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.

Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.

Predictors of 6-year event-free survival in Alagille syndrome patients treated with maralixibat, an ileal bile acid transporter inhibitor.

BACKGROUND AND 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 and transplant-free survival in patients with ALGS treated with maralixibat (MRX), an ileal bile acid transporter inhibitor. APPROACH AND RESULTS: We assessed patients with ALGS from 3 clinical trials of MRX with up to 6 years of follow-up. Event-free survival was defined as the absence of LT, surgical biliary diversion, hepatic decompensation, or death; transplant-free survival was the absence of LT or death. Forty-three potential predictors were evaluated, including age, pruritus (ItchRO[Obs] 0-4 scale), biochemistries, platelets, and serum bile acids. Harrell's concordance statistic assessed goodness-of-fit, and 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 the criteria of receiving MRX for ≥48 weeks with laboratory values available at week 48 (W48). The median duration of MRX was 4.7 years (IQR: 1.6-5.8); 16 had events (10 LT, 3 decompensation, 2 death, and 1 surgical biliary diversion). The 6-year event-free survival 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 serum bile acid < 200 µmol/L (85% vs. 49%; p = 0.001). These parameters were also predictive of 6-year transplant-free survival. CONCLUSIONS: Improvement in pruritus by 48 weeks, and lower W48 bilirubin and serum bile acid levels were associated with fewer events. These data may help identify potential markers of disease progression for ALGS patients treated with MRX.

Costs of pediatric liver transplantation among commercially insured and Medicaid-insured patients with cholestasis in the US.

Children with rare cholestatic liver diseases, such as Alagille syndrome, progressive familial intrahepatic cholestasis, and biliary atresia typically require liver transplantation (LT). The objective of this analysis was to assess the economic burden of LT on these patients. Health care resource utilization and costs associated with pediatric LT were retrospectively assessed using insurance claims data from the US IBM MarketScan Commercial and Medicaid databases collected between October 2015 and December 2019. Inclusion criteria were as follows: ≥1 procedure code for LT, <18 years old at transplant, and ≥6 months of insurance eligibility at baseline. A cholestatic liver disease population who received LT was selected in the absence of specific diagnosis codes by excluding other severe liver conditions (ie, acute liver failure, malignancy) and by excluding severely decompensated individuals requiring ICU admission before LT. Annualized rates were reported. Over a mean study duration of 1.8 years, 53 commercially insured and 100 Medicaid-insured children received LT, with mean (SD) ages at baseline of 6.9 (6.0) and 5.7 (5.4) years, respectively. During this period, commercially insured and Medicaid-insured patients had annualized means of 65.3 and 52.8 medical visits, respectively. Most were outpatient visits, although the burden of inpatient visits was also high, with mean inpatient stays (inclusive of LT stay) of 37.2 and 31.6 days per year, respectively. Commercially insured and Medicaid-insured patients averaged US$512,124 and $211,863 in medical costs and $26,998 and $15,704 in pharmacy costs, respectively. These costs remained substantial throughout the first year after transplant. Overall, pediatric LT resulted in substantial health care resource utilization and cost burden in both commercially- and Medicaid-insured patients. Novel targeted medications that negate the need for pediatric LT could decrease the associated morbidity and costs.

Health Care Resource Utilization by Patients with Alagille Syndrome.

OBJECTIVE: To assess and characterize health care resource utilization (HRU) in children with the rare, genetic, multisystem disorder, Alagille syndrome. STUDY DESIGN: This retrospective analysis reviewed commercially insured and Medicaid-insured claims from October 1, 2015 to December 31, 2019 to assess HRU in patients with Alagille syndrome. As there is no specific International Classification ofDiseases-10 code for Alagille syndrome, patients were identified using the following algorithm: ≥1 claim with diagnosis code Q44.7 (other congenital malformations of the liver); <18 years of age, with no history of biliary atresia (International Classification ofDiseases-10 code: Q44.2); and ≥6 months of insurance eligibility prior to diagnosis. HRU was summarized per patient per year over all available claims postdiagnosis. RESULTS: A total of 171 commercially insured and 215 Medicaid-insured patients with Alagille syndrome were available for analysis. Annually, commercially insured and Medicaid-insured patients averaged 31 medical visits (range, 1.5-237) and 48 medical visits (range, 0.7-690), respectively. The most common visits were outpatient with the majority encompassing lab/imaging and primary care visits (commercially insured: 21 [range, 0.0-183]; Medicaid-insured: 26 [range, 0.0-609]). Inpatient visits were the highest driver of costs in both the commercial and Medicaid populations. CONCLUSIONS: Patients with Alagille syndrome have a substantial HRU burden driven largely by numerous outpatient visits and costly inpatient stays. Given the complexity and variability of Alagille syndrome presentation, patients may benefit from multidisciplinary and subspecialized care.

