A Study to Evaluate Seladelpar in Subjects With Nonalcoholic Steatohepatitis (NASH)

Study Overview
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Brief Summary
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A Phase 2, Double-Blind (DB), Randomized, Placebo-Controlled Study Followed by an Open-Label Extension Period to Evaluate the Activity of Seladelpar in Subjects with Nonalcoholic Steatohepatitis (NASH) OLE phase was not analyzed due to the early termination of the study

Detailed Description
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Primary Objectives To evaluate the effect of seladelpar on hepatic fat fraction, as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) at Week 12 in the DB phase To evaluate the safety and tolerability of seladelpar in the DB and OLE phases Secondary Objectives To evaluate the effect of seladelpar on MRI- PDFF at Week 26 and Week 52 in the DB phase To evaluate the effect of seladelpar on histological improvement of nonalcoholic fatty liver disease activity score (NAS) at Week 52 in the DB phase To evaluate the effect of seladelpar on histological improvement of fibrosis at Week 52 in the DB phase To evaluate the effect of seladelpar on metabolic biochemical markers and biochemical markers of inflammation in the DB and OLE phases

Official Title
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A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study Followed by an Open-Label Extension Period to Evaluate the Activity of Seladelpar in Subjects With Nonalcoholic Steatohepatitis (NASH)

Conditions
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NASH - Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Seladelpar
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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DB Inclusion Criteria: Must be able to provide written informed consent (signed and dated) and any authorizations required by local law 18 to 75 years old (inclusive) Histological evidence of definite NASH on a liver biopsy (obtained during the screening period or historical liver biopsy obtained no more than 90 days prior to the initial screening visit) NAS of 4 points or greater with a score of at least 1 point in each component (steatosis, lobular inflammation, and ballooning) Fibrosis stage 1, 2, or 3 on liver biopsy MRI-PDFF ≥ 10% 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 30 days after the last dose of study drug. 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 of study drug. DB Exclusion Criteria: Significant 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 reliably quantify alcohol intake Treatment with drugs associated with nonalcoholic fatty liver disease (NAFLD) (amiodarone, methotrexate, oral glucocorticoids at doses greater than 5 mg/day, tamoxifen, estrogens at doses greater than those used for hormone replacement or contraception, anabolic steroids (such as testosterone and valproic acid) for more than 4 weeks within the last 2 months prior to the initial screening Treatment with pioglitazone or high-dose vitamin E (>400 IU/day) within the last 2 months prior to the initial screening Initiation of treatment with a glucagon-like peptide-1 (GLP-1) agonist or a dose change within the last 2 months prior to the initial screening Prior or planned bariatric surgery (a prior reversed sleeve gastrectomy is permitted) Poorly controlled type 2 diabetes mellitus as defined by hemoglobin A1c [HbA1c] 9.5% or higher or type 1 diabetes mellitus Diabetic patients who are taking sodium/glucose cotransporter 2 (SGLT-2) inhibitors must be on a stable dose within 2 months prior to the initial screening and throughout the study Significant weight loss within the last 6 months (e.g., > 10%) Use of any weight-loss medication for 3 months prior to and during the study period Body mass index (BMI) < 18.5 kg/m2 Hepatic decompensation defined as the presence of any of the following: Serum albumin less than 3.5 g/dL International normalized ratio (INR) greater than 1.4 (unless due to therapeutic anticoagulants) Total bilirubin greater than 2 mg/dL with the exception of Gilbert syndrome History of esophageal varices, ascites, or hepatic encephalopathy Other chronic liver diseases Active hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg) Active hepatitis C as defined by presence of hepatitis C virus antibody (HCV AB) plus a positive HCV RNA History or evidence of current active autoimmune hepatitis History or evidence of primary biliary cholangitis (PBC) History or evidence of primary sclerosing cholangitis History or evidence of Wilson's disease History or evidence of alpha-1-antitrypsin deficiency History or evidence of hemochromatosis History or evidence of drug-induced liver disease, as defined exposure and history Known bile duct obstruction Suspected or proven liver cancer ALT > 200 U/L AST < 20 U/L Creatine kinase (CK) > upper limit of normal (ULN) Serum creatinine > ULN Platelet < lower limit of normal (LLN) Inability to obtain a liver biopsy History of biliary diversion Known history of human immunodeficiency virus (HIV) infection History of malignancy diagnosed or treated within 2 years Recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted Cervical carcinoma in-situ is allowed if appropriately treated prior to Screening Participants under active evaluation for malignancy are not eligible Active substance abuse, based on Investigator judgment, including inhaled or injected drugs, within 1 year prior to the initial screening Females who are pregnant or breastfeeding Patients unable to undergo MRI-PDFF due to: Contraindication to MRI examination Severe claustrophobia impacting ability to perform MRI during the study, despite mild sedation/treatment with an anxiolytic Weight or girth exceeds the scanner capacities Treatment with any other investigational therapy or device within 30 days or within five half-lives, whichever is longer, prior to the initial screening Active, serious medical disease with likely life expectancy < 5 years Any other condition(s) that would compromise the safety of the subject or compromise study quality as judged by the Investigator OLE Phase Enrollment Criteria Subjects must fulfill the following before allowing to start OLE dosing: Provide informed consent on or before Day 1 and prior to any OLE-related study procedures. Completed through the Week 52 biopsy and Week 56 lab assessments in the DB phase Meet the above DB phase Inclusion and Exclusion Criteria before Day 1 of the OLE phase, with the exception of the following: AST < 20 U/L Inability to obtain a liver biopsy (no new biopsy required for OLE) Unable to undergo MRI-PDFF (no imaging performed in OLE)

