Primary Biliary Cholangitis
Conditions
Keywords
Primary Biliary Cholangitis (PBC), PBC
Brief summary
The purposes of this study are to evaluate the treatment effect of seladelpar on composite biochemical improvement in cholestasis markers based on ALP and total bilirubin and to evaluate the safety of seladelpar over 12 months of treatment compared to placebo. The study also checked the effect of treatment on the symptoms of PBC, including pruritus.
Interventions
DRUGSeladelpar 10 mg
Seladelpar 10 mg one capsule daily for double-blind period, for a duration of up to 12 months
DRUGPlacebo
One capsule daily for double-blind period, for a duration of up to 12 months
DRUGSeladelpar 5 mg
If down-titration needed, one capsule daily for double-blind period, for a duration of up to 12 months
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Must have given written informed consent (signed and dated) and any authorizations required by local law. * Male or female with a definitive diagnosis of primary biliary cholangitis (PBC). * Ursodeoxycholic acid (UDCA) for the past 12 months (stable dose for \>3 months prior to screening) or intolerant to UDCA (last dose of UDCA \>3 months prior to screening). * Laboratory parameters measured by the Central Laboratory at screening: * Alkaline phosphatase (ALP) ≥1.67× ULN (upper limit of normal) * Aspartate aminotransferase (AST) ≤3× ULN * Alanine aminotransferase (ALT) ≤3× ULN * Total bilirubin ≤2× ULN * Estimated glomerular filtration rate (eGFR) \>45 mL/min/1.73 m\^2 (calculated by the Modification of Diet in Renal Disease study equation). * International normalized ratio (INR) below 1.1× ULN (For individuals on anticoagulation therapy, INR must be maintained in the range required for prophylaxis for their specific disease). * Platelet count ≥100 ×10\^3/µL. * Females of reproductive potential must use at least 1 barrier contraceptive and a second effective birth control method during the study and for at least 90 days after the last dose. Male individuals who are sexually active with female partners of reproductive potential must use barrier contraception, and their female partners must use a second effective birth control method during the study and for at least 90 days after the last dose. Key
Exclusion criteria
* Previous exposure to seladelpar (MBX-8025). * A medical condition other than PBC that, in the investigator's opinion, would preclude full participation in the study (e.g., cancer) or confound its results (e.g., Paget's disease, any active infection). * Advanced PBC as defined by the Rotterdam criteria (albumin below the lower limit of normal and total bilirubin above 1.0 × ULN). * Presence of clinically important hepatic decompensation, including the following: * History of liver transplantation, current placement on liver transplantation list, or current Model for End-Stage Liver Disease (MELD) score ≥12. For individuals on anticoagulation medication, evaluation of the baseline INR, in concert with their current dose adjustments of their anticoagulant medication, will be taken into account when calculating the MELD score. This will be done in consultation with the medical monitor. * Complications of portal hypertension, including known esophageal varices, history of variceal bleeds or related interventions (e.g., transjugular intrahepatic portosystemic shunt placement), ascites, and hepatic encephalopathy. * Cirrhosis with complications, including history or presence of spontaneous bacterial peritonitis, hepatocellular carcinoma, or hepatorenal syndrome. * Other chronic liver diseases: * Current features of autoimmune hepatitis (AIH) as determined by the investigator based on immunoserology, liver biochemistry, or historic confirmed liver histology. * PSC determined by the presence of diagnostic cholangiographic findings. * History or clinical evidence of alcoholic liver disease. * History or clinical evidence of alpha-1-antitrypsin deficiency. * History of biopsy confirmed nonalcoholic steatohepatitis (NASH). * History or evidence of Gilbert's syndrome with elevated total bilirubin. * History or evidence of hemochromatosis. * Hepatitis B, defined as the presence of hepatitis B surface antigen. * Hepatitis C, defined as the presence of hepatitis C virus ribonucleic acid. * History, evidence, or high suspicion of hepatobiliary malignancy based on imaging, screening laboratory values, and/or clinical symptoms. * Known history of human immunodeficiency virus (HIV) or positive antibody test at screening * Clinically important alcohol consumption, defined as more than 2 drink units per day (equivalent to 20 g) in women and 3 drink units per day (equivalent to 30 g) in men, or inability to quantify alcohol intake reliably. * History of malignancy diagnosed or treated, actively or within 2 years, or ongoing evaluation for malignancy; localized treatment of squamous or noninvasive basal cell skin cancers and cervical carcinoma in situ is allowed if appropriately treated prior to screening. * Treatment with obeticholic acid (OCA) or fibrates (e.g., bezafibrate, fenofibrate, elafibranor, lanifibranor, pemafibrate, saroglitizar) 6 weeks prior to screening. * Treatment with colchicine, methotrexate, azathioprine, or long-term systemic corticosteroids (\>2 weeks) during 2 months prior to screening * Treatment with anti-pruritic drugs (e.g., cholestyramine, naltrexone, rifampicin, sertraline, or any experimental approach) must be on a stable dose within 1 month prior to screening * Treatment with any other investigational therapy or device within 30 days or within 5 half-lives, whichever is longer, prior to screening * For females, pregnancy or breastfeeding. * Any other condition(s) that would compromise the safety of the individual or compromise the quality of the clinical study, as judged by the investigator. * Immunosuppressant therapies. * Other medications that effect liver or gastrointestinal (GI) functions, such as absorption of medications or the roux-en-y gastric bypass procedure, may be prohibited and should be discussed with the medical monitor on a case-by-case basis. * Active Coronavirus Disease-2019 (COVID-19) infection during Screening. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Response Criteria for the Composite Endpoint of ALP <1.67 × Upper Limit of Normal (ULN), ≥15% Reduction in ALP, and Total Bilirubin ≤ 1.0× ULN at Month 12 | Month 12 | Percentages were rounded-off. |
