Open Label Study to Evaluate Efficacy and Long Term Safety of LUM001 (Maralixibat) in the Treatment of Cholestatic Liver Disease in Patients With Progressive Familial Intrahepatic Cholestasis

Open Label Study of the Efficacy and Long Term Safety of LUM001 (Maralixibat), an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment of Cholestatic Liver Disease in Pediatric Patients With Progressive Familial Intrahepatic Cholestasis

This is an open label study in children with Progressive Familial Intrahepatic Cholestasis (PFIC) designed to evaluate the safety and efficacy of LUM001, also known as Maralixibat (MRX). Efficacy will be assessed by evaluating the effect of LUM001 on pruritus and the biochemical markers of pruritus associated with PFIC.

The study is divided into 5 parts: a 4-week dose escalation period, a 4-week stable dosing period, a 5-week stable dosing period, a 59-week long-term exposure period, and an optional follow-up treatment period for eligible participants who continue treatment with LUM001. Participants in the optional follow-up treatment period will continue to receive study drug until they are eligible to enter another LUM001 study or until LUM001 is available commercially, whichever occurs first.

Inclusion Criteria

1. Male or female subjects between the ages of 12 months and 18 years inclusive.

2. Diagnosis of PFIC based on:

1. Intrahepatic cholestasis manifest by total serum bile acid >3x upper limit of normal (ULN) for age and, b or c:

2. Two documented mutant alleles in ATP8B1, or ABCB11.

3. 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 <100 IU/L at screening. 4. Females of childbearing potential must have a negative urine or serum pregnancy test [β human chorionic gonadotropin (β-hCG)] during screening and a negative urine pregnancy test at the Baseline (Day 0) visit.

   5. Males and females of child-bearing potential who are sexually active, or are not currently sexually active during the study, but become sexually active during the period of the study and 30 days following the last dose of study drug, must agree and use acceptable contraception during the trial, as described in Section 8.7.1. of the protocol 6. Informed consent and assent (per IRB/EC) as appropriate. 7. Access to phone for scheduled calls from study site. 8. Caregivers and children above the age of assent must have the ability to read and understand one of the following languages: English, Spanish, US Spanish, French, German or Polish.

   9. Subjects expected to have a consistent caregiver(s) for the duration of the first 13 weeks of the study.

   10. Caregivers (and age appropriate subjects) must be willing and able to use an eDiary device as required by the study. To accommodate potential cultural restrictions within the FIC1 affected population a paper version of the ItchRO diary will be made available.

   11. Caregivers (and age appropriate subjects) using the eDiary must digitally accept the licensing agreement in the eDiary software at the outset of the study.

   12. Caregivers (and age appropriate subjects) must complete at least 10 eDiary reports (morning or evening) during each of two consecutive weeks of the screening period, prior to assignment (maximum possible reports = 14 per week). Subjects using a paper diary must complete the same number of reports within the same timeframe

   Exclusion 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 < 30 g/L, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy].
   5. ALT >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 half-lives 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 Medical monitor, may compromise the safety of the subject, or interfere with the subject participating in or completing the study