FXR Effect on Severe Alcohol-Associated Hepatitis (FRESH) Study

A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Dose-Escalation, Proof-of-Concept Study Evaluating the Safety, Tolerability, Efficacy and Pharmacokinetics of INT-787 in Subjects With Severe Alcohol Associated Hepatitis

The purpose of this trial is to assess dose related safety, efficacy, and pharmacokinetics (PK) of INT-787 in participants with severe alcohol-associated hepatitis (sAH).

This is a Phase 2a, randomized, double-blind, placebo-controlled, dose-escalation, proof-of-concept study to evaluate the safety, tolerability, efficacy, and PK of INT-787 in participants, initially admitted to the hospital, with severe alcohol-associated hepatitis (sAH). The study aims to demonstrate and provide rationale for the selection of optimal dose(s) of INT-787 in the target population of participants with sAH. INT-787 will be evaluated for safety and tolerability prior to dose escalation. Overall efficacy, compared to placebo, will be assessed for each dose cohort.

Additionally, PK measurements at various study timepoints will allow the Sponsor to better understand the systemic exposure of INT-787 and the relationship between exposure and efficacy and safety. Such insights in participants with more advanced liver disease will provide valuable information for future clinical trials of INT-787.

The placebo-treated participants will provide important natural history information on outcomes in this participant population with sAH treated with supportive care. The placebo-treated participants within cohorts are meant to blind the study drug administration while the data across dose cohorts will be used in the overall analysis.

Inclusion Criteria:

1. Males or females aged 18 to 65 years (inclusive)

2. Clinical diagnosis of sAH based on all the following:

   1. History of ongoing excess alcohol (>60 g/day [male] or >40 g/day [female]) use for ≥6 months, with <60 days of abstinence prior to the onset of jaundice
   2. Serum total bilirubin >3.0 mg/dL
   3. Aspartate aminotransferase (AST) ≥50 U/L
   4. AST/Aspartate aminotransferase (ALT) ratio ≥1.5
   5. Onset of jaundice within prior 8 weeks
   6. Cohort 1 through Cohort 4: Maddrey's Discriminant Factor (mDF) ≥32 and ≤70
   7. Cohort 5 and Cohort 6: mDF ≥32

3. Cohort 1 through Cohort 4: MELD score ≥18 to ≤25 (inclusive) and Cohort 5 and Cohort 6: MELD score ≥21 to ≤30

4. Female participants must be postmenopausal, surgically sterile, or, if premenopausal (and not surgically sterile), be prepared to use ≥1 highly effective method of contraception from the initiation of Screening and for 90 days after the last dose of investigational product as follows:

   • Surgical sterilization (bilateral tubal occlusion, etc.)

   • Placement of an intrauterine device (IUD) or intrauterine system (e.g., intrauterine hormone-releasing system [IUS])

   • Combined (estrogen and progesterone containing) hormonal contraceptive associated with inhibition of ovulation:

     • Oral
     • Intravaginal
     • Transdermal

   • Progesterone-only hormonal contraception associated with inhibition of ovulation:

     • Oral
     • Injectable
     • Implantable

   • Sexual abstinence: When in line with the preferred and usual lifestyle of the participant, is defined as avoiding all types of activity that could result in conception (pregnancy) from the initiation of Screening and until at least 90 days after the last dose of investigational product

Exclusion Criteria:

1. Participants taking products containing obeticholic acid in the 30 days prior to randomization
2. Participants taking >2 doses of systemic corticosteroids within 30 days prior to randomization.
3. Participants who have been inpatient at a referral hospital for >7 days prior to transfer.
4. Pregnancy, planned pregnancy, potential for pregnancy (e.g., unwillingness to use effective birth control during the study), or current or planned breast feeding.
5. Abstinence from alcohol consumption for >2 months before Day 1.
6. AST or ALT >400 U/L.
7. Cohort 1 through Cohort 4: mDF <32 or >70.
8. Cohort 5 and Cohort 6: mDF <32
9. Cohort 1 through Cohort 4: MELD score <18 or >25.
10. Cohort 5 and Cohort 6: MELD <21 or >30
11. Other causes of liver disease including chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive), chronic hepatitis C virus (HCV) RNA positive, drug-induced liver injury (DILI), biliary obstruction, and autoimmune liver disease.
12. Current or previous history of hepatocellular carcinoma (HCC)
13. History of liver transplantation or currently listed for liver transplant

Note: Additional protocol defined Inclusion/Exclusion criteria apply.