In patients with progressive familial intrahepatic cholestasis (PFIC), impairment of the egress of bile acids from the liver leads to cholestasis, hepatocellular injury and damage, and progressive liver disease that may ultimately lead to the need for liver transplantation. Itch is a common symptom associated with cholestasis, it can occur at all stages of cholestatic liver disease, with or without jaundice. MedDRA version: 20.0 Level: SOC Classification code 10010331 Term: Congenital, familial
Conditions
Interventions
Product Name: LUM001
Pharmaceutical Form: Oral solution
INN or Proposed INN: maralixibat chloride
CAS Number: 228113-66-4
Current Sponsor code: LUM001
Concentration unit: µg/kg microgram(s)/kilogram
C
Sponsors
Mirum Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: To participate in this study subjects must meet the following criteria: 1. Male or female subjects between the ages of 12 months and 18 years inclusive. 2. Diagnosis of PFIC based on: a. Intrahepatic cholestasis manifest by total serum bile acid >3x upper limit of normal (ULN) for age. and, b or c: b. Two documented mutant alleles in ATP8B1, or ABCB11. c. Evidence of chronic liver disease, excluding those listed in (see Section 16.3), with one or more of the following criteria: 1. Duration of biochemical or clinical abnormalities of >6 months, or 2. Pathologic evidence of progressive liver disease, or 3. Sibling of known individual affected by PFIC (predicted to be chronic). 3. GGTP =65 years) no F.1.3.1 Number of subjects for
Exclusion criteria
Exclusion criteria: Subjects will be excluded from the study if they meet any of the following criteria: 1. Chronic diarrhea requiring specific intravenous fluid or nutritional intervention for the diarrhea and/or its sequelae. 2. Surgical disruption of the enterohepatic circulation at the time at screening. Subjects who have undergone reversal of a prior surgical procedure intended to disrupt enterohepatic circulation and who and have a permanently restored flow of bile acids from the liver to the terminal ileum may be eligible for the study upon consultation with the Medical Monitor. 3. Liver transplant. 4. Decompensated cirrhosis [international normalized ratio (INR) > 1.5, albumin 15×ULN at screening. 6. History or presence of other liver disease (see Section 16.3). 7. 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). 8. Liver mass on imaging. 9. Known diagnosis of human immunodeficiency virus (HIV) infection. 10. Cancers except for in situ carcinoma, or cancers treated at least 5 years prior to screening with no evidence of recurrence. 11. Any female who is pregnant or lactating or who is planning to become pregnant within 20 weeks of assignment. 12. Any known history of alcohol or substance abuse. 13. Administration of bile acid or lipid binding resins within 30 days prior to Baseline / Day 0 and throughout the trial. 14. Administration of sodium phenylbutyrate within 30 days prior to Baseline / Day 0 and throughout the trial. 15. Investigational drug, biologic, or medical device within 30 days prior to screening, or 5 halflives of the study agent, whichever is longer. 16. History of non-adherence to medical regimens, unreliability, mental instability or incompetence that could compromise the validity of informed consent or lead to non-adherence with the study protocol based on Investigator judgment. 17. Any other conditions or abnormalities which, in the opinion of the Investigator or Sponsor Medical Monitor, may compromise the safety of the subject, or interfere with the subject participating in or completing the study. Subjects will be excluded from the optional follow-up treatment period if they meet the following criteria: 1. Surgical disruption of the enterohepatic circulation. 2. Investigational drug other than LUM001, biologic, or medical device within 30 days prior to re-entry, or 5 half-lives of the study agent, whichever is longer.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Objectives up to/including Wk 72: ? -To evaluate the long-term safety/tolerability of LUM001 in pediatric subjects (PS) with PFIC ? -To evaluate the effect of LUM001 on serum bile acids in PS with PFIC at 13 wks of treatment ? -To evaluate the effect of LUM001 on biochem. markers of cholestasis and liver disease at 13 wks of treatment ? -To evaluate the effect of LUM001 on pruritus in PS with PFIC at 13 wks of treatment Objectives of Optional Follow-up Treatm. Period (Post Wk 72): ? -To offer eligible subjects in the LUM001-501 continued study treatment beyond Week 72 until: (i) the subjects are eligible to enter another LUM001 study or (ii) LUM001 is available commercially ? -To obtain safety/efficacy data in subjects treated long-term on LUM001 ? -To explore a BID and higher daily dosing regimen of LUM001 ? -To identify genetic indicators of treatment response, incl. exome sequencing ? -To assess alpha-fetoprotein levels ? -To assess LUM001 formulation palatability;Secondary Objective: To allow the possibility of analysis of serum markers of treatment response using metabolomic and proteomic analysis on previously collected serum samples.;Primary end point(s): The primary efficacy endpoint is mean change from baseline to Week 13 in fasting serum bile acids. ;Timepoint(s) of evaluation of this end point: Day: 0, 28, 56, 91, 168, 196, 252, 336, 420, 504, 588, 602, 672, 756, 840, every three months thereafter, and at the EOT visit. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary efficacy endpoints include change from baseline to Week 48 in biochemical markers of cholestasis and liver disease (ALT, total and direct bilirubin) and change from baseline to Week 48 in pruritus as measured by the average daily score of the ItchRO instrument. The safety and long-term durability of effect of LUM001 in patients will be assessed during 124-weeks of treatment.;Timepoint(s) of evaluation of this end point: Continuous variables will be summarized using descriptive statistics including n, mean, median, standard deviation, and range (i.e., minimum and maximum). Qualitative variables will be summarized using counts and percentages. Summaries will be provided by study phase (Weeks 0-13, 14-72, 73-124) and over the entire study duration (Weeks 0-124), by visit and by stable dosing dose group (if appropriate). All data will be reported in data listings. All statistical tests will be conducted at the 0.05 significance level using two-tailed tests and p-values will be reported. Given the rare nature of PFIC, the statistical power of any comparison is limited. As such the analysis will be largely descriptive in nature. | — |
Countries
France, Poland, United Kingdom
Contacts
Public ContactChief Scientific Officer
Mirum Pharmaceuticals, Inc.
Outcome results
None listed