A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Efruxifermin in Subjects with Non-Cirrhotic Nonalcoholic Steatohepatitis (NASH)/Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Fibrosis

Prior treatment

• History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening; Note: Significant alcohol consumption is defined as an average exceeding 1 ethanol containing drink/day in female subjects and 2 ethanol containing drinks/day in male subjects.
• Weight loss > 10% within 90 days prior to the collection date of the liver biopsy specimen used to assess subject eligibility.
• Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or stroke within 90 days prior to screening and through randomization.
• Use of any investigational medication within 30 days or 5 half lives, whichever is longer, prior to screening or concurrent participation in another therapeutic clinical study.
• Use of any prohibited medication(s) as outlined in Table 2 of the protocol including any prior exposure to EFX.
• Positive urine drug screen for amphetamines, cocaine, or opiates (e.g., heroin, morphine) at screening. Subjects with a positive urine drug screen due to prescription medication (e.g., opiates, methylphenidate) are eligible if the prescription and diagnosis are reviewed and approved by the Investigator. Subjects on stable methadone or buprenorphine maintenance treatment for at least 180 days prior to screening may be included in the study.
• Unstable Type 2 diabetes defined as: a. Insulin dose adjustment > 35% within 30 days prior to screening through randomization, b. Any prior history of diabetic ketoacidosis and/or hyperglycemic, hyperosmolar state.
• Hypoglycemia unawareness, hospitalization due to hypoglycemia, or history of severe hypoglycemia (hypoglycemia requiring outside assistance to regain normal neurologic status) within 90 days prior to screening.
• Subjects with a T-score of ≤ ─1.75 at the femoral neck or lumbar spine based on a centrally read DXA scan performed during screening. Note: A historical DXA scan performed within 90 days prior to screening may be accepted as the screening DXA scan. The historical scan must have been performed on a scanner previously qualified by the central imaging vendor that is available for use at post-baseline visits.
• Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV RNA positive). Subjects cured of HCV infection < 2 years prior to the Screening visit (based on date of RNA PCR negative confirmation following conclusion of treatment) are not eligible.
• Prior (< 2 years prior to screening) or planned (during the study period) bariatric surgery (e.g., gastroplasty, Roux-en-Y gastric bypass) or reversal or removal of intragastric balloon. Surgery failure < 2 years prior to screening is also exclusionary.
• Current or prior history of hepatocellular carcinoma (HCC).

Other illness

• Human immunodeficiency virus (HIV) infection.
• History of pancreatitis.
• Known hypersensitivity to the study drug, the metabolites, or formulation excipients.
• Type 1 diabetes.
• Poorly controlled hypertension (systolic blood pressure > 160 mm Hg, or diastolic blood pressure > 100 mm Hg) at the Screening visit or Pre Baseline visit. Note: Vital signs for eligibility assessment may be repeated one time at the Investigator’s discretion
• Chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive) or acute hepatitis A infection (hepatitis A immunoglobulin M [IgM] antibody positive). For subjects with positive hepatitis B core antibody (HBcAb), HBV DNA by quantitative polymerase chain reaction (PCR) will be required.
• History of liver transplantation.
• Current diagnosis of Cushing’s syndrome.

Lab values

• Uncontrolled cardiac arrhythmia or confirmed QT interval corrected using Fridericia’s formula (QTcF) > 450 msec for males and > 470 msec for females at the screening electrocardiogram (ECG) assessment. Subjects with cardiac pacemakers and elevated QTcF (> 450 msec for males and > 470 msec for females) may be allowed to participate if, in the Investigator’s opinion, the subject’s cardiac function is stable. Note: ECG for eligibility assessment may be repeated one time at the Investigator’s discretion
• Presence of any laboratory abnormality or significant systemic or major illnesses (other than liver disease) that, in the opinion of the Investigator, compromises the subject’s ability to safely participate in and complete the study including, but not limited to: a. Pulmonary disease, heart failure, renal failure, organ transplantation, serious psychiatric disease, malignancy, history of substance abuse and/or a psychiatric condition requiring hospitalization and/or emergency room visit within 180 days of screening.
• Other causes of liver disease based on medical history and/or centralized review of liver histology and/or central laboratory results, including but not limited to: alcoholic liver disease, autoimmune disorders (e.g., primary biliary cholangitis [PBC], primary sclerosing cholangitis [PSC], autoimmune hepatitis), drug induced hepatotoxicity, Wilson disease, or clinically significant iron overload.

