A Phase 2a Study of ALN-PNP With and Without a GLP1R Agonist in Adult Patients With Homozygous PNPLA3-Related MASLD

A Two-Part, Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study of ALN-PNP With and Without a GLP1R Agonist in Adults With Homozygous PNPLA3-Related Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

This study will test a study drug called ALN-PNP with and without another drug that is used for controlling blood sugar, appetite, and weight (for example, tirzepatide), to see if it can help treat MASLD, also known as fatty liver disease. ALN-PNP reduces the amount of Patatin-like phospholipase domain-containing protein 3 (PNPLA3), a protein that liver cells make, which may help decrease liver fat if there is an abnormal PNPLA3 protein.

The goal of this study is to understand the effect of ALN-PNP with or without tirzepatide on reducing liver fat.

The study is looking at:

• How well ALN-PNP with and without tirzepatide works
• What side effects ALN-PNP might cause
• How much ALN-PNP is in the blood at different times
• How the body and the liver change after having ALN-PNP, which can help researchers understand why ALN-PNP works better in some people than others

Study Overview

• Status: Not yet recruiting
• Conditions: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
• Intervention / Treatment: Drug: ALN-PNP; Drug: Tirzepatide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 204
• Phase: Phase 2

Contacts and Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

Part A and Part B:

1. Homozygous for the PNPLA3 p.I148M genotype
2. Liver fat by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) ≥15% at visit 3
3. Has a Body Mass Index (BMI) ≥30 to <45 kg/m^2 at visit 2

Part A: To be eligible for randomization on study day 1:

1. Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤3 × Upper Limit of Normal (ULN) as described in the protocol
2. On a stable dose of tirzepatide at randomization (≥5 mg weekly)

Key Exclusion Criteria:

1. Evidence or diagnosis of portal hypertension or cirrhosis from any cause, including cirrhosis due to MASH, as determined by the investigator, based on medical history, clinical assessment, imaging, and/or liver biopsy
2. Known chronic liver disease other than MASLD, as determined by the investigator, as defined in the protocol
3. Contraindications to MRI examinations, including but not limited to persons with MRI-incompatible cardiac pacemaker and implants made of metal, severe claustrophobia, size restrictions
4. Any contraindication listed in the Zepbound® United States Prescribing Information (USPI), as defined in the protocol

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

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: A1	Drug: ALN-PNP; Administered per the protocol; Drug: Tirzepatide; Administered per the protocol; Other Names: Zepbound®
Experimental: Part A: A2	Drug: Tirzepatide; Administered per the protocol; Other Names: Zepbound®; Drug: Placebo; Administered per the protocol Placebo matching ALN-PNP
Experimental: Part B: B1	Drug: ALN-PNP; Administered per the protocol; Drug: Tirzepatide; Administered per the protocol; Other Names: Zepbound®
Experimental: Part B: B2	Drug: Tirzepatide; Administered per the protocol; Other Names: Zepbound®; Drug: Placebo; Administered per the protocol Placebo matching ALN-PNP
Experimental: Part B: B3	Drug: ALN-PNP; Administered per the protocol
Placebo Comparator: Part B: B4	Drug: Placebo; Administered per the protocol Placebo matching ALN-PNP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change in liver fat	Part A	From baseline at week 24
Percent change in liver fat	Part B	From baseline at week 48

Secondary Outcome Measures

Outcome Measure	Time Frame
Achievement of liver fat <5%	At weeks 24 and 48
Occurence of Treatment-Emergent Adverse Events (TEAEs)	Through week 60
Severity of TEAEs	Through week 60

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Estimated): April 20, 2026
• Primary Completion (Estimated): November 27, 2029
• Study Completion (Estimated): November 27, 2029

Study Registration Dates

• First Submitted: April 7, 2026
• First Submitted That Met QC Criteria: April 7, 2026
• First Posted (Actual): April 14, 2026

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Nonalcoholic Steatohepatitis (NASH); Fatty Liver Disease; Non-Alcoholic Fatty Liver Disease (NAFLD); Metabolic Dysfunction-Associated Steatohepatitis (MASH); Homozygous PNPLA3-Related MASLD
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Amino Acids, Peptides, and Proteins; Proteins; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide; Tirzepatide
• Other Study ID Numbers: ALN-PNP-MASLD-2543

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)
• 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