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

Regeneron Pharmaceuticals

Status and phase: Enrolling; Phase 2

Conditions: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Treatments: Drug: ALN-PNP; Drug: Placebo; Drug: Tirzepatide

Study type: Interventional

Funder types: Industry

Identifiers

NCT07527910

ALN-PNP-MASLD-2543

Details and patient eligibility

About

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

Enrollment: 204 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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204 participants in 6 patient groups, including a placebo group

Part A: A1

Experimental group

Treatment:

Drug: Tirzepatide

Drug: ALN-PNP

Part A: A2

Experimental group

Treatment:

Drug: Tirzepatide

Drug: Placebo

Part B: B1

Experimental group

Treatment:

Drug: Tirzepatide

Drug: ALN-PNP

Part B: B2

Experimental group

Treatment:

Drug: Tirzepatide

Drug: Placebo

Part B: B3

Experimental group

Treatment:

Drug: ALN-PNP

Part B: B4

Placebo Comparator group

Treatment:

Drug: Placebo