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

Prior treatment

• Where a biopsy is used to assess subject eligibility, weight loss > 10% is not permitted within 90 days prior to the collection date of the liver biopsy specimen used to assess subject eligibility through randomization. For all other subjects, weight loss > 10% is not permitted within 90 days prior to screening through randomization
• 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
• 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. Note: Without written approval from the Sponsor, a historical biopsy cannot be used for screening eligibility if the biopsy was collected prior to or during treatment with an investigational drug
• Use of any prohibited medication(s), 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 T2D defined as: a. Insulin dose adjustment > 35% within 30 days prior to screening through randomization b. Any prior history of diabetic ketoacidosis and/or hyperosmolar hyperglycaemic state
• Hypoglycaemia unawareness, hospitalization due to hypoglycaemia, or history of severe hypoglycaemia (hypoglycaemia requiring outside assistance to regain normal neurologic status) within 90 days prior to screening
• Any history of osteoporosis or a T-score of ≤ ─2.5 at the femoral neck or lumbar spine based on a centrally read dual-energy X-ray absorptiometry (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
• Any current or prior history of decompensated liver disease including ascites, hepatic encephalopathy (HE), or variceal bleeding
• 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

• Current diagnosis of Cushing’s syndrome
• Type 2 diabetes
• Human immunodeficiency virus (HIV) infection
• Child-Pugh score > 6 (Class B or C) at screening, unless due to haemolytic anaemia, therapeutic anticoagulation, or Gilbert’s syndrome
• Known hypersensitivity to the study drug, its metabolites, or formulation excipients
• Poorly controlled hypertension (average of triplicate systolic blood pressure measurement > 160 mm Hg, or average of triplicate 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
• Model for End-Stage Liver Disease 3.0 (MELD-3) score > 12 at screening, unless due to hemolytic anemia, therapeutic anticoagulation, or Gilbert’s syndrome
• History of significant pancreatic disorders (acute pancreatitis, chronic pancreatitis, hereditary pancreatitis, and pancreatic cancer)
• 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

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 ECG assessment. Subjects with cardiac pacemakers or pre-existing right bundle branch block (RBBB) 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,malignancy, history of substance abuse and/or a serious psychiatric condition, defined as requiring hospitalization and/or emergency room visit within 180 days of screening
• 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. Note: Subjects who were previously diagnosed with chronic HCV infection who achieved sustained viral response (SVR) following treatment, or subjects with spontaneous clearance of HCV infection (positive serology for HCV infection, negative for HCV RNA at screening, and no documented history of acute HCV infection within 2 years prior to screening) may be enrolled
• 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, clinically significant iron overload, or alpha-1-antitryspin deficiency. Additional requirements for Wilson disease and alpha-1-antitryspin deficiency are outlined

Other

• Life expectancy of less than 2 years
• Cohort 1 only: 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 years of age, inclusive, on the day of signing informed consent. Note: The minimum age for participation as an adult will be based on the age of legal consent for clinical research as defined by local regulations in each participating country
• Central laboratory tests that meet all of the following criteria at screening: a. Albumin ≥ 3.5 g/dL; b. 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); c. Hemoglobin A1c (HbA1c) ≤ 9.5%; d. International Normalized Ratio (INR) ≤ 1.3, unless due to therapeutic anticoagulation; e. Direct bilirubin ≤ 0.5 mg/dL; f. Creatine kinase (CK) < 3 × upper limit of normal (ULN); g. Triglyceride (TG) level ≤ 500 mg/dL; h. 25-Hydroxy Vitamin D ≥ 13 ng/mL Note: Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion. A subject who fails to meet Inclusion Criterion 8h will be allowed to retest 25-Hydroxy Vitamin D during the same screening period OR rescreen provided that they agree to take supplementation with Vitamin D
• Central laboratory tests that meet all of the following criteria at screening and pre-baseline: a. Total bilirubin < 1.3 mg/dL. For subjects with Gilbert’s syndrome or hemolytic anemia, total bilirubin may be elevated if direct bilirubin ≤ ULN at screening; b. Platelet count ≥ 75,000/µL; c. Alanine aminotransferase (ALT) ≤ 5 × ULN; d. Aspartate aminotransferase (AST) ≤ 5 x ULN; e. Alkaline phosphatase (ALP) < 1.5 × ULN Note: Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion
• 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), with a minimum of 28 days between blood draws to confirm either criterion 10a or 10b above. Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion.
• Use of any conditionally allowed medications must follow the stable dose and adjustment criteria
• Willing and able to give written informed consent prior to any study specific procedures being performed
• Female subjects of childbearing potential 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
• Previous history or presence of type 2 diabetes (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 at screening
• Subjects who require a centrally read biopsy to satisfy Inclusion 5 or Inclusion 6a who do not have a historical liver biopsy specimen (collected ≤ 365 days prior to screening and available for submission to the central readers) must meet either Inclusion criterion prior to collection of a liver biopsy specimen during the screening period: a. FibroScan® liver stiffness measurement (LSM) kilopascals (kPa) b. ELF score
• Cohort 1 Subjects only: Biopsy-proven compensated cirrhosis (fibrosis stage 4) due to NASH/MASH based on a centrally read biopsy. Must have had a liver biopsy specimen collected during screening or ≤ 365 days prior to screening with fibrosis stage 4 and meets ONE of the following: a. NAFLD activity score (NAS) of ≥ 3 with at least 1-point each in: — Steatosis (scored 0 to 3), — Ballooning degeneration (scored 0 to 2), and — Lobular inflammation (scored 0 to 3) OR b. Evidence of current or prior steatosis (as defined in Inclusion 7) and 2 current coexisting features of metabolic comorbidities (T2D, obesity, dyslipidemia, elevated blood pressure, elevated fasting glucose) to corroborate a diagnosis of NASH/MASH as the cause of cirrhosis (Noureddin 2020)