Biliary atresia (BA) is a rare, inflammatory condition of the biliary tree that presents in the first weeks of life and leads to bile duct obstruction and consequent liver injury, fibrosis and cirrhosis which lead to portal hypertension and a decline in hepatic synthetic function. Untreated, the outcome of BA is uniformly fatal. The 2 most important improvements in the care of BA patients to date are the Kasai hepatoportoenterostomy (HPE
Conditions
Interventions
Product Name: Maralixibat
Pharmaceutical Form: Oral solution
INN or Proposed INN: MARALIXIBAT CHLORIDE
CAS Number: 228113-66-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equ
Sponsors
Mirum Pharmaceuticals Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Informed consent (by the legally authorized representative) per the Institutional Review Board/ Independent Ethics Committee (IRB/IEC) 2.Male or female participants with a body weight =2500 g who are =21 days old and =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1.Chronic diarrhea requiring ongoing IV fluid or nutritional intervention at screening, during the screening period, or during the 30 days prior to screening 2.History of surgical disruption of the enterohepatic circulation other than HPE 3.HPE performed by laparoscopy 4.Not tolerating enteral feeds full enteral feeds at screening or during the screening period 5.Evidence of another pathology involving the intrahepatic bile ducts (e.g., paucity, sclerosing cholangitis) 6.Diagnosis of polysplenia syndrome, including evidence of BA splenic malformation syndrome, or major malformation of another organ system 7.Diagnosis of cystic BA (based on clinician judgment, including but not limited to ultrasonography and cholangiography results) 8.Decompensated cirrhosis (international normalized ratio [INR] >1.5 after correction of possible vitamin K deficiency, history or presence of clinically significant ascites, known varices, variceal hemorrhage, and/or encephalopathy) 9.Previous or imminent need for liver transplantation 10.Known hypersensitivity to maralixibat or any of its excipients 11.Previous use of an IBAT inhibitor, N-acetyl cysteine, or immunoglobulins 12.Receipt of investigational drug, biologic, or medical device within 30 days or 5 half-lives (whichever is longer) prior to screening 13.Treatment with other medications containing propylene glycol (PG) or alcohol or any substrate for alcohol dehydrogenase (e.g., ethanol). For participants <1 month of age only. 14.Known caregiver history of unreliability, mental instability, or cognitive impairment that, in the opinion of the investigator or sponsor medical monitor, could compromise the validity of informed consent, compromise the safety of the participant, or lead to nonadherence with the study protocol or inability to conduct the study procedures 15.Presence of other significant liver disease or any other conditions or abnormalities which, in the opinion of the investigator or sponsor medical monitor, may compromise the safety of the participant or interfere with the participant participating in or completing the study 16.History or presence of any other disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs, including bile salt metabolism in the intestine (e.g., inflammatory bowel disease), per investigator discretion
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: •To evaluate the efficacy of maralixibat on biliary drainage after hepatoportoenterostomy (HPE) in participants with BA;Secondary Objective: •To evaluate changes in serum bile acid (sBA) levels with maralixibat treatment •To evaluate the rate of bilirubin normalization with maralixibat treatment •To evaluate native liver survival with maralixibat treatment •To evaluate biochemical markers of cholestasis and liver disease with maralixibat treatment •To evaluate the safety, tolerability, and pharmacokinetics of maralixibat ;Primary end point(s): Primary Efficacy Endpoint: • Mean change in total serum bilirubin levels from baseline to Week 26 ;Timepoint(s) of evaluation of this end point: The primary analysis on the primary efficacy endpoint will be conducted over the primary cohort in the ITT population. A restricted maximum likelihood (REML)-based mixed-effects model for repeated measures (MMRM) will be used as the primary analysis method. The repeated measures include post-baseline visits during the double-blind phase up through Week 26, with the change from baseline in total bilirubin as the dependent variable. The treatment group-by-visit interaction will be tested for inclusion in the model before finalizing it. If the interaction term is positive (p < 0.10), the effect size will be considered to depend on visit and marginal analyses by visit will be presented. Otherwise, the primary test will be conducted using the main effects model. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Efficacy Endpoints (to Week 26): •Mean change from baseline in total preprandial sBA to Week 26 •Proportion of participants with total serum bilirubin levels 6 mg/dL) • Mean spleen size below lower costal margin (centimeters) • Proportion of participants with total serum bilirubin levels 6 mg/dL up to Week 26 • Mean change in total serum bilirubin levels from baseline to Week 26 by total serum bilirubin levels at Week 13 (6 mg/dL) Proportion of participants with total serum bilirubin levels 6 mg/dL) • Relationship between stool color at screening and difference between maralixibat and placebo groups in mean change from baseline in total serum bilirubin levels at Week 26 • Markers of liver fibrosis (serum matrix metalloproteinase-7 [if blood volumes allow], AST-to-platelet ratio index [APRI], elastography [where available]) • Mean change from baseline in serum 7a-hydroxy-4-cholesten-3-one (7aC4) and Pediatric End Stage Liver Disease (PELD) score (if blood volume allows) • Mean change in growth parameters (height, weight, tricep skinfold, and mid-upper-arm and head circumferences [z-scores]) over time during the study period • Mean change in health-related quality of life as assessed by Pediatric Quality of Life Inventory (PedsQL) over time during the study period • Impact of maralixibat treatment on healthcare utilization (incidence of BA-related hospitalization, total inpatient days, selected surgical procedures, emergency room visits, etc.) over time during the study period • Incidence of diagnosed cholangitis during the study period • Severity of pruritus, as assessed by the Clinician Scratch Scale (CSS) Open-Label Extention (OLE) Efficacy Endpoints (to Week 104): • Time to liver transplantation or death • Time to clinical event, including liver transplantation, liver decompensation (hepatic encephalopathy, variceal bleeding, new persistent ascites), and death • Mean spleen size below lower costal margin (centimeters) • Proportion | — |
Countries
China, France, Germany, Hong Kong, Italy, Mexico, Poland, Singapore, Taiwan, United Kingdom, United States, Viet Nam
Contacts
Public ContactChief Development Officer
Mirum Pharmaceuticals, Inc.
Outcome results
None listed