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | First dose date up to last dose plus 30 days (up to 13.4 months) | Percentages were rounded-off. |
| Percentage of Participants With Shift of ≥ 2 CTCAE Grades From Baseline in Treatment-emergent Laboratory Abnormalities Related to Hematology and Select Liver Biochemistry | First dose date up to last dose (up to 13.4 months) | Treatment-emergent graded laboratory abnormalities were defined as values that increase at least 2 toxicity grade from baseline at any time post baseline. The laboratory abnormalities were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: potentially life-threatening laboratory abnormality. The data is reported for shift of ≥ 2 grades from baseline in values for hematology and select liver biochemistry. Hematology includes parameters like RBCs, (erythrocytes), hemoglobin, hematocrit, platelets, WBC, WBC differentials (absolute and percentage) including basophils, neutrophils, lymphocytes, eosinophils, and monocytes, etc. Biochemistry included select liver function tests like blood bilirubin, gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase. Percentages were rounded-off. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ALP ≤1.0× ULN at Month 12 | Month 12 | Percentages were rounded-off. |
| Change From Baseline in Weekly Averaged Pruritus Numerical Rating Scale (NRS) in Participants With NRS ≥ 4 at Month 6 | Baseline, Month 6 | Pruritus NRS is used to rate the intensity of the itching experienced by the participants in the past 24 hours from no itching to worst possible itching by selecting a number from 0 to 10 on Itch Scale. Zero means no itching and 10 means worst imaginable itching. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Chile, Czechia, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Mexico, New Zealand, Poland, Romania, Russia, South Korea, Spain, Switzerland, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the Asia Pacific, Europe, Latin America, and North America.
Pre-assignment details
360 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo to match seladelpar, orally, once daily, for a duration of up to 12 months. | 65 |
| Seladelpar Participants received seladelpar 10 mg, orally, once daily, for a duration of up to 12 months. | 128 |
| Total | 193 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Protocol Deviation | 1 | 1 |
| Overall Study | Reason Not Specified | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 5 |
Baseline characteristics
| Characteristic | Placebo | Total | Seladelpar |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 41 Participants | 29 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants | 152 Participants | 99 Participants |
| Age, Continuous | 57 years STANDARD_DEVIATION 9.2 | 57 years STANDARD_DEVIATION 9.7 | 57 years STANDARD_DEVIATION 10 |
| Alkaline Phosphatase (ALP) Levels | 313.8 U/L STANDARD_DEVIATION 117.68 | 314.3 U/L STANDARD_DEVIATION 120.9 | 314.6 U/L STANDARD_DEVIATION 122.96 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 27 Participants | 56 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 135 Participants | 97 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Pruritus Numerical Rating Scale (NRS) for Participants With Baseline Pruritus NRS ≥ 4 | 6.6 score on a scale STANDARD_DEVIATION 1.44 | 6.3 score on a scale STANDARD_DEVIATION 1.43 | 6.1 score on a scale STANDARD_DEVIATION 1.42 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 11 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 56 Participants | 170 Participants | 114 Participants |
| Region of Enrollment Argentina | 13 Participants | 29 Participants | 16 Participants |
| Region of Enrollment Australia | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Austria | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Belgium | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment Canada | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Chile | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Czechia | 1 Participants | 3 Participants | 2 Participants |
| Region of Enrollment France | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Germany | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Greece | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment Hungary | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Israel | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment Italy | 4 Participants | 8 Participants | 4 Participants |
| Region of Enrollment Mexico | 6 Participants | 12 Participants | 6 Participants |
| Region of Enrollment New Zealand | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment Poland | 5 Participants | 7 Participants | 2 Participants |
| Region of Enrollment Romania | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Russia | 1 Participants | 9 Participants | 8 Participants |
| Region of Enrollment South Korea | 3 Participants | 7 Participants | 4 Participants |
| Region of Enrollment Spain | 4 Participants | 11 Participants | 7 Participants |
| Region of Enrollment Switzerland | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment Turkey | 1 Participants | 8 Participants | 7 Participants |
| Region of Enrollment United Kingdom | 2 Participants | 8 Participants | 6 Participants |
| Region of Enrollment United States | 13 Participants | 61 Participants | 48 Participants |
| Sex: Female, Male Female | 60 Participants | 183 Participants | 123 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 65 | 0 / 128 |
| other Total, other adverse events | 40 / 65 | 66 / 128 |
| serious Total, serious adverse events | 4 / 65 | 9 / 128 |
Outcome results
Primary
Percentage of Participants With Response Criteria for the Composite Endpoint of ALP <1.67 × Upper Limit of Normal (ULN), ≥15% Reduction in ALP, and Total Bilirubin ≤ 1.0× ULN at Month 12
Percentages were rounded-off.