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
Interventional Model Description: Randomization: 1:2:2:2 (placebo: seladelpar 10 mg: 20 mg: 50 mg)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Seladelpar 10 mg<br>Subjects enrolled will receive seladelpar 10 mg, 20 mg, 50 mg or placebo daily for 52 weeks. | Drug: Seladelpar<br>* 10 mg, 20 mg, or 50 mg<br>* Other names: MBX-8025;|
| Experimental: Seladelpar 20 mg<br>Subjects enrolled will receive seladelpar 10 mg, 20 mg, 50 mg or placebo daily for 52 weeks. | Drug: Seladelpar<br>* 10 mg, 20 mg, or 50 mg<br>* Other names: MBX-8025;|
| Experimental: Seladelpar 50 mg<br>Subjects enrolled will receive seladelpar 10 mg, 20 mg, 50 mg or placebo daily for 52 weeks. | Drug: Seladelpar<br>* 10 mg, 20 mg, or 50 mg<br>* Other names: MBX-8025;|
| Placebo Comparator: Placebo<br>Subjects enrolled will receive seladelpar 10 mg, 20 mg, 50 mg or placebo daily for 52 weeks. | Drug: Placebos<br>* Matching placebo Capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline in Magnetic Resonance Imaging-proton Density Fat Fraction (MRI-PDFF) | Evaluate the effect of seladelpar on hepatic fat fraction, as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) at Week 12 in the double-blind (DB) phase. MRI-PDFF Relative (Percent) Change From Baseline to Week 12 - ANCOVA - mITT Population MRI-PDFF exam was used to quantify the hepatic proton density fat fraction noninvasively. The fat fraction is the proportion of mobile protons in liver tissue attributable to fat and thus, is a noninvasive magnetic resonance-based biomarker of liver triglyceride concentration. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Improvement of 2 Points or More in the Nonalcoholic Fatty Liver Disease Activity Score (NAS) | Histopathology nonalcoholic fatty liver disease activity score (NAS) change from baseline ≤-2 (Improvements of 2 points or more in NAS) - mITT Population Total NAS score represents the sum of scores for steatosis, lobular inflammation, and ballooning, and ranges from 0-8. Diagnosis of NASH (or, alternatively, fatty liver not diagnostic of NASH) should be made first, then NAS is used to grade activity. NAS scores of 0-2 occurred in cases largely considered not diagnostic of NASH, scores of 3-4 were evenly divided among those considered not diagnostic, borderline, or positive for NASH. Scores of 5-8 occurred in cases that were largely considered diagnostic of NASH | Week 52 | 
| Percent Change From Baseline in Alanine Aminotransferase (ALT) at Week 12 and Week 52 | Alanine Aminotransferase (ALT) Relative (percent) change of from Baseline to Weeks 12 and Week 52 - mITT Population A decreased serum levels of alanine aminotransferase (ALT) is a marker of liver function improvement. | Week 12, Week 52 | 
| Percent Change From Baseline in Aspartate Aminotransferase (AST) at Week 12 and Week 52 | Relative (Percent) Change of Aspartate Aminotransferase (AST) From Baseline to Weeks 12 and Week 52 - mITT Population A decreased serum levels of Aspartate Aminotransferase (AST) is a marker of liver function improvement. | Weeks 12, Week 52 | 
