Seladelpar (MBX-8025) in Subjects With Primary Biliary Cholangitis (PBC)

Study Overview
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Brief Summary
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An 8-week, dose ranging, open label, randomized, Phase 2 study with a 44-week extension, to evaluate the safety and efficacy of MBX-8025 in subjects with Primary Biliary Cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA)

Detailed Description
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Primary: To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 8 weeks of treatment Secondary: To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 12 and 26 weeks of treatment To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 52 weeks of treatment To evaluate the pharmacokinetics (PK) of MBX-8025 Exploratory: To evaluate the effect of MBX-8025 on bile acids, additional markers of inflammation and renal function MBX-8025 doses of 1 mg and 15 mg may be evaluated if dose adjustment occurs

Official Title
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An 8-week, Dose Ranging, Open Label, Randomized, Phase 2 Study With a 44-week Extension, to Evaluate the Safety and Efficacy of MBX-8025 in Subjects With Primary Biliary Cholangitis (PBC) and an Inadequate Response to or Intolerance to Ursodeoxycholic Acid (UDCA)

Conditions
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Primary Biliary Cirrhosis

Intervention / Treatment
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* Drug: MBX-8025 2 mg Capsule
* Drug: MBX-8025 5 mg Capsule
* Drug: MBX-8025 10 mg Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have given written informed consent (signed and dated) and any authorizations required by local law 18 to 75 years old (inclusive) Male or female with a diagnosis of PBC, by at least two of the following criteria: History of AP above ULN for at least six months Positive AMA titers (>1/40 on immunofluorescence or M2 positive by enzyme linked immunosorbent assay (ELISA) or positive PBC-specific antinuclear antibodies Documented liver biopsy result consistent with PBC On a stable and recommended dose of UDCA for the past twelve months or intolerant to UDCA AP ≥ 1.67 × ULN Females of reproductive potential must use at least one barrier contraceptive and a second effective birth control method during the study and for at least 90 days after the last dose. Male subjects 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 Exclusion Criteria: A medical condition, other than PBC, that in the investigator's opinion would preclude full participation in the study or confound its results (e.g., cancer on active treatment) AST or ALT > 3 × ULN Total bilirubin > 2.0 mg/dL Total bilirubin > ULN AND albumin < LLN with the exception to subjects with Gilbert's Syndrome. Subjects with Gilbert's syndrome are excluded if Direct Bilirubin > ULN. Auto-immune hepatitis Primary sclerosing cholangitis Known history of alpha-1-Antitrypsin deficiency Known history of chronic viral hepatitis Creatine kinase above ULN Serum creatinine above ULN For females, pregnancy or breast-feeding Use of colchicine, methotrexate, azathioprine, or systemic steroids in the two months preceding screening Current use of fibrates or simvastatin Current use of obeticholic acid Use of an experimental or unapproved treatment for PBC Use of experimental or unapproved immunosuppressant Adverse event leading to MBX-8025 discontinuation from CymaBay's phase 2 PBC study (CB8025-21528) Any other condition(s) that would compromise the safety of the subject or compromise the quality of the clinical study, as judged by the Investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MBX-8025 (2 mg)<br>MBX-8025 2 mg capsule once daily | Drug: MBX-8025 2 mg Capsule<br>* Initial 8-week treatment: • MBX-8025 2 mg Extension: The 2 mg group will be started after safety and efficacy review of the 5 mg and the 10 mg groups has been completed. Subjects will initially enter the extension on their assigned dose. The dose might be up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose might be re-adjusted for safety or efficacy reasons.<br>* Other names: seladelpar;|
