A Study Evaluating Efruxifermin in Subjects With Non-Cirrhotic Nonalcoholic Steatohepatitis (NASH)/Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Fibrosis

This is a Phase 3, multi-center, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of efruxifermin (EFX) in subjects with non-cirrhotic nonalcoholic steatohepatitis (NASH)/metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis stage 2 or 3 (F2 or F3).

Approximately 1,650 subjects will be enrolled into 2 cohorts.

* 750 F2/F3 subjects in Cohort 1

* 900 F3 subjects in Cohort 2

Cohort 1 will enroll approximately 750 subjects with biopsy-confirmed NASH/MASH and fibrosis stage F2 or F3. Subjects in Cohort 1 will undergo evaluation of histologic efficacy endpoints at Week 52.

Cohort 2 will enroll approximately 900 subjects with biopsy-confirmed fibrosis stage F3. Subjects in Cohort 2 may enroll regardless of NAFLD Activity Score (NAS). Subjects in Cohort 2 will undergo liver biopsy assessment at Week 96.

Eligible subjects will be randomized in a 1:1:1 ratio to receive:

* EFX 28 mg administered subcutaneously once weekly

* EFX 50 mg administered subcutaneously once weekly

* Placebo administered subcutaneously once weekly

Subjects will participate in:

* a screening period of up to 12 weeks,

* a 52-week primary histology endpoint treatment period,

* long-term treatment and clinical outcomes follow-up for up to approximately -240 weeks total treatment duration, and

* a follow-up visit approximately 30 days after the last dose of study drug.

The study will evaluate the effects of EFX compared with placebo on histologic improvement in NASH/MASH, fibrosis regression, progression to cirrhosis, noninvasive markers of liver fibrosis, liver-related clinical outcomes, and long-term safety.

Clinical outcomes assessments include evaluation of liver-related events and all-cause mortality. Key secondary and long-term outcome assessments include evaluation of fibrosis progression, liver stiffness by FibroScan, Enhanced Liver Fibrosis (ELF) score, and progression to cirrhosis at prespecified time points including Weeks 96 and 240.

An interim analysis of the primary clinical outcomes endpoint may be performed after all subjects in Cohort 2 have completed the Week 96 visit or discontinued from the study and a prespecified number of clinical outcome events have occurred.

Subjects who discontinue study drug may continue study assessments according to the protocol schedule to support long-term efficacy and safety evaluations.

Primary Outcome Measures

1. Cohort 1 Only: Resolution of NASH/MASH and a ≥ 1 stage improvement in fibrosis
   Based on NAS (scored by 0-1 for steatosis, 0-3 for inflammation, and 0-2 for ballooning) and NASH CRN fibrosis score (scored by a fibrosis score of 0-4, where 0 = no fibrosis, 1 = centrilobular pericellular fibrosis, 2 = centrilobular and periportal fibrosis, 3 = bridging fibrosis, 4 = cirrhosis)
2. Event-free survival
   Based on time from randomization to the first clinical event including evidence of disease progression, liver decompensation events, liver transplantation or eligibility for liver transplantation, and all-cause mortality.

Secondary Outcome Measures

1. Cohort 1 Only: Resolution of NASH/MASH and no worsening of fibrosis
   Based on NAS (scored by 0-1 for steatosis, 0-3 for inflammation, and 0-2 for ballooning) and NASH CRN fibrosis score (scored by a fibrosis score of 0-4, where 0 = no fibrosis, 1 = centrilobular pericellular fibrosis, 2 = centrilobular and periportal fibrosis, 3 = bridging fibrosis, 4 = cirrhosis)
2. Cohort 1 Only: ≥ 1 stage improvement in fibrosis and no worsening of steatohepatitis
   Based on NAS (scored by 0-1 for steatosis, 0-3 for inflammation, and 0-2 for ballooning) and NASH CRN fibrosis score (scored by a fibrosis score of 0-4, where 0 = no fibrosis, 1 = centrilobular pericellular fibrosis, 2 = centrilobular and periportal fibrosis, 3 = bridging fibrosis, 4 = cirrhosis)
3. Resolution of NASH/MASH and no worsening of fibrosis
   Based on NAS (scored by 0-1 for steatosis, 0-3 for inflammation, and 0-2 for ballooning) and NASH CRN fibrosis score (scored by a fibrosis score of 0-4, where 0 = no fibrosis, 1 = centrilobular pericellular fibrosis, 2 = centrilobular and periportal fibrosis, 3 = bridging fibrosis, 4 = cirrhosis)
4. Change from baseline of non-invasive markers of liver fibrosis: ELF score
   ELF (scale of 6.7 to 9.8 when higher scores indicative of increased fibrosis)
5. Change from baseline of non-invasive markers of liver fibrosis: ELF score components (TIMP-1, HA, PIIINP, Pro-C3)
   Tissue inhibitor of metalloproteinase-1 \[TIMP-1\], hyaluronic acid \[HA\], amino terminal pro-peptide of type 3 procollagen \[PIIINP\]), and propeptide of type 3 procollagen (Pro-C3)
6. Change from baseline in non-invasive markers of liver fibrosis: ELF score
   ELF score scale of 6.7 to 9.8 when higher scores are indicative of increased fibrosis
7. Change from baseline in non-invasive markers of liver fibrosis: ELF score components: TIMP-1, HA, PIIINP, Pro-C3
8. Change from baseline of non-invasive markers of liver fibrosis: Fibroscan, CAP
   Liver stiffness assessed by transient elastography (FibroScan®) (kPa, CAP)
9. Change from baseline of non-invasive markers of liver fibrosis: Fibroscan
   Liver stiffness assessed by transient elastography (FibroScan)
10. Change from baseline of markers of liver injury: ALT, AST, GGT
    ALT (U/L), AST (U/L), GGT (U/L)
11. Change from baseline of markers of liver injury: Uric Acid
    Uric acid (mg/dL)
12. Change from baseline of lipoproteins: Total cholesterol, TG, Non-HDL-C, HDL-C, and LDL-C
    Total cholesterol (mg/dL), TG (mg/dL), Non-HDL-C (mg/dL), HDL-C (mg/dL), and LDL-C (mg/dL)
13. Change from baseline of markers of insulin sensitivity and glycemic control: HbA1c
    HbA1c (%)
14. Change from baseline of markers of insulin sensitivity and glycemic control: Adiponectin
    Adiponectin (mg/L)
15. Change from baseline of body weight (kg)
16. To assess the safety and tolerability of EFX through the reporting of extent of exposure (weeks)
17. To assess the safety and tolerability of EFX through the reporting of adverse events (severity of events)
18. To assess the safety and tolerability of EFX through the reporting of adverse events (frequency of events)
19. To assess the safety and tolerability of EFX through the reporting of abnormal clinical laboratory tests, ECGs, ultrasounds, vital sign assessments (number of patients)
20. To assess the immunogenicity of EFX through the reporting of antidrug antibodies (number of patients)