unexpected histological findings

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

Primary Objectives

1. 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
2. To evaluate the safety and tolerability of seladelpar in the DB and OLE phases

Secondary Objectives

1. To evaluate the effect of seladelpar on MRI- PDFF at Week 26 and Week 52 in the DB phase
2. To evaluate the effect of seladelpar on histological improvement of nonalcoholic fatty liver disease activity score (NAS) at Week 52 in the DB phase
3. To evaluate the effect of seladelpar on histological improvement of fibrosis at Week 52 in the DB phase
4. To evaluate the effect of seladelpar on metabolic biochemical markers and biochemical markers of inflammation in the DB and OLE phases

DB Inclusion Criteria:

1. Must be able to provide written informed consent (signed and dated) and any authorizations required by local law
2. 18 to 75 years old (inclusive)
3. 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)
4. NAS of 4 points or greater with a score of at least 1 point in each component (steatosis, lobular inflammation, and ballooning)
5. Fibrosis stage 1, 2, or 3 on liver biopsy
6. MRI-PDFF ≥ 10%
7. 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:

1. 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

2. 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

3. Treatment with pioglitazone or high-dose vitamin E (>400 IU/day) within the last 2 months prior to the initial screening

4. 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

5. Prior or planned bariatric surgery (a prior reversed sleeve gastrectomy is permitted)

6. Poorly controlled type 2 diabetes mellitus as defined by hemoglobin A1c [HbA1c] 9.5% or higher or type 1 diabetes mellitus

7. 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

8. Significant weight loss within the last 6 months (e.g., > 10%)

9. Use of any weight-loss medication for 3 months prior to and during the study period

10. Body mass index (BMI) < 18.5 kg/m2

11. 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

12. 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

13. ALT > 200 U/L

14. AST < 20 U/L

15. Creatine kinase (CK) > upper limit of normal (ULN)

16. Serum creatinine > ULN

17. Platelet < lower limit of normal (LLN)

18. Inability to obtain a liver biopsy

19. History of biliary diversion

20. Known history of human immunodeficiency virus (HIV) infection

21. 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

22. Active substance abuse, based on Investigator judgment, including inhaled or injected drugs, within 1 year prior to the initial screening

23. Females who are pregnant or breastfeeding

24. 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

25. Treatment with any other investigational therapy or device within 30 days or within five half-lives, whichever is longer, prior to the initial screening

26. Active, serious medical disease with likely life expectancy < 5 years

27. 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:

1. Provide informed consent on or before Day 1 and prior to any OLE-related study procedures.

2. Completed through the Week 52 biopsy and Week 56 lab assessments in the DB phase

3. 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)

Double Blind Placebo Controlled