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.
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.