| Experimental: MBX-8025 (5 mg)<br>MBX-8025 5 mg capsule once daily | Drug: MBX-8025 5 mg Capsule<br>* Initial 8-week treatment: • MBX-8025 5 mg Extension: Subjects will initially enter the extension on their assigned dose. The dose might be up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose might be re-adjusted for safety or efficacy reasons.<br>* Other names: seladelpar;|
| Experimental: MBX-8025 (10 mg)<br>MBX-8025 10 mg capsule once daily | Drug: MBX-8025 10 mg Capsule<br>* Initial 8-week treatment: • MBX-8025 10 mg Extension: Subjects will initially enter the extension on their assigned dose. The dose might be up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose might be re-adjusted for safety or efficacy reasons.<br>* Other names: seladelpar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Change From Baseline in Serum Alkaline Phosphatase (ALP) at Week 8 | Relative change from baseline in serum ALP levels at Week 8 (endpoint). The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline in Serum Alkaline Phosphatase (ALP) at Week 12 and Week 52 | Absolute change in ALP from baseline to Weeks 12 and 52 The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 
| Change in Aspartate Aminotransferase (AST) From Baseline to 12 Weeks and 52 Weeks | Change from baseline in AST levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 
| Change in Alanine Aminotransferase (ALT) From Baseline to 12 Weeks and 52 Weeks | Change from baseline in ALT levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 
| Change in Gamma-glutamyl Transferase (GGT) From Baseline to 12 Weeks and 52 Weeks | Change from baseline in GGT levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 
| Change in Bilirubin - Total Bilirubin (TB) From Baseline to 12 Weeks and 52 Weeks | Change from baseline in TB levels at endpoint is being reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 
| Percentage of Participants Meet Composite Endpoint Criteria of ALP and Total Bilirubin | Participant meets composite endpoint is defined by participant meets all of the following criteria: ALP < 1.67 × upper limit of normal (ULN) Total Bilirubin within normal limit > 15% decrease in ALP Endpoint of Alkaline Phosphatase and Total Bilirubin by Visit (mITT Population) | 12 Weeks and 52 Weeks | 
| Percentage of Participants Meet Published PBC Response Criteria - Paris I | Percentage of participants with response based on Paris I risk score was defined as ALP less than or equal to (≤) 3x ULN and aspartate aminotransferase (AST) less than or equal to (≤) 2 x ULN and Total Bilirubin ≤ 1 mg/dL. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 
| Percentage of Participants Meet Published PBC Response Criteria - Paris II | Percentage of participants with response based on Paris II risk score was defined as ALP≤1.5xULN and AST≤1.5xULN and Total Bilirubin ≤ 1 mg/dL. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 
| Percentage of Participants Meet Published PBC Response Criteria - Toronto I | Percentage of participants with response based on Toronto I risk score defined as ALP ≤ 1.67 x ULN. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 
| UK-PBC Risk Score Value | The UK-PBC Risk Score at endpoint is defined by the mean percentage risk that a PBC patient treated with ursodeoxycholic acid (UDCA) would develop liver failure requiring liver transplantation in 5, 10 and 15 years from diagnosis. The higher the score might indicate higher risk to death or live transplantation. Formula used for UK-PBC risk score = 1- 0.982 ^EXP(0.0287854*(ALP12 x ULN-1.722136304) - 0.0422873*(((TA12 xULN/10)^-1) - 8.675729006) + 1.4199 * (LN(BIL12 x ULN/10)+2.709607778)-1.960303*(Albumin x LLN-1.17673001)-0.4161954*(Platelet x LLN-1.873564875)). Where, Baseline survivor function = 0.982, 0.941, and 0.893 for 5 years, 10 years and 15 years respectively. ALP12, TA12 and BIL12 refers to the ALP, transaminases (ALT, AST), and total bilirubin assessments, respectively. The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 
| Change From Baseline in Pruritus Visual Analog Score (VAS) at Week 12 and Week 52 | VAS is the commonly used graphic tool for self-reporting of pruritus intensity in patients. VAS is a simple to use, validated, reliable and widely applicable tool that does not determine the impact of pruritus to quality of life. It comprises of a 100-mm horizontal line labelled as no symptom on left end and worst imaginable symptom on right end. Based on the intensity of the itch patient is instructed to draw a vertical line on the horizontal scale having a range [VAS values (unit: mm) ranging from 0 to 100, where 0 represents no itching and 100 worst possible itching]. The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 
