Lancet Gastroenterol Hepatol. 2024 Jul;9(7):620-631.doi: 10.1016/S2468-1253(24)00080-3. Epub 2024 May 6.

Alexander G Miethke ¹, Adib Moukarzel ², Gilda Porta ³, Joshue Covarrubias Esquer ⁴, Piotr Czubkowski ⁵, Felipe Ordonez ⁶, Antonella Mosca ⁷, Amal A Aqul ⁸, Robert H Squires ⁹, Etienne Sokal ¹⁰, Daniel D'Agostino ¹¹, Ulrich Baumann ¹², Lorenzo D'Antiga ¹³, Nagraj Kasi ¹⁴, Nolwenn Laborde ¹⁵, Cigdem Arikan ¹⁶, Chuan-Hao Lin ¹⁷, Susan Gilmour ¹⁸, Naveen Mittal ¹⁹, Fang Kuan Chiou ²⁰, Simon P Horslen ⁹, Wolf-Dietrich Huber ²¹, Thomas Jaecklin ²², Tiago Nunes ²³, Anamaria Lascau ²³, Lara Longpre ²³, Douglas B Mogul ²³, Will Garner ²³, Pamela Vig ²³, Vera F Hupertz ²⁴, Regino P Gonzalez-Peralta ²⁵, Udeme Ekong ²⁶, Jane Hartley ²⁷, Noemie Laverdure ²⁸, Nadia Ovchinsky ²⁹, Richard J Thompson ³⁰

Author information

¹UC Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: alexander.miethke@cchmc.org.

²Pediatric Gastroenterology, Hepatology and Nutrition, Hotel Dieu De France Saint Joseph University Hospital, Beirut, Lebanon.

³Gastroenterology and Pediatrics, Hospital Sirio Libanes, Sao Paulo, Brazil.

⁴Department of Pediatrics, Nois De Mexico SA De CV, Jalisco, Mexico.

⁵Department of Gastroenterology, Hepatology, and Immunology, The Children's Memorial Health Institute, Warsaw, Poland.

⁶Pediatric Gastroenterology, Cardioinfantil Foundation-Lacardio, Bogota, Colombia.

⁷Transplant Department, Ospedale Pediatrico Bambino Gesu Irccs, Lazio, Italy.

⁸Pediatric Gastroenterology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

⁹Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.

¹⁰Gastroenterology and Hepatology, UClouvain, Cliniques Universitaires St Luc, Brussels, Belgium.

¹¹Department of Pediatric Gastro-hepatology, Hospital Italiano De Buenos Aires, Buenos Aires, Argentina.

¹²Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.

¹³Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy; Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

¹⁴Pediatric Gastroenterology, Medical University of South Carolina, Charleston, SC, USA.

¹⁵Pediatric Hereditary Metabolic Diseases, Hôpital Des Enfants-CHU Toulouse, Toulouse, France.

¹⁶Pediatrics Department, Koc University School of Medicine, Istanbul, Turkey.

¹⁷Gastroenterology, Hepatology and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA.

¹⁸Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.

¹⁹Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

²⁰Paediatric Gastroenterology, Hepatology and Nutrition, KK Women's and Children's Hospital, Singapore.

²¹Department of Pediatric Nephrology and Gastroentereology, Medical University of Vienna, Vienna, Austria.

²²Galapagos, Basel, Switzerland.

²³Clinical Development, Scientific Affairs and Engagement, Biometrics, and Research Departments, Mirum Pharmaceuticals, Foster City, CA, USA.

²⁴Pediatric Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic Children's, Cleveland, OH, USA.

²⁵Pediatric Gastroenterology, AdventHealth for Children and AdventHealth Transplant Institute, Orlando, FL, USA.

²⁶Transplant Hepatology, Pediatric Hepatology, Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, DC, USA.

²⁷Paediatric Hepatology, Birmingham Women's and Children's Hospital, Birmingham, UK.

²⁸Pediatric Hepatology, Gastroenterology, and Nutrition Unit, Hopital Femme Mere Enfant, Hospices Civils De Lyon, Lyon, France.

²⁹Pediatric Gastroenterology and Hepatology, New York University Grossman School of Medicine, New York, NY, USA.

³⁰Department of Inflammation Biology, Institute of Liver Studies, King's College London, London, UK.

Abstract

Background: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC.

Methods: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 μg/kg, then escalated to 570 μg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22.

Findings: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 μmol/L (95% CI -257 to -94) for maralixibat versus 11 μmol/L (-58 to 80) for placebo, also representing a significant difference of -187 μmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred.

Interpretation: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC.

Funding: Mirum Pharmaceuticals.