Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

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.

Transition care to adolescent hepatology in a tertiary center for rare adult-child liver disease.

AIMS: This study analyzed the results of a transition program in a patient population with a rare liver disease of pediatric onset. METHOD: Data were collected on the clinical course of an adolescent population with a rare disease of pediatric onset and enrolled in a transition program between 1994 and 2022. RESULTS: A total of 238 adolescents (including 34 having undergone a liver transplant on enrolling in the program) were included. Eight patients were lost to follow-up before the first transition consultation and 16 families requested follow-up in an adult hepatology department closer to their home. Overall, 214 initial transition consultations were carried out; 29 patients were subsequently lost to follow-up and 13 switched center. Overall, 15.4 % of the patients enrolled in our program were lost to follow-up. Five adult patients underwent a liver transplantation during this 28-year period. Overall mortality was 3.2 %, graft survival was 91.5 %, and posttransplant survival was 92 %. In total, the current active file represents 183 patients with a median age of 24.3 years (18-51) and a median follow-up period of 5.8 years (6 months to 28 years). CONCLUSION: The implementation of a transition program to adult medicine for adolescents with a rare liver disease should follow the recommendations but must be adapted in line with local practice conditions. This process requires close collaboration between the pediatric and adult medicine teams based on a mutual desire to constantly improve practices and enhance knowledge.

Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis.

BACKGROUND: Cholestasis is a frequent and severe condition during childhood. Genetic cholestatic diseases represent up to 25% of pediatric cholestasis. Molecular analysis by targeted-capture next generation sequencing (NGS) has recently emerged as an efficient diagnostic tool. The objective of this study is to evaluate the use of NGS in children with cholestasis. METHODS: Children presenting cholestasis were included between 2015 and 2020. Molecular sequencing was performed by targeted capture of a panel of 34 genes involved in cholestasis and jaundice. Patients were classified into three categories: certain diagnosis; suggested diagnosis (when genotype was consistent with phenotype for conditions without any available OMIM or ORPHANET-number); uncertain diagnosis (when clinical and para-clinical findings were not consistent enough with molecular findings). RESULTS: A certain diagnosis was established in 169 patients among the 602 included (28.1%). Molecular studies led to a suggested diagnosis in 40 patients (6.6%) and to an uncertain diagnosis in 21 patients (3.5%). In 372 children (61.7%), no molecular defect was identified. CONCLUSIONS: NGS is a useful diagnostic tool in pediatric cholestasis, providing a certain diagnosis in 28.1% of the patients included in this study. In the remaining patients, especially those with variants of uncertain significance, the imputability of the variants requires further investigations.

Porto-Sinusoidal Vascular Disease: A Pediatric Study of 30 Patients.

OBJECTIVES: Porto-sinusoidal vascular disease (PSVD) refers to a broad spectrum of histological lesions and phenotypic expressions. There are only a few reported pediatric cases in the literature. The primary outcomes of this study were to describe the phenotype of children with PSVD, to specify their mode of presentation and their clinical, biological, histological, and radiological characteristics as well as to identify their underlying etiologies. METHODS: This is a descriptive, retrospective, and monocentric study of children followed at our reference center for rare vascular liver diseases. RESULTS: Our study included 30 children ages 2months to 17.4years at the time of diagnosis. in most cases, the diagnosis was made incidentally without manifestation of any clinical symptom but rather on the finding of splenomegaly on physical examination (n = 9) or biological abnormalities (n = 13). In the other cases, the main presenting symptom was an upper gastrointestinal bleeding (n = 6). At the first visit, liver laboratory values were either normal (37%) or slightly disturbed. Anemia and/or thrombocytopenia associated with hypersplenism were found in 60% of patients. Liver biopsy was necessary for diagnosis. A total of 80% of cases had no identified etiology. After a median follow-up of 4.5 years, 33% had not developed portal hypertension (PHT) and we reported the first pediatric case of hepatocellular carcinoma in PSVD children. CONCLUSIONS: PSVD is responsible for nonspecific symptomatology with variable evolution sometimes marked by serious complications requiring invasive treatments or even liver transplantation. Regular monitoring is essential to prevent, detect, and treat complications.

Correlation Between Clinical Signs and High-resolution Manometry Data in Children.

OBJECTIVES: High-resolution manometry (HRM) is the gold standard for diagnosis of esophageal motility disorders. However, clinical signs associated with these disorders are nonspecific, and it is difficult to correlate clinical signs with HRM data. The main objective of our study was to assess the positive predictive value (PPV) and negative predictive value (NPV) of each clinical sign, as well as their sensitivity and specificity in the diagnosis of esophageal motility disorders. METHODS: This is a bicentric retrospective cohort study based on HRM data collected between May 2012 and May 2016. The studied symptoms were weight loss, feeding difficulties, swallowing disorders, dysphagia, food blockages, vomiting, gastroesophageal reflux disease (GERD), belching, and respiratory symptoms. HRM data were analyzed according to the Chicago Classification (3.0). RESULTS: In total, 271 HRM data were analyzed, of which 90.4% showed abnormal results. HRM was well tolerated in 91% of the cases. The most common esophageal motility disorder was ineffective esophageal motility (38%). Weight loss was significantly associated (P = 0.003) with an abnormal HRM with a 96% PPV. CONCLUSIONS: With nonspecific clinical signs suggesting an esophageal motility disorder, weight loss was a predictive sign of abnormal HRM results. HRM was well tolerated in pediatric patients, and ineffective esophageal motility appears to be the most frequent motility disorder in our cohort, as already observed in adult patient studies.