Time frame: Month 12
Population: The Intend-to-treat Analysis Set was defined as any participant who was randomized into the study and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Response Criteria for the Composite Endpoint of ALP <1.67 × Upper Limit of Normal (ULN), ≥15% Reduction in ALP, and Total Bilirubin ≤ 1.0× ULN at Month 12 | 20.0 percentage of participants |
| Seladelpar | Percentage of Participants With Response Criteria for the Composite Endpoint of ALP <1.67 × Upper Limit of Normal (ULN), ≥15% Reduction in ALP, and Total Bilirubin ≤ 1.0× ULN at Month 12 | 61.7 percentage of participants |
p-value: <0.000195% CI: [27.7, 53.4]Cochran-Mantel-Haenszel
Primary
Percentage of Participants With Shift of ≥ 2 CTCAE Grades From Baseline in Treatment-emergent Laboratory Abnormalities Related to Hematology and Select Liver Biochemistry
Treatment-emergent graded laboratory abnormalities were defined as values that increase at least 2 toxicity grade from baseline at any time post baseline. The laboratory abnormalities were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: potentially life-threatening laboratory abnormality. The data is reported for shift of ≥ 2 grades from baseline in values for hematology and select liver biochemistry. Hematology includes parameters like RBCs, (erythrocytes), hemoglobin, hematocrit, platelets, WBC, WBC differentials (absolute and percentage) including basophils, neutrophils, lymphocytes, eosinophils, and monocytes, etc. Biochemistry included select liver function tests like blood bilirubin, gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase. Percentages were rounded-off.
Time frame: First dose date up to last dose (up to 13.4 months)
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With Shift of ≥ 2 CTCAE Grades From Baseline in Treatment-emergent Laboratory Abnormalities Related to Hematology and Select Liver Biochemistry | Shift ≥ 2 CTCAE grades in haematology | 12.3 percentage of participants |
| Placebo | Percentage of Participants With Shift of ≥ 2 CTCAE Grades From Baseline in Treatment-emergent Laboratory Abnormalities Related to Hematology and Select Liver Biochemistry | Shift ≥ 2 CTCAE grades in biochemistry | 6.2 percentage of participants |
| Seladelpar | Percentage of Participants With Shift of ≥ 2 CTCAE Grades From Baseline in Treatment-emergent Laboratory Abnormalities Related to Hematology and Select Liver Biochemistry | Shift ≥ 2 CTCAE grades in haematology | 14.1 percentage of participants |
| Seladelpar | Percentage of Participants With Shift of ≥ 2 CTCAE Grades From Baseline in Treatment-emergent Laboratory Abnormalities Related to Hematology and Select Liver Biochemistry | Shift ≥ 2 CTCAE grades in biochemistry | 7.0 percentage of participants |
Primary
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
Percentages were rounded-off.
Time frame: First dose date up to last dose plus 30 days (up to 13.4 months)
Population: The Safety Analysis Set was defined as any participant who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 84.6 percentage of participants |
| Placebo | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 6.2 percentage of participants |
| Seladelpar | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 86.7 percentage of participants |
| Seladelpar | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 7.0 percentage of participants |
Secondary
Change From Baseline in Weekly Averaged Pruritus Numerical Rating Scale (NRS) in Participants With NRS ≥ 4 at Month 6
Pruritus NRS is used to rate the intensity of the itching experienced by the participants in the past 24 hours from no itching to worst possible itching by selecting a number from 0 to 10 on Itch Scale. Zero means no itching and 10 means worst imaginable itching.
Time frame: Baseline, Month 6
Population: The Moderate to Severe Pruritus NRS Analysis Set included participants in the Intent-to-treat Analysis Set who had a baseline NRS value ≥ 4. Participants with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Weekly Averaged Pruritus Numerical Rating Scale (NRS) in Participants With NRS ≥ 4 at Month 6 | -1.7 score on scale | Standard Error 0.41 |
| Seladelpar | Change From Baseline in Weekly Averaged Pruritus Numerical Rating Scale (NRS) in Participants With NRS ≥ 4 at Month 6 | -3.2 score on scale | Standard Error 0.28 |
p-value: 0.004795% CI: [-2.5, -0.5]MMRM
Secondary
Percentage of Participants With ALP ≤1.0× ULN at Month 12
Percentages were rounded-off.
Time frame: Month 12
Population: Participants in Intent-to-treat Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With ALP ≤1.0× ULN at Month 12 | 0.0 percentage of participants |
| Seladelpar | Percentage of Participants With ALP ≤1.0× ULN at Month 12 | 25.0 percentage of participants |
p-value: <0.000195% CI: [18.3, 33.2]Cochran-Mantel-Haenszel