| Percent Change From Baseline in Gamma Glutamyl Transferase (GGT) at Week 12 and Week 52 | Relative (Percent) Change of Gamma Glutamyl Transferase (GGT) From Baseline to Weeks 12 and Week 52 - mITT Population A decreased serum levels of Gamma Glutamyl Transferase (GGT) is a marker of liver function improvement. | Weeks 12, Week 52 | 
| Number of Participants With Decrease in MRI-PDFF ≥ 30% From Baseline at Week 12 and Week 52 | Number of Participants with a relative decrease in MRI-PDFF ≥30% (ie, percent change ≥ 30%) at Weeks 12, and 52/ET (Early Termination) in the DB phase - mITT Population. MRI-PDFF exam was used to quantify the hepatic proton density fat fraction noninvasively. The fat fraction is the proportion of mobile protons in liver tissue attributable to fat and thus, is a noninvasive magnetic resonance-based biomarker of liver triglyceride concentration. MRI-PDFF response defined as ≥30% relative decline in MRI-PDFF is associated with ≥1 stage improvement in fibrosis and may be used as a surrogate marker of fibrosis regression in early phase clinical trials for NASH | Week 12, Week 52 | 
| Percentage Change From Baseline in Magnetic Resonance Imaging-proton Density Fat Fraction (MRI-PDFF) at Week 52 | Percentage Change from Baseline in MRI-PDFF to Weeks 52//ET - mITT Population MRI-PDFF exam was used to quantify the hepatic proton density fat fraction noninvasively. The fat fraction is the proportion of mobile protons in liver tissue attributable to fat and thus, is a noninvasive magnetic resonance-based biomarker of liver triglyceride concentration. | Week 52 | 
| Number of Liver Biopsy Responders With Reversal of NASH Reversal of NASH (Ballooning Score of 0 and Lobular Inflammation Score of 0 or 1) and no Worsening of Hepatic Fibrosis at Week 52 | Liver Biopsy Responders with reversal of NASH (ballooning score of 0 and lobular inflammation score of 0 or 1 and no worsening of hepatic fibrosis) at Week 52/ET. The reversal of NASH was defined as the absence of hepatocellular ballooning (score of 0) and no or minimal inflammation (lobular inflammation score of 0 or 1). | Week 52 | 
| Percentage of Participants With Improvement by at Least 1 Stage in Fibrosis From Baseline at Week 12 and Week 52 | Proportion of subjects with improvement by at least 1 stage in fibrosis without worsening of NASH (ie, improvement by at least 1 fibrosis stage without worsening of NAS) at Week 52/ET - Cochran-Mantel-Haenszel - mITTb Population There five liver fibrosis stages (F0: no scarring (no fibrosis); F1: minimal scarring; F2: scarring has occurred and extends outside the liver area (significant fibrosis); F3: fibrosis spreading and forming bridges with other fibrotic liver areas (severe fibrosis); F4: cirrhosis or advanced scarring) | Week 52 |