Intervention: Seladelpar
Trial phase: Phase 2
SMILES: CCO[C@H](COc1ccc(C(F)(F)F)cc1)CSc1ccc(OCC(=O)O)c(C)c1
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 50
Group description: Subjects were randomized to receive seladelpar 50 mg daily for 52 weeks.

AEs are only summarized in DB phase, not OLE phase.
Eligibility criteria:
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)