| Change From Baseline in PBC-40 Quality of Life (QoL) at Week 12 and Week 52 | The PBC-40 QoL questionnaire is a disease-specific health-related tool developed for measuring the psychometric profile in PBC patients. It has 10 domains and 43 questions relevant to PBC, including Cognitive, Social, Emotional Function, Fatigue, Itch, and Other Symptoms. Questions in domains: 1) digestion and diet (questions 1-3); 2) experiences (questions 4-7); 3) itching (questions 8-10); 4) fatigue (questions 11-18); 5) effort and planning (questions 19-21); 6) memory and concentration (questions 22-27); 7) affects to you as person (questions 28-33); 8) affects to your social life (questions 34-37); 9) overall impact on your life (questions 38-40); 10) general health and well-being (questions A-C). Within a domain, items are scored from 1 to 5 and the individual item scores are summed to give a total domain score. High scores represent high impact and low scores low impact of PBC on QoL (mITT Population). | 12 weeks and 52 weeks | 
| Percentage of Participants Meet Published PBC Response Criteria - Barcelona | Percentage of participants with response based on Barcelona risk scores was defined as Normalization of ALP or a Decrease of ALP ≥ 40%. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 
| Absolute Change in MELD Score From Baseline to 12 Weeks and 52 Weeks | Change from baseline to 12 weeks and 52 weeks in Model for End-stage Liver Disease (MELD) Score (mITT Population) The MELD score ranges from 6 to 40 and is a measure of how severe a patient's liver disease is. The higher the score, the more likely the patients will need a liver transplant. A calculated prognostic risk factor used to assess the potential need for a liver transplant. MELD(i) score = 10*[0.957*ln(creatinine mg/dL) + 0. 378*ln(total bilirubin mg/dL) + 1.120*ln (INR) + 0.643]. If MELD(i) is less than or equal to 11 then MELD = MELD(i). If MELD(i) is greater than 11 then MELD = MELD(i) + (1.32 *(137 - (Na)) - (0.033*MELD(i)*(137 - Na)) | 12 weeks and 52 weeks | 
| Change in GLOBE PBC Score From Baseline to 12 Weeks and 52 Weeks | Change from Baseline to 12 weeks and 52 weeks in Global PBC Study Group (GLOBE) score (mITT Population) The GLOBE score is a validated risk assessment tool providing an estimate of transplant-free survival for patients with PBC. It was developed by the Global PBC Study Group using Cox regression model on over 4,000 patients with PBC. Lower GLOBE score predicts lower risk. It is calculated from the following equation: GLOBE score = (0.044378 * age + 0.93982 * LN(total bilirubin/ULN) +(0.335648 * LN(alkaline phosphatase/ULN)) - 2.266708 * albumin /LLN -0.002581 * platelet count per 109/L) + 1.216865 | 12 weeks and 52 weeks | 
| Participants Meet Rotterdam Criteria | participants with Response Based on Rotterdam Criteria at Weeks 12 and 52 Rotterdam Published PBC Response Criteria by Visit (mITT Population) Rotterdam criteria: Early (normal total bilirubin and normal albumin), Moderately advanced (either abnormal albumin or abnormal total bilirubin), and Advanced (both abnormal albumin and abnormal total bilirubin). From Early stage to Moderate Stage and to Advanced Stage, it becomes worse and worse in abnormality. | 12 weeks and 52 weeks | 
| Percentage of Participants Meet Composite Endpoint of AP and Total Bilirubin Criteria at Week 12 and Week 52 | Percentage of participants with Response Defined by Composite Endpoint (ALP< 1.67 * Upper Limit of Normal [ULN] at Endpoint, Total Bilirubin [BIL] within Normal Limits at Endpoint, and Greater Than Equal To [≥] 15% ALP Reduction) from Baseline to Week 12 and Week 52 The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 
| Percent Change in Serum Alkaline Phosphatase (ALP) | Percent change in ALP from baseline to Weeks 12 and 52 The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. | 12 weeks and 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PBC, Primary Biliary Cholangitis (PBC)