Author information

¹Section of Pediatric Gastroenterology, Hepatology and Nutrition and the Digestive Health Institute, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, Colorado, USA.

²Pediatric Hepatology and Liver Transplantation Unit, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques (AVB-CG), FSMR FILFOIE, ERN RARE LIVER, Hôpital Bicêtre, AP-HP, Faculté de Médecine Paris-Saclay, Le Kremlin-Bicêtre, and Inserm U1193, Hepatinov, Université Paris-Saclay, Orsay, France.

³The Hospital for Sick Children and the University of Toronto, Division of Gastroenterology, Hepatology and Nutrition, Toronto, Ontario, Canada.

⁴Paediatric Liver Centre, King's College Hospital, London, UK.

⁵Mirum Pharmaceuticals, Inc., Foster City, California, USA.

⁶Toronto General Hospital and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.

⁷Institute of Liver Studies, King's College London, London, UK.

Abstract

Background aims: Refractory pruritus and other complications of cholestasis are indications for liver transplantation (LT) in patients with Alagille syndrome (ALGS). We evaluated predictors of event-free survival (EFS) and transplant-free survival (TFS) in ALGS patients treated with maralixibat (MRX), an ileal bile acid transporter inhibitor.

Approach results: We assessed ALGS patients from three clinical trials of MRX with up to 6 years of follow-up. EFS was defined as absence of LT, surgical biliary diversion (SBD), hepatic decompensation, or death; TFS was absence of LT or death. Forty-six potential predictors were evaluated, including age, pruritus (ItchRO[Obs] 0-4 scale), biochemistries, platelets, and serum bile acids (sBA). Harrell's concordance statistic assessed goodness-of-fit, then Cox proportional hazard models confirmed the statistical significance of the predictors identified. A further analysis was performed to identify cutoffs using a grid search. Seventy-six individuals met criteria of receiving MRX for ≥ 48 weeks with laboratory values available at Week 48 (W48). Median duration of MRX was 4.7 years (IQR: 1.6-5.8); 16 had events (10 LT, 3 decompensation, 2 death, 1 SBD). 6-year EFS improved with a clinically meaningful > 1-point ItchRO(Obs) reduction from baseline to W48 (88% vs. 57%; p = 0.005), W48 bilirubin < 6.5 mg/dL (90% vs. 43%; p < 0.0001), and W48 sBA < 200 µmol/L (85% vs. 49%; p = 0.001). These parameters were also predictive of 6-year TFS.

Conclusions: Improvement in pruritus over 48 weeks and lower W48 bilirubin and sBA levels were associated with fewer events. These data may help identify potential markers of disease progression for MRX-treated ALGS patients.