A Study to Evaluate the Efficacy and Safety of ALN-HSD in Adult Participants With Non-alcoholic Steatohepatitis (NASH) With Fibrosis With Genetic Risk Factors

Study Overview
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Brief Summary
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The study is researching an investigational drug called ALN-HSD (called study drug in this form). The study is focused on participants who are known to have non-alcoholic steatohepatitis (NASH). NASH is a form of non-alcoholic fatty liver disease (NAFLD). NASH occurs when fat builds up in liver cells, damaging them, and making the liver inflamed and stiff from fibrosis (scar tissue). NASH can progress to cirrhosis (long term scarring) and liver failure (when your liver cannot perform its job). The aim of the study is to see the effect of the study drug on lessening liver scarring side effects related to NASH. The study is looking at several other research questions, including: How ALN-HSD works to improve liver function and lessen NASH related inflammation in the liver What side effects may happen from receiving the study drug How much study drug and study drug metabolites (byproduct of the body breaking down the study drug) are in your blood at different times Better understanding of the study drug and NASH

Official Title
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A Master Protocol of Randomized, Double-Blind, Placebo-Controlled, Phase 2 Studies of siRNA Gene Silencing for the Treatment of Non- Alcoholic Steatohepatitis (NASH) in Participants With Genetic Risk Factors

Conditions
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Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: ALN-HSD
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Adult male or female ≥18 years (or country's legal age of adulthood) A diagnosis of NASH with fibrosis (F) stage 2 or 3 NAS score ≥4 according to the NASH CRN histological scoring system Meets genotype criteria for study enrollment in either Study 1 or Study 2, as defined in the protocol A Vibration-Controlled Transient Elastography (VCTE) liver stiffness measurement, as defined in the protocol Key Exclusion Criteria: Evidence of other forms of known chronic liver disease Known history of alcohol or other substance abuse within the last year History of Type 1 diabetes Bariatric surgery within approximately 5 years prior to or planned during the study period Prior exposure to any investigational drug targeting HSD17B13 or PNPLA3 (eg, ALNHSD or ARO-HSD, AZD2693) Note: Other protocol-defined Inclusion/Exclusion Criteria 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
Interventional Model Description: Number of Arms is 3 per study and planned enrollment is 150 per study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Study 1 ALN-HSD Low Dose<br> | Drug: ALN-HSD<br>* Administered by subcutaneous injection (SC)<br>|
| Active Comparator: Study 1 ALN-HSD High Dose<br> | Drug: ALN-HSD<br>* Administered by subcutaneous injection (SC)<br>|
| Placebo Comparator: Study 1 Placebo<br> | Drug: Placebo<br>* Administered by SC injection<br>|
| Active Comparator: Study 2 ALN-HSD Low Dose<br> | Drug: ALN-HSD<br>* Administered by subcutaneous injection (SC)<br>|
| Active Comparator: Study 2 ALN-HSD High Dose<br> | Drug: ALN-HSD<br>* Administered by subcutaneous injection (SC)<br>|
| Placebo Comparator: Study 2 Placebo<br> | Drug: Placebo<br>* Administered by SC injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in qFibrosis | Study 1 and Study 2 Change in the continuous quantitative liver fibrosis (qFibrosis) score measured by second harmonic generation/two-photon excitation microscopy | Baseline to week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of clinical research network (CRN) fibrosis (F) stage ≥1 stage on liver biopsy without worsening of non-alcoholic steatohepatitis (NASH) | Study 1 and Study 2 Assessment will be based on the proportion of ALN-HSD treated participants relative to placebo achieving at least a 1 stage improvement in fibrosis (NASH Clinical Research Network system) by liver biopsy with no worsening of NAS. | Baseline to week 52 | 
| Resolution of NASH with no worsening of fibrosis on liver biopsy | Study 1 and Study 2 Resolution of NASH (steatohepatitis) is defined as absent fatty liver disease or isolated or simple steatosis without steatohepatitis and a non-alcoholic fatty liver disease activity score (NAS) score of 0-1 for inflammation, 0 for ballooning, and any value for steatosis | Baseline to week 52 | 
| Change from baseline in serum alanine aminotransferase (ALT) | Study 1 and Study 2 | Baseline to week 52 | 
| Change from baseline in serum aspartate aminotransferase (AST) | Study 1 and Study 2 | Baseline to week 52 | 
| Change from baseline in enhanced liver fibrosis (ELF) | Study 1 and Study 2 | Baseline to week 52 | 
| Change from baseline in N-terminal type III collagen propeptide (PRO-C3) | Study 1 and Study 2 | Baseline to week 52 | 
| Change from baseline of non-invasive fibrosis biomarkers (NIS-4) | Study 1 and Study 2 | Baseline to week 52 | 
| Change from baseline in Fibrosis-4 (FIB-4) | Study 1 and Study 2 | Baseline to week 52 | 
| Change from baseline in hepatic hydroxysteroid 17β dehydrogenase 13 (HSD17B13) transcript level | Study 1 and Study 2 | Baseline to week 52 | 
| Change from baseline in liver quantitative ballooning (qBallooning) | Study 1 and Study 2 | Baseline to week 52 | 
| Incidence of progression in qFibrosis on liver biopsy | Study 1 and Study 2 | Baseline to week 52 | 
| Incidence and severity of treatment emergent adverse events (TEAEs) | Study 1 and Study 2 | Baseline to week 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NASH, NASH with Fibrosis, NAFLD, Non Alcoholic Fatty Liver Disease