally, numeric reductions in TB (-0.4 mg/dL; p=0.7) were observed. No new safety signals were identified. The most common TEAEs were GI-related with diarrhoea (50%) being mostly mild and transient. Conclusions Significant and sustained improvements in pruritus, sBA, TB, and growth are observed with up to 2 years of MRX treatment across the broadest range of genetic PFIC types studied to date. These data suggest overall improved liver health with MRX treatment which can be maintained long-term.

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