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

NCT07527910 | Not Yet Recruiting Phase 2 FDA Drug

• 1 other identifier: ALN-PNP-MASLD-2543
• Study Type: interventional
• Target: 204
• Locations: 0 countries
• Sites: N/A

Brief Summary

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

Conditions

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Keywords

Homozygous PNPLA3-Related MASLD; Fatty Liver Disease; Metabolic Dysfunction-Associated Steatohepatitis (MASH); Non-Alcoholic Fatty Liver Disease (NAFLD); Nonalcoholic Steatohepatitis (NASH)

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• 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

Study Arms (6)

Part A: A1

EXPERIMENTAL

Drug: ALN-PNP; Drug: Tirzepatide

Part A: A2

EXPERIMENTAL

Drug: Tirzepatide; Drug: Placebo

Part B: B1

EXPERIMENTAL

Drug: ALN-PNP; Drug: Tirzepatide

Part B: B2

EXPERIMENTAL

Drug: Tirzepatide; Drug: Placebo

Part B: B3

EXPERIMENTAL

Drug: ALN-PNP

Part B: B4

PLACEBO COMPARATOR

Drug: Placebo

Interventions

ALN-PNP DRUG

Administered per the protocol

Part A: A1; Part B: B1; Part B: B3

Tirzepatide DRUG

Administered per the protocol

Also known as: Zepbound®

Part A: A1; Part A: A2; Part B: B1; Part B: B2

Placebo DRUG

Administered per the protocol Placebo matching ALN-PNP

Part A: A2; Part B: B2; Part B: B4

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part A and Part B:
• Homozygous for the PNPLA3 p.I148M genotype
• Liver fat by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) ≥15% at visit 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:
• Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤3 × Upper Limit of Normal (ULN) as described in the protocol
• On a stable dose of tirzepatide at randomization (≥5 mg weekly)

You may not qualify if:

• 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
• Known chronic liver disease other than MASLD, as determined by the investigator, as defined in the protocol
• Contraindications to MRI examinations, including but not limited to persons with MRI-incompatible cardiac pacemaker and implants made of metal, severe claustrophobia, size restrictions
• Any contraindication listed in the Zepbound® United States Prescribing Information (USPI), as defined in the protocol

Sponsors & Collaborators

• Regeneron Pharmaceuticals: lead

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Interventions

Tirzepatide

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Proteins; Amino Acids, Peptides, and Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide

Study Officials

• Clinical Trial Management

  Regeneron Pharmaceuticals

  STUDY DIRECTOR

Central Study Contacts

Clinical Trials Administrator

CONTACT

844-734-6643; clinicaltrials@regeneron.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 7, 2026
• First Posted: April 14, 2026
• Study Start: April 20, 2026
• Primary Completion (Estimated): November 27, 2029
• Study Completion (Estimated): November 27, 2029
• Last Updated: April 14, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• 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
• 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