Other

• Presence of cirrhosis on liver biopsy (stage 4 fibrosis).
• Life expectancy of less than 2 years.
• Unable to safely undergo a liver biopsy.
• Unavailable for follow-up assessment or concern for subject’s compliance with the protocol procedures.

• Males and non-pregnant, non-lactating females between 18–80 (between 19–80 in the Republic of Korea) years of age, inclusive, on the day of signing informed consent.
• Female subjects of childbearing potential (see definition in Appendix C) must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at baseline/Day 1.
• Male and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix C.
• Previous history or presence of T2D (as determined by medical history or based on screening lab values if previously undiagnosed [i.e., HbA1c ≥ 6.5%]) or 2 out of 4 components of metabolic syndrome (obesity, dyslipidemia, elevated blood pressure, elevated fasting glucose)
• Body mass index (BMI) ≥ 25.0 kg/m2
• Cohort 1 Subjects who do not have a historical liver biopsy specimen that meets Inclusion Criteria 7 must meet either inclusion criterion 4a OR 4b OR 4c prior to collection of a liver biopsy specimen during the Screening visit:REDACTED. Cohort 2 Subjects who do not have a historical liver biopsy specimen that meets Inclusion Criteria 7 must meet either inclusion criterion 4d OR 4e OR 4f prior to collection of a liver biopsy specimen during the Screening visit: REDACTEDNote for both Cohort 1 and Cohort 2: If a historical value for FibroScan® is available within 12 weeks prior to randomization, then the screening FibroScan® does not need to be repeated.
• Central laboratory tests at screening or pre-baseline that meet all of the following criteria: a. Estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73m2 (> 30 mL/min/1.73m2 in the Republic of Korea), as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) at Screening; b. Hemoglobin A1c (HbA1c) ≤ 9.5% at Screening; International Normalized Ratio (INR) < 1.3 at Screening, unless due to therapeutic anticoagulation; d. Total bilirubin < 1.3 mg/dL at Screening and Pre-baseline and direct bilirubin ≤ 0.5 mg/dL at Screening. For subjects with Gilbert’s syndrome or hemolytic anemia, total bilirubin may be elevated if direct bilirubin ≤ ULN; e. Creatine kinase (CK) < 3 × upper limit of normal (ULN) at Screening; f. Platelet count ≥ 100,000/μL at Screening; g. Triglyceride (TG) level ≤ 500 mg/dL at Screening; h. Aspartate aminotransferase (AST) > 17 for females and > 20 for males at Screening and Pre-baseline; Note: The AST inclusion criteria does not apply to subjects with an eligible historical liver biopsy performed ≤ 180 days prior to screening in either Cohort 1 or Cohort 2 as defined in Inclusion Criteria 7. i. AST ≤ 5 × ULN at Screening and Pre-baseline; j. Alanine aminotransferase (ALT) ≤ 5 × ULN at Screening and Pre-baseline; k. Alkaline phosphatase (ALP) < 2 × ULN at Screening and Prebaseline; l. 25-Hydroxy Vitamin D ≥ 13 ng/mL at Screening. Note: Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion. A subject who fails to meet Inclusion Criterion 5l will be allowed to retest 25-Hydroxy Vitamin D during the same screening period OR rescreen provided they agree to take supplementation with Vitamin D. See Section 5.3 for details.
• Documented stability of ALT and AST levels, as evidenced by no significant worsening of ALT and AST values at pre-baseline relative to screening values and the following parameters: a. If the screening and pre-baseline ALT and AST values are both ≤ 1.5 × ULN, there is no limit to the difference between the values. b. If at least 1 of the screening or pre-baseline ALT or AST values is > 1.5 × ULN and shows worsening at pre-baseline, the percent increase must be ≤ 50%. Note: Subjects must have ALT and AST repeated during the screening period (Pre-Baseline visit) at minimum 28 days between blood draws to confirm either criterion 6a or 6b above. Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion.
• Cohort 1: Biopsy-proven NASH/MASH. Must have had a liver biopsy obtained ≤ 180 days prior to screening with fibrosis stage 2 or 3 and a non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of ≥ 4 with at least 1 point in each of the following components: 1. Steatosis (scored 0 to 3), 2. Ballooning degeneration (scored 0 to 2), and 3. Lobular inflammation (scored 0 to 3) b. Cohort 2: REDACTED Note: For subjects with weight loss ≥ 5% in the 180 days prior to randomization, the historical liver biopsy must have been collected within 90 days prior to screening. Note: REDACTED
  • Use of any conditionally allowed medications must follow the stable dose and adjustment criteria as outlined in Table 3.
  • Willing and able to give written informed consent prior to any study specific procedures being performed.