Hepatorenal dysfunction assessment with the Model for End-Stage Liver Disease Excluding INR score predicts worse survival after heart transplant in pediatric Fontan patients.

BACKGROUND: Fontan physiology results in multiorgan dysfunction, most notably affecting the liver and kidney. We evaluated the utility of Model for End-Stage Liver Disease Excluding INR (MELD-XI) score, a score evaluating the function of both liver and kidney to identify Fontan patients at increased risk for morbidity and mortality post-heart transplant. METHODS: The Pediatric Heart Transplant Society database was queried to identify Fontan patients listed for heart transplant between January 2005 and December 2018. MELD-XI scores were calculated at listing and heart transplant. A multivariable analysis was conducted to identify risk factors for post-heart transplant mortality. Demographic, clinical characteristics, and survival differences were evaluated and compared between the high and low MELD-XI score cohorts. The impact of changing MELD-XI scores during the waitlist period on post-heart transplant outcomes was also evaluated. RESULTS: Of 565 Fontan patients who underwent transplantation, 524 (93%) had calculable MELD-XI scores at the time of heart transplant: 421 calculable at listing and 392 calculable at listing and at heart transplant. On multivariable analysis, only MELD-XI score (squared) (hazard ratio, 1.007), history of protein-losing enteropathy (hazard ratio, 2.1), and ventricular assist device use at transplant (hazard ratio, 3.4) were risk factors for early phase post-heart transplant mortality. Patients with high MELD-XI scores at heart transplant had inferior survival post-heart transplant (P = .02); those in the high MELD-XI score cohort at wait listing and heart transplant tend to have the worst post-heart transplant survival; however, this was not significant (P = .42). CONCLUSIONS: The MELD-XI, an easily calculated score, serves as a valuable aid in identifying pediatric Fontan patients at increased risk for post-heart transplant mortality.

Barriers to access in pediatric living-donor liver transplantation.

Children receiving a LDLT have superior post-transplant outcomes, but this procedure is only used for 10% of transplant recipients. Better understanding about barriers toward LDLT and the sociodemographic characteristics that influence these underlying mechanisms would help to inform strategies to increase its use. We conducted an online, anonymous survey of parents/caregivers for children awaiting, or have received, a liver transplant regarding their knowledge and attitudes about LDLT. The survey was completed by 217 respondents. While 97% of respondents understood an individual could donate a portion of their liver, only 72% knew the steps in evaluation, and 69% understood the donor surgery was covered by the recipient's insurance. Individuals with public insurance were less likely than those with private insurance to know the steps for LDLT evaluation (44% vs 82%; P < 0.001). Respondents with public insurance were less likely to know someone that had been a living donor (44% vs 56%; P = 0.005) as were individuals without a college degree (64% vs 85%; P = 0.007). Nearly all respondents generally trusted their healthcare team. Among respondents, 82% believed they were well-informed about LDLT but individuals with public insurance were significantly less likely to feel well-informed (67% vs 87%; P = 0.03) and to understand how donor surgery might impact donor work/time off (44% vs 81%; P = 0.001). Substantial gaps exist in parental understanding about LDLT, including its evaluation, potential benefits, and complications. Greater emphasis on addressing these barriers, especially to individuals with fewer resources, will be helpful to expand the use of LDLT.

Expansion of the Liver Donor Supply Through Greater Use of Split-Liver Transplantation: Identifying Optimal Recipients.

The increased use of split-liver transplantation (SLT) represents a strategy to increase the supply of organs. Although outcomes after SLT and whole liver transplantation (WLT) are similar on average among pediatric recipients, we hypothesized that the relationship between graft type and outcomes may vary depending on patient, donor, and surgical characteristics. We evaluated graft survival among pediatric (<18 years) deceased donor, liver-only transplant recipients from March 2002 until December 2015 using data from the Scientific Registry of Transplant Recipients. Graft survival was assessed in a Cox proportional hazards model, with and without effect modification between graft type and donor, recipient, and surgical characteristics, to identify conditions where the risk of graft loss for SLT and WLT were similar. In a traditional multivariable model, characteristics associated with graft loss included donor age >50 years, recipient weight <10 kg, acute hepatic necrosis, autoimmune diseases, tumor, public insurance, and cold ischemia time (CIT) >8 hours. In an analysis that explored whether these characteristics modified the relationship between graft type and graft loss, many characteristics associated with loss actually had similar outcomes regardless of graft type, including weight <10 kg, acute hepatic necrosis, autoimmune diseases, and tumor. In contrast, several subgroups had worse outcomes when SLT was used, including recipient weight 10-35 kg, non-biliary atresia cholestasis, and metabolic disease. Allocation score, share type, or CIT did not modify risk of graft type and graft failure. Although one might anticipate that individuals with higher rates of graft loss would be worse candidates for SLT, data suggest that these patients actually have similar rates of graft loss. These findings can guide surgical decision making and may support policy changes that promote the increased use of SLT for specific pediatric recipients.

