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

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)

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)

Study Overview

• Status: Completed
• Conditions: Primary Biliary Cirrhosis
• Intervention / Treatment: Drug: MBX-8025 2 mg Capsule; Drug: MBX-8025 5 mg Capsule; Drug: MBX-8025 10 mg Capsule

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 119
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary Liver Unit
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto Centre for Liver Disease
• Germany
  • Berlin, Germany, 10117
    • Outpatient Clinic of Internal Medicine
  • Erlangen, Germany, 91054
    • University Hospital Erlangen
  • Hamburg, Germany, 20099
    • Ifi-Studien und Projekte GmbH, An der Asklepios Klinik St. Georg
  • Hannover, Germany, 30625
    • Center of Internal Medicine - Medical School of Hannover
  • Mainz, Germany, 55131
    • University Medical Centre of the Johannes Guttenberg-University
  • Marburg, Germany, 35043
    • Universitätsklinikum Gießen und Marburg GmbH
  • Tubingen, Germany, 72076
    • Medizinische Universitätsklinik Tübingen
• United Kingdom
  • Birmingham, United Kingdom, B15 2GW
    • University Hospitals Birmingham
  • Cambridge, United Kingdom, CB2 0QQ
    • Cambridge University Hospitals NHS Foundation Trust
  • Hull, United Kingdom, HU3 2JZ
    • Hull and East Yorkshire Hospitals NHS Trust
  • London, United Kingdom, NW3 2QR
    • Royal Free London NHS Foundation Trust
  • Plymouth, United Kingdom, PL6 8DH
    • Plymouth Hospitals NHS Trust
  • Portsmouth, United Kingdom, PO6 3LY
    • Portsmouth Hospitals NHS Trust
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Institute for Liver Health
  • California
    • Coronado, California, United States, 92118
      • Southern California Research Center
    • Palo Alto, California, United States, 94305
      • Standford University Medicine
    • Sacramento, California, United States, 95817
      • University of California, Davis Medical Center
    • Ventura, California, United States, 93003
      • Ventura Clinical Trials
  • Florida
    • Lakewood Ranch, Florida, United States, 34211
      • Florida Research Institute
    • Miami, Florida, United States, 33136
      • University of Miami - Center for Liver Diseases
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Digestive Healthcare of Georgia
    • Atlanta, Georgia, United States, 30308
      • Atlanta Gastroenterology Associates, LLC
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
  • Michigan
    • Novi, Michigan, United States, 48377
      • Henry Ford Health System
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • Saint Louis University, Gastroenterology & Hepatology
  • New York
    • Manhasset, New York, United States, 11030
      • Northwell Health - Center for Liver Disease and Transplantation
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • New York, New York, United States, 10029
      • The Mount Sinai Medical Center
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Northest Clinical Research Center, LLC.
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center Investigation Drug Service
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Live Oak, Texas, United States, 78233
      • Gastroenterology Consultants of SA
  • Virginia
    • Newport News, Virginia, United States, 23602
      • Bon Secours St. Mary's Immaculate Hospital
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Must have given written informed consent (signed and dated) and any authorizations required by local law
2. 18 to 75 years old (inclusive)

3. 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
4. On a stable and recommended dose of UDCA for the past twelve months or intolerant to UDCA
5. AP ≥ 1.67 × ULN
6. 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:

1. 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)
2. AST or ALT > 3 × ULN
3. Total bilirubin > 2.0 mg/dL
4. 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.
5. Auto-immune hepatitis
6. Primary sclerosing cholangitis
7. Known history of alpha-1-Antitrypsin deficiency
8. Known history of chronic viral hepatitis
9. Creatine kinase above ULN
10. Serum creatinine above ULN
11. For females, pregnancy or breast-feeding
12. Use of colchicine, methotrexate, azathioprine, or systemic steroids in the two months preceding screening
13. Current use of fibrates or simvastatin
14. Current use of obeticholic acid
15. Use of an experimental or unapproved treatment for PBC
16. Use of experimental or unapproved immunosuppressant
17. Adverse event leading to MBX-8025 discontinuation from CymaBay's phase 2 PBC study (CB8025-21528)
18. 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MBX-8025 (2 mg); MBX-8025 2 mg capsule once daily	Drug: MBX-8025 2 mg Capsule; 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.; Other Names: MBX-8025; seladelpar
Experimental: MBX-8025 (5 mg); MBX-8025 5 mg capsule once daily	Drug: MBX-8025 5 mg Capsule; 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.; Other Names: MBX-8025; seladelpar
Experimental: MBX-8025 (10 mg); MBX-8025 10 mg capsule once daily	Drug: MBX-8025 10 mg Capsule; 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.; Other Names: MBX-8025; seladelpar

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: CymaBay Therapeutics, Inc.

Publications and helpful links

General Publications

• Bowlus CL, Galambos MR, Aspinall RJ, Hirschfield GM, Jones DEJ, Dorffel Y, Gordon SC, Harrison SA, Kremer AE, Mayo MJ, Thuluvath PJ, Levy C, Swain MG, Neff GW, Sheridan DA, Stanca CM, Berg CP, Goel A, Shiffman ML, Vierling JM, Boudes P, Steinberg A, Choi YJ, McWherter CA. A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis. J Hepatol. 2022 Aug;77(2):353-364. doi: 10.1016/j.jhep.2022.02.033. Epub 2022 Mar 30.

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2016
• Primary Completion (Actual): September 7, 2018
• Study Completion (Actual): July 8, 2019

Study Registration Dates

• First Submitted: November 2, 2016
• First Submitted That Met QC Criteria: November 2, 2016
• First Posted (Estimate): November 4, 2016

Study Record Updates

• Last Update Posted (Actual): July 14, 2022
• Last Update Submitted That Met QC Criteria: June 21, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: PBC; Primary Biliary Cholangitis (PBC)
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Cholestasis; Liver Cirrhosis; Cholangitis; Liver Cirrhosis, Biliary; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Seladelpar
• Other Study ID Numbers: CB8025-21629

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO