A Precision Medicine Approach Using Gene Silencing to Treat a Chronic Liver Disease Called Metabolic Dysfunction-Associated Steatohepatitis (MASH) in Adult Participants at Increased Genetic Risk for This Condition (NASHGEN-2)

A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of siRNA Gene Silencing for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH) in Participants With Genetic Risk Factors

This study is researching an investigational drug, ALN-HSD called "study drug". This study is focused on participants who are known to have Metabolic dysfunction-Associated SteatoHepatitis (MASH). MASH is a form of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). MASH occurs when fat builds up in liver cells, damaging them, and making the liver inflamed and stiff from fibrosis (scar tissue). MASH can progress to cirrhosis (long term scarring) and liver failure (when the liver cannot perform its job). The aim of the study is to see the effect of the study drug on lessening liver scarring related to MASH.

The study is looking at several other research questions, including:

• How ALN-HSD works to improve liver function and lessen MASH-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 the blood at different times
• Better understanding of the study drug and MASH

Study Overview

• Status: Recruiting
• Conditions: Metabolic Dysfunction-Associated SteatoHepatitis (MASH)
• Intervention / Treatment: Drug: Placebo; Drug: ALN-HSD

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Clinical Trials Administrator; Phone Number: 844-734-6643; Email: clinicaltrials@regeneron.com