Pediatric Liver Tumors.

Although liver tumors are rare in the pediatric population, they are common in the setting of children with specific risk factors requiring increased awareness and, in some instances, screening. The evaluation of a liver mass in children is largely driven by the age at diagnosis, the presence of any medical comorbidities, and initial testing with alpha fetoprotein and imaging. Specific guidelines for the management of different tumors have been implemented in recent years such that a multidisciplinary approach is ideal and care should be provided by centers with experience in their management.

Characteristics of Hepatitis B Virus-associated Hepatocellular Carcinoma in Children: A Multi-center Study.

INTRODUCTION: Pediatricians and liver specialists in the United States and Canada continue to encounter hepatitis B virus (HBV) infection in high-risk populations, including unvaccinated children, adopted children, and immigrants. Although hepatocellular carcinoma (HCC) is a known complication of HBV, there exists a paucity of data regarding the clinical presentation of HBV-associated HCC in children in these countries. METHODS: Investigators at 4 medical centers with large numbers of HBV-positive children queried their pathology and/or oncology databases to identify all cases of HBV-infected children <18 years old presenting with HCC between 1990 and 2015. Clinical data were extracted from chart review. RESULTS: The group identified 8 patients, 8 to 17 years old, including 6 (75%) males. All individuals were assumed to be infected through vertical transmission. Three (38%) presented initially to the emergency room, 2 (25%) to a general pediatrician, 1 (13%) to a hepatologist, and the initial location was not documented in 2 (25%) cases. Three patients were asymptomatic, but the most common symptoms were abdominal pain (50%) and fatigue (38%). Hepatomegaly was present in 5 (63%) patients. Viral load was not documented in any patient. Only 3 patients had their HBeAg status documented and all individuals were HBeAg(-) and anti-HBe(+). Aspartate aminotransferase (AST) ranged from 13 to 575 IU/L, and alanine aminotransferase (ALT) ranged from 14 to 212 IU/L; 4 patients had AST and ALT < 1.5 times the upper limit of normal. Three patients had elevated bilirubin and gamma glutamyl transpeptidase (GGT), and 3 had normal bilirubin and GGT; 1 patient had unknown bilirubin and a separate patient had unknown GGT. Alpha-fetoprotein (AFP) was elevated in 3 patients (range 2.556-7.600 ng/mL), normal in 2 patients, and not documented in 3 patients. Ultrasound was initially used to identify the tumor in 5 patients whereas computerized axial tomography scan was used in 3 patients. Six patients had multiple nodules on initial imaging. CONCLUSIONS: Although rare, HBV-associated HCC occurs in young children, often with normal liver enzymes, bilirubin, GGT, and AFP. Only routine imaging with ultrasound or computerized axial tomography scan consistently identified the tumor. These data may help inform screening for HCC including age of initiation and the role for imaging over laboratory testing.

Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome: a prospective, open-label, dose-escalation study.

OBJECTIVE: To investigate the efficacy of etanercept in improving the symptoms and underlying inflammation in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS: Fifteen patients with TRAPS were enrolled in a prospective, open-label, dose-escalation study. Patients recorded attacks, symptom severity, and use of ancillary medications in a daily diary. Blood samples were collected during each period and measured for levels of acute-phase reactants. Between 7 years and 9 years after the conclusion of the initial study, patients completed a followup survey and were evaluated to determine the long-term outcome of etanercept treatment. RESULTS: Etanercept treatment significantly attenuated the total symptom score and reduced the frequency of symptoms. Etanercept also reduced levels of acute-phase reactants, particularly during asymptomatic periods. During a 10-year followup period, patients continued to receive etanercept for a median of 3.3 years, with a number of patients switching to anti-interleukin-1ß receptor therapy or not receiving biologic agents, most frequently citing injection site reactions and lack of efficacy as reasons for discontinuation. However, patients continuing to receive etanercept had reduced symptoms at followup. CONCLUSION: Etanercept reduces symptoms and serum levels of inflammatory markers of TRAPS in a dose-dependent manner, but does not completely normalize symptoms or acute-phase reactant levels. Although long-term adherence to etanercept is poor, continuing to receive etanercept may provide continued symptomatic benefit.