A Study of Efruxifermin in Subjects With Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH) (Symmetry)

Study Overview
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Brief Summary
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This is a multi-center evaluation of efruxifermin (EFX) in a randomized, double-blind, placebo-controlled study in cirrhotic subjects with biopsy-proven F4 compensated NASH.

Official Title
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A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Efruxifermin in Subjects With Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH)

Conditions
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NASH - Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: EFX
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and non-pregnant, non-lactating females between 18-75 years of age inclusive, based on the date of signing informed consent. Main Study Only: Previous history or presence of Type 2 diabetes or 2 out of 4 components of metabolic syndrome (obesity, dyslipidemia, elevated blood pressure, elevated fasting glucose). Main Study Only: Biopsy-proven compensated cirrhosis due to NASH. Cohort D Only: Diagnosis of type 2 diabetes Cohort D Only: Use of GLP-1R agonist for at least 90 days Cohort D Only: Biopsy-proven liver fibrosis stages 1, 2, or 3 Exclusion Criteria: Main Study Only: Weight loss > 10% in the 90 days prior to screening until randomization or from the time of collection of the liver biopsy used to assess subject eligibility until randomization, whichever is longer. Type 1 diabetes or uncontrolled Type 2 diabetes Cohort D Only: Weight loss > 5% in the 90 days prior to screening Cohort D Only: Presence of cirrhosis on liver biopsy Other inclusion and exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EFX 28 mg (Main Study)<br> | Drug: EFX<br>* Investigational drug, Efruxifermin<br>|
| Experimental: EFX 50 mg (Main Study)<br> | Drug: EFX<br>* Investigational drug, Efruxifermin<br>|
| Placebo Comparator: Placebo (Main Study)<br> | Drug: Placebo<br>* Placebo<br>|
| Experimental: EFX 50 mg (Cohort D)<br> | Drug: EFX<br>* Investigational drug, Efruxifermin<br>|
| Placebo Comparator: Placebo (Cohort D)<br> | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main: Change from baseline in fibrosis with no worsening steatohepatitis assessed by NASH CRN system | Proportion of subjects who achieve ≥ 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) and no worsening of steatohepatitis at Week 36. | Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main: Resolution of NASH with no worsening of fibrosis assessed by the NASH CRN system | Proportion of subjects who achieve NASH resolution (defined as a NAS of 0-1 for inflammation and 0 for ballooning) as determined by the NASH CRN criteria at Week 36 and Week 96 | Week 36, Week 96 | 
| Main: Change from baseline in fibrosis in subjects with no worsening of steatohepatitis assessed by the NASH CRN system | Proportion of subjects who achieve ≥ 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) and no worsening of steatohepatitis at Week 96 | Week 96 | 
| Main: Change from baseline in fibrosis in subjects with no worsening of steatohepatitis assessed by the NASH CRN system | Proportion of subjects who achieve ≥ 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) at Week 36 and Week 96 | Week 36, Week 96 | 
| Main: Change from baseline in non-invasive markers of fibrosis | Change from baseline in ELF score, Pro-C3 (ug/L),and liver stiffness assessed by liver elastography (kPa, CAP) | Week 36, Week 48, Week 72, Week 96 | 
| Main: Change from baseline in lipoproteins | Change from baseline in Triglycerides (mg/dL), total cholesterol (mg/dL), HDL-C (mg/dL), non-HDL-C (mg/dL), and LDL-C (mg/dL) | Week 36, Week 48, Week 72, Week 96 | 
| Main: Change from baseline of markers in insulin sensitivity and glycemic control | Change from baseline in HbA1c (%), C-peptide (ug/L), adiponectin (mg/L), insulin (mIU/L), and HOMA-IR | Week 36, Week 48, Week 72, Week 96 | 
| Main: Change from baseline in body weight | Change from baseline in body weight (kg) | Week 36, Week 48, Week 96 | 
| Main: To assess the immunogenicity of EFX | Detect and measure ADA, including NAb, against EFX | Through Week 96 | 
| Main: To assess the safety and tolerability of EFX | Safety and tolerability will be assessed through the reporting of AEs, clinical laboratory tests, ECGs, ultrasounds, vital sign assessments, and concomitant medication usage | Through Week 96 | 
| Cohort D: To assess the safety and tolerability of EFX compared to placebo when added to an existing GLP-1R agonist in subjects with type 2 diabetes and liver fibrosis due to NASH | Safety and tolerability will be assessed through the reporting of AEs, clinical laboratory assessments, ECGs, ultrasounds, vital sign assessments, and concomitant medication usage | Through Week 12 |