Study Locations

• Japan
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 062-8618
      • Terminated
      • JCHO Hokkaido Hospital
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • Recruiting
    • Fundacion de Investigacion (FDI) Clinical Research
  • San Juan, Puerto Rico, 00909
    • Terminated
    • Klinical Investigations
  • San Juan, Puerto Rico, 00909
    • Terminated
    • Latin Clinical Trial Center
  • San Juan
    • Guaynabo, San Juan, Puerto Rico, 00969
      • Terminated
      • Isis Clinical Research Center
• South Korea
  • Busan, South Korea, 49241
    • Terminated
    • Pusan National University Hospital
  • Daegu, South Korea, 42601
    • Terminated
    • Keimyung University Dongsan Hospital
  • Daegu, South Korea, 41944
    • Terminated
    • Kyungpook National University Hospital
  • Seoul, South Korea, 04763
    • Terminated
    • Hanyang University Seoul Hospital
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, South Korea, 13620
      • Terminated
      • Seoul National University Bundang Hospital
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Recruiting
      • Arizona Liver Health
    • Flagstaff, Arizona, United States, 86001
      • Terminated
      • The Institute for Liver Health II LLC DBA Arizona Clinical Trials - Flagstaff
    • Peoria, Arizona, United States, 85381
      • Recruiting
      • The Institute for Liver Health II LLC DBA Arizona Liver Health - Peoria
    • Tucson, Arizona, United States, 85715
      • Recruiting
      • Del Sol Research Management, LLC
    • Tucson, Arizona, United States, 85712
      • Recruiting
      • Adobe Clinical Research
    • Tucson, Arizona, United States, 85712
      • Recruiting
      • Arizona Liver Health - Tucson
  • California
    • Canoga Park, California, United States, 91304
      • Terminated
      • San Fernando Valley Health Institute
    • Chula Vista, California, United States, 91911
      • Terminated
      • Velocity Clinical Research
    • Coronado, California, United States, 92118
      • Recruiting
      • Southern California Research Center
    • Fountain Valley, California, United States, 92708
      • Recruiting
      • Ark Clinical Research - Fountain Valley
    • Gardena, California, United States, 90247
      • Terminated
      • Velocity Clinical Research
    • Huntington Park, California, United States, 90255
      • Terminated
      • Velocity Clinical Research - Huntington Park
    • Lancaster, California, United States, 93534
      • Recruiting
      • Om Research LLC
    • Long Beach, California, United States, 90815
      • Recruiting
      • Ark Clinical Research - Long Beach
    • Los Angeles, California, United States, 90057
      • Terminated
      • Velocity Clinical Research - Westlake
    • Orange, California, United States, 92868
      • Recruiting
      • Clinnova Research Solutions
    • Orange, California, United States, 92868
      • Recruiting
      • Knowledge Research Center, St. Joseph's Medical Tower
    • Panorama City, California, United States, 91402
      • Terminated
      • National Research Institute
    • Pasadena, California, United States, 91105
      • Recruiting
      • California Liver Research Institute
    • Poway, California, United States, 92064
      • Terminated
      • Cadena Care Inst.
    • Rialto, California, United States, 92377
      • Recruiting
      • Inland Empire Liver Foundation
    • San Diego, California, United States, 92114
      • Terminated
      • Precision Research Institute - San Diego
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Anschutz Medical Campus
  • Florida
    • Bradenton, Florida, United States, 34209
      • Terminated
      • Synergy Healthcare LLC
    • Hialeah Gardens, Florida, United States, 33016
      • Recruiting
      • Evolution Clinical Trials
    • Jupiter, Florida, United States, 33458
      • Recruiting
      • Health Awareness, Inc.
    • Miami, Florida, United States, 33173
      • Recruiting
      • Genoma Research Group, Inc.
    • Miami, Florida, United States, 33186
      • Recruiting
      • Med Research of Florida, LLC
    • Miami, Florida, United States, 33175
      • Terminated
      • US Associates in Research, LLC
    • Miami, Florida, United States, 33155
      • Terminated
      • Miami Clinical Research
    • Miami, Florida, United States, 33157
      • Terminated
      • International Medical Investigational Centers (IMIC) Incorporated
    • Orlando, Florida, United States, 32803
      • Recruiting
      • Charter Research LLC - Orlando
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Indiana University School of Medicine
    • Newburgh, Indiana, United States, 47630
      • Recruiting
      • Deaconess Clinic - GI Specialty Center
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • Recruiting
      • Tandem Clinical Research
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Terminated
      • Mercy Medical Center
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Recruiting
      • GI Associates
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Recruiting
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Recruiting
      • Penn State Health Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania - Perelman Center for Advanced Medicine
  • Texas
    • Austin, Texas, United States, 78757
      • Recruiting
      • Pinnacle Clinical Research - Austin
    • Austin, Texas, United States, 78757
      • Recruiting
      • American Research Corporation
    • Austin, Texas, United States, 78745
      • Terminated
      • Austin Clinical Research, LLC
    • Brownsville, Texas, United States, 78520
      • Terminated
      • South Texas Research Institute (STRI) - Brownsville
    • Cedar Park, Texas, United States, 78613
      • Terminated
      • Velocity Clinical Research - Austin
    • Dallas, Texas, United States, 75203
      • Recruiting
      • Methodist Dallas Medical Center
    • Edinburg, Texas, United States, 78539
      • Terminated
      • South Texas Research Institute (STRI) - Edinburg
    • Fort Worth, Texas, United States, 76104
      • Recruiting
      • GI Alliance Research
    • Friendswood, Texas, United States, 77546
      • Terminated
      • Allure Health at Mt. Olympus Medical Research
    • Georgetown, Texas, United States, 78628
      • Recruiting
      • Advanced Medical Trials
    • Houston, Texas, United States, 77099
      • Recruiting
      • Pioneer Research Solutions, Inc.
    • Katy, Texas, United States, 77494
      • Terminated
      • R & H Clinical Research, Inc.
    • Pharr, Texas, United States, 78577
      • Terminated
      • Great Lakes Research Institute
    • San Antonio, Texas, United States, 78215
      • Recruiting
      • American Research Corporation at the Texas Liver Institute
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • Pinnacle Clinical Research - San Antonio
    • Stafford, Texas, United States, 77477
      • Terminated
      • R & H Clinical Research
  • Utah
    • Murray, Utah, United States, 84107
      • Terminated
      • Intermountain Health
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Recruiting
      • University of Virginia Medical Center
    • Richmond, Virginia, United States, 23249
      • Recruiting
      • Richmond Veterans Administration Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Adult male or female ≥18 years (or country's legal age of adulthood)
2. A diagnosis of MASH with Fibrosis (F) stage 2 or 3, according to the NASH-CRN
3. NAS score ≥3, as defined in the protocol
4. Meets genotype criteria for study enrollment, as defined in the protocol
5. Has a protocol defined FibroScan®-AST (FAST) score at screening or within approximately 12 weeks of screening

