Cholestatic Liver Disease
Conditions
Keywords
PFIC, ALGS, Maralixibat, Bile Duct Diseases, Liver Diseases, Biliary Tract Diseases, Digestive System Diseases, Pediatric
Brief summary
Evaluate the long-term safety of maralixibat (MRX) in subjects with cholestatic liver disease including, but not limited to, Alagille Syndrome (ALGS), Progressive Familial Intrahepatic Cholestasis (PFIC) and Biliary Atresia.
Detailed description
This is a multicenter, open-label study of maralixibat in subjects diagnosed with cholestatic liver disease (including, but not limited to ALGS, PFIC or Biliary Atresia) who have previously participated in a maralixibat clinical study. All subjects received maralixibat in the previous studies and will continues to receive maralixibat in this study.
Interventions
DRUGMaralixibat
Maralixibat chloride oral solution orally twice daily (up to 1200\* mcg/kg/day), and according to indication. \*equivalent to 1140 mcg/kg/day maralixibat
Sponsors
Mirum Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Months to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects will need to meet all criteria below to be considered eligible for the study. 1. Provide informed consent and assent (as applicable) per the Institutional Review Board/Ethics Committee (IRB/EC). 2. Previously participated in a maralixibat study and with approval of the Medical Monitor. Previous participation is defined as: * Having completed the EOT Visit, for subjects coming from the maralixibat Phase 2 studies. * Having completed the entire duration of the study (i.e., core and extension, if applicable), for subjects coming from the maralixibat Phase 3 studies. 3. At least 1 year of age 4. Males, and females of non-childbearing potential. Males and non-pregnant, non-lactating females of childbearing potential who are sexually active must agree to use acceptable contraception during the study and 30 days following the last dose of the study medication. Females of childbearing potential must have a negative pregnancy test. 5. Caregivers (and/or age appropriate subjects) must have access to email or phone for scheduled remote visits if applicable. 6. Subject and caregiver willingness to comply with all study visits and requirements.
Exclusion criteria
A subject will be excluded from the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events | From informed consent through approximately 4.5 years, including 30 days after last dose. | TEAE = Treatment-emergent Adverse Event; AESI = Adverse Event of Special Interest.. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Long-Term Effect on Pruritus | From Baseline through Week 160, including Change from Baseline values. | Change from Baseline in Pruritus Severity assessed using the Clinician Scratch Score (CSS), a 5-point scale where 0 indicates no evidence of scratching and 4 indicates cutaneous mutilation with bleeding, hemorrhage, and scarring. |
| Long-Term Effect on Serum Bile Acid Levels | From Baseline through Week 160, including Change from Baseline values. | — |
Countries
Australia, Belgium, Canada, France, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 52 participants were enrolled at 17 sites across 8 countries (Australia, Belgium, Canada, France, Poland, Spain, United Kingdom and United States). Participants were previously on maralixibat for an average of 4 years before entering this study.
Pre-assignment details
The screening period starts when informed consent (by the legally authorized representative) is signed.The duration of the screening period is up to 4 weeks, during which all procedures listed for the screening visit in the schedule of assessment must be completed. A total of 43 subjects completed the study and a total of 9 discontinued early.
Participants by arm
| Arm | Count |
|---|---|
| Maralixibat: ALGS Participants will all receive Maralixibat oral solution
Maralixibat chloride oral solution orally twice daily Up to 1.2\* mg/kg/day), and according to indication.
\*equivalent to 1.14 mg/kg/day maralixibat. Doses reported here are in maralixibat chloride.
Participants with ALGS received maralixibat doses in the range of 0.15 mg/kg QD to 0.45 mg/kg BID. | 40 |
| Maralixibat: PFIC Participants will all receive Maralixibat oral solution
Maralixibat chloride oral solution orally twice daily Up to 1.2\* mg/kg/day), and according to indication.
\*equivalent to 1.14 mg/kg/day maralixibat. Doses reported here are in maralixibat chloride.
Participants with PFIC received maralixibat doses in the range of 0.3 mg/kg QD to 0.6 mg/kg BID. | 12 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Listed for liver transplant | 1 | 0 |
| Overall Study | Liver transplant | 3 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Maralixibat: ALGS | Total | Maralixibat: PFIC |
|---|---|---|---|
| Age, Customized Age Categorical 13 to 18 years | 9 Participants | 10 Participants | 1 Participants |
| Age, Customized Age Categorical > 18 years | 5 Participants | 5 Participants | 0 Participants |
| Age, Customized Age Categorical 5 to 8 years | 8 Participants | 12 Participants | 4 Participants |
| Age, Customized Age Categorical 9 to 12 years | 18 Participants | 25 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 6 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 32 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 14 Participants | 14 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants | 15 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 32 Participants | 10 Participants |
| Region of Enrollment Australia | 4 participants | 4 participants | 0 participants |
| Region of Enrollment Belgium | 2 participants | 2 participants | 0 participants |
| Region of Enrollment Canada | 2 participants | 2 participants | 0 participants |
| Region of Enrollment France | 4 participants | 4 participants | 0 participants |
| Region of Enrollment Poland | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Spain | 1 participants | 1 participants | 0 participants |
| Region of Enrollment United Kingdom | 8 participants | 11 participants | 3 participants |
| Region of Enrollment United States | 18 participants | 26 participants | 8 participants |
| Sex: Female, Male Female | 19 Participants | 26 Participants | 7 Participants |
| Sex: Female, Male Male | 21 Participants | 26 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 40 | 0 / 12 |
| other Total, other adverse events | 36 / 40 | 12 / 12 |
| serious Total, serious adverse events | 10 / 40 | 3 / 12 |
Outcome results
Primary
Incidence of Treatment-Emergent Adverse Events
TEAE = Treatment-emergent Adverse Event; AESI = Adverse Event of Special Interest..
