RESPONSE: Response to Seladelpar in Subjects With Primary Biliary Cholangitis (PBC) and an Inadequate Control to or an Intolerance to Ursodeoxycholic Acid (UDCA)

Phase 3

Completed

Conditions: Primary Biliary Cholangitis

Interventions: Drug: Seladelpar 10 mg
Drug: Placebo
Drug: Seladelpar 5 mg

Registration Number: NCT04620733

Lead Sponsor: CymaBay Therapeutics, Inc.

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 193

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/Exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Seladelpar	Seladelpar 5 mg	Participants will receive seladelpar 10 mg (or 5 mg down-titrated, for those participants who met specific safety monitoring criteria or had tolerability issues), orally, once daily, for a duration of up to 12 months.
Seladelpar	Seladelpar 10 mg	Participants will receive seladelpar 10 mg (or 5 mg down-titrated, for those participants who met specific safety monitoring criteria or had tolerability issues), orally, once daily, for a duration of up to 12 months.
Placebo	Placebo	Participants will receive placebo to match seladelpar, orally, once daily, for a duration of up to 12 months.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (134): The Institute for Liver Health DBA Arizona Liver Health
🇺🇸
Chandler, Arizona, United States
Arkansas Diagnostic Center
🇺🇸
Little Rock, Arkansas, United States
Stanford University School of Medicine
🇺🇸
Palo Alto, California, United States
California Liver Research Institute
🇺🇸
Pasadena, California, United States
University of California, Davis Medical Center
🇺🇸
Sacramento, California, United States
California Pacific Medical Center - Sutter Pacific Medical Foundation
🇺🇸
San Francisco, California, United States
Covenant Metabolic Specialists, LLC
🇺🇸
Fort Myers, Florida, United States
Florida Research Institute
🇺🇸
Lakewood Ranch, Florida, United States
Schiff Center for Liver Diseases/University of Miami
🇺🇸
Miami, Florida, United States
Covenant Research and Clinics, LLC
🇺🇸
Sarasota, Florida, United States
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The Institute for Liver Health DBA Arizona Liver Health
🇺🇸Chandler, Arizona, United States