Key Exclusion Criteria:

1. Evidence of other forms of known chronic liver disease, as defined in the protocol
2. Known history of alcohol or other substance abuse within the last year or at any time during screening, as defined in the protocol
3. History of Type 1 diabetes
4. Bariatric surgery within approximately 5 years prior to or planned during the study period
5. Prior exposure to any investigational drug targeting HSD17B13 or patatin-like phospholipase domain containing 3 (PNPLA3) (eg, ALN-HSD, ARO-HSD, ALN-PNP, AZD2693)

Note: Other protocol-defined Inclusion/Exclusion Criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Randomized 1:1	Drug: Placebo; Administered per the protocol
Experimental: ALN-HSD; Randomized 1:1	Drug: ALN-HSD; Administered per the protocol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in quantitative liver Fibrosis (qFibrosis)	Change in the continuous qFibrosis score measured by second harmonic generation/two-photon excitation microscopy	Baseline to week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in NIS4, a non-invasive fibrosis biomarker of NASH		Baseline to week 52
Change in Fibrosis-4 (FIB-4)		Baseline to week 52
Incidence of progression in qFibrosis on liver biopsy		Baseline to week 52
Resolution of MASH with no worsening of NASH-CRN fibrosis on liver biopsy	Resolution of MASH (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
Improvement of Non-Alcoholic Steatohepatitis Clinical Research Network (NASH-CRN) Fibrosis (F) stage by ≥1 stage without worsening of MASH on liver biopsy		Baseline to week 52
Change in serum ALanine aminoTransferase (ALT)		Baseline to week 52
Change in serum ASpartate aminoTransferase (AST)		Baseline to week 52
Change in Enhanced Liver Fibrosis (ELF)		Baseline to week 52
Change in N-terminal type III Collagen PROropeptide (PRO-C3)		Baseline to week 52
Change in hepatic HydroxySteroiD 17β dehydrogenase 13 (HSD17B13) transcript level		Baseline to week 52
Occurrence of Treatment-Emergent Adverse Events (TEAEs)		Baseline to week 84
Severity of TEAEs		Baseline to week 84

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Publications and helpful links

Helpful Links

• Study Informational Website

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2023
• Primary Completion (Estimated): April 27, 2028
• Study Completion (Estimated): December 7, 2028

Study Registration Dates

• First Submitted: August 15, 2022
• First Submitted That Met QC Criteria: August 26, 2022
• First Posted (Actual): August 29, 2022

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD); Histologically confirmed MASH; Genetic risk alleles for MASH at the HSD17B13 locus; Non-Alcoholic SteatoHepatitis (NASH)
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs
• Other Study ID Numbers: ALN-HSD-NASH-2130

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing

IPD Sharing Time Frame

When Regeneron has:

• received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc.) for the product and indication or has globally discontinued development of the product for all indications on or after April 2020 and has no plans for future development
• made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry)
• has the legal authority to share the data, and
• ensured the ability to protect participant privacy

• IPD Sharing Access Criteria: Qualified researchers can submit a proposal for access to individual patient or aggregate level data from a Regeneron-sponsored clinical trial through Vivli. Regeneron's Independent Research Request Evaluation Criteria can be found at: https://www.regeneron.com/sites/default/files/Regeneron-External-Data-Sharing-Policy-and-Independent-Research-Request-Evaluation-Criteria.pdf
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No