Time frame: From informed consent through approximately 4.5 years, including 30 days after last dose.
Population: Includes all participants with Alagille Syndrome (ALGS) or Progressive Familial Intrahepatic Cholestasis (PFIC) who received at least one dose of maralixibat.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Maralixibat: ALGS | Incidence of Treatment-Emergent Adverse Events | At least one TEAE | 36 Participants |
| Maralixibat: ALGS | Incidence of Treatment-Emergent Adverse Events | TEAE ≥ 3 | 9 Participants |
| Maralixibat: ALGS | Incidence of Treatment-Emergent Adverse Events | Serious TEAE | 10 Participants |
| Maralixibat: ALGS | Incidence of Treatment-Emergent Adverse Events | Serious Treatment-Related Adverse Event | 0 Participants |
| Maralixibat: ALGS | Incidence of Treatment-Emergent Adverse Events | Serious Treatment-Related TEAE | 0 Participants |
| Maralixibat: ALGS | Incidence of Treatment-Emergent Adverse Events | TEAE Leading to Discontinuation of Study Drug | 3 Participants |
| Maralixibat: ALGS | Incidence of Treatment-Emergent Adverse Events | Treatment-emergent AESI | 0 Participants |
| Maralixibat: ALGS | Incidence of Treatment-Emergent Adverse Events | TEAE Leading to Death | 1 Participants |
| Maralixibat: PFIC | Incidence of Treatment-Emergent Adverse Events | Treatment-emergent AESI | 1 Participants |
| Maralixibat: PFIC | Incidence of Treatment-Emergent Adverse Events | At least one TEAE | 12 Participants |
| Maralixibat: PFIC | Incidence of Treatment-Emergent Adverse Events | Serious Treatment-Related TEAE | 0 Participants |
| Maralixibat: PFIC | Incidence of Treatment-Emergent Adverse Events | TEAE ≥ 3 | 4 Participants |
| Maralixibat: PFIC | Incidence of Treatment-Emergent Adverse Events | TEAE Leading to Discontinuation of Study Drug | 1 Participants |
| Maralixibat: PFIC | Incidence of Treatment-Emergent Adverse Events | Serious TEAE | 3 Participants |
| Maralixibat: PFIC | Incidence of Treatment-Emergent Adverse Events | TEAE Leading to Death | 0 Participants |
| Maralixibat: PFIC | Incidence of Treatment-Emergent Adverse Events | Serious Treatment-Related Adverse Event | 0 Participants |
Secondary
Long-Term Effect on Pruritus
Change from Baseline in Pruritus Severity assessed using the Clinician Scratch Score (CSS), a 5-point scale where 0 indicates no evidence of scratching and 4 indicates cutaneous mutilation with bleeding, hemorrhage, and scarring.
Time frame: From Baseline through Week 160, including Change from Baseline values.
Population: Includes all participants with Alagille Syndrome (ALGS) or Progressive Familial Intrahepatic Cholestasis (PFIC) who received at least one dose of maralixibat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Maralixibat: ALGS | Long-Term Effect on Pruritus | -0.4 score on a scale | Standard Deviation 0.89 |
| Maralixibat: PFIC | Long-Term Effect on Pruritus | -0.3 score on a scale | Standard Deviation 1.12 |
Secondary
Long-Term Effect on Serum Bile Acid Levels
Time frame: From Baseline through Week 160, including Change from Baseline values.
Population: Includes all participants with Alagille Syndrome (ALGS) or Progressive Familial Intrahepatic Cholestasis (PFIC) who received at least one dose of maralixibat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Maralixibat: ALGS | Long-Term Effect on Serum Bile Acid Levels | -15.948 µmol/L | Standard Deviation 31.4239 |
| Maralixibat: PFIC | Long-Term Effect on Serum Bile Acid Levels | -82.647 µmol/L | Standard Deviation 136.4354 |
| Maralixibat: Overall | Long-Term Effect on Serum Bile Acid Levels | -59.994 µmol/L | Standard Deviation 111.0334 |