A Trial to Learn if ALN-PNP is Safe and Well Tolerated in Healthy Adults and Adult Participants With Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

A Three-Part, Phase 1/2a, Randomized, Double-blind, Placebo-Controlled, Single and Multiple Dose Study of the Safety, Tolerability, and Pharmacokinetics of ALN-PNP, an siRNA Targeting PNPLA3, in Healthy Adults and Adult Participants With MASLD

This study is researching an experimental drug called ALN-PNP (called "study drug"). This is a first in human study. The study drug is not approved by any public health agency such as the United States Food and Drug Administration (FDA) for any kind of treatment.

This study consists of 3 parts. Part A is focused on healthy participants. Parts B and C of the study are focused on participants who are known to have MASLD and a specific variant of the PNPLA3 gene.

The aim of the study is to see how safe, tolerable and effective the study drug is.

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

• What side effects may happen from taking the study drug (Parts A, B and C)
• How much study drug (Parts A, B and C) and study drug metabolites (byproduct of the body breaking down the study drug) (Parts B and C) are in the blood at different times
• Whether the body makes antibodies against the study drug (which could make the study drug less effective or could lead to side effects) (Part A, B and C)
• Explore impact of Japanese ethnicity on safety and PK (Pharmacokinetics, or study of what the body does to the drug) of single doses of ALN-PNP over time (Part A)
• How the study drug works to change liver fat content in MASLD (Part B and C)
• Better understanding of the study drug and MASLD (Part B and C)

Study Overview

• Status: Recruiting
• Conditions: Healthy Volunteers; Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
• Intervention / Treatment: Drug: Placebo (PB); Drug: ALN-PNP

• Study Type: Interventional
• Enrollment (Estimated): 172
• Phase: Phase 2; Phase 1

Contacts and Locations

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

Study Locations

• United States
  • California
    • Glendale, California, United States, 91206
      • Completed
      • California Clinical Trials Medical Group
    • Los Angeles, California, United States, 90057
      • Recruiting
      • Velocity Clinical Research
  • Florida
    • Miami, Florida, United States, 33186
      • Recruiting
      • Med Research of Florida, LLC
    • Miami, Florida, United States, 33173
      • Recruiting
      • Genoma Research Group, Inc
  • Louisiana
    • Marrero, Louisiana, United States, 70072
      • Recruiting
      • Tandem Clinical Research
  • Texas
    • Houston, Texas, United States, 77099
      • Recruiting
      • Pioneer Research Solutions

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 51 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Key Inclusion Criteria:

Part A (Healthy Adults):

1. From 18 to 55 years of age

2. For Japanese cohorts ONLY; the Japanese participant must:

   1. Be Japanese, born in Japan, and have both biologic parents and 4 biologic grandparents who are ethnically Japanese and born in Japan
   2. Have maintained a Japanese lifestyle, with no significant change since leaving Japan, including having access to Japanese food and adhering to a Japanese diet
   3. Be living <10 years outside of Japan
3. Has a Body Mass Index (BMI) between 18 and 32 kg/m^2, inclusive, at the screening visit
4. Is judged by the investigator to be in good health, as described in the protocol
5. Is in good health based on laboratory safety testing obtained at the screening visit and approximately within 24 hours prior to administration of study drug

Part B and Part C (Participants with MASLD):

1. Part B: From 18 to 65 years of age
2. Part C: From 18 to 75 years of age
3. BMI from 23.0 kg/m2 to 40.0 kg/m2, inclusive, for East Asians (including but not limited to South Koreans, Chinese, Taiwanese, and Japanese) and BMI from 27.0 kg/m2 to 40.0 kg/m2, inclusive, for any other ethnicity at screening visit 1
4. Liver fat content ≥8.5% as measured by MRI-PDFF at screening visit 3

Key Exclusion Criteria:

Part A:

1. History of clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, psychiatric, neurological, or dermatologic disease, as assessed by the investigator, that may confound the results of the study or poses an additional risk to the participant by study participation
2. Presents any concern to the study investigator that might confound the results of the study or poses an additional risk to the participant by their participation in the study
3. Hospitalized for any reason within 30 days of the screening visit
4. Using the Modification of Diet in Renal Disease equation, has a glomerular filtration rate as described in the protocol at the screening visit
5. Has Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) or total bilirubin above the Upper Limit of Normal (ULN) range
6. Is a current smoker or former smoker, including e-cigarettes, who stopped smoking within 3 months prior to the screening visit
7. Has a history of alcohol or drug abuse per investigator opinion
8. Is positive for hepatitis C antibody and if so, positive for qualitative (ie, detected or not detected) Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) test at the screening visit

Part B and Part C:

1. Evidence of other forms of known chronic liver disease, as defined in the protocol
2. Has a contraindication to MRI examinations, as defined in the protocol
3. History of Type 1 diabetes
4. Has lost or gained more than 4.0% body weight over the 3 months prior to or during the screening period
5. Has known Human Immunodeficiency Virus (HIV) infection, evidence of current or chronic Hepatitis B Virus (HBV) infection, or current or chronic HCV infection, as defined in the protocol
6. Bariatric surgery within approximately 5 years (Part B) or 3 years (Part C) prior or planned during the study period

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

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Cohorts	Drug: Placebo (PB); Administered per the protocol; Drug: ALN-PNP; Administered per the protocol
Experimental: Part B: Cohorts	Drug: Placebo (PB); Administered per the protocol; Drug: ALN-PNP; Administered per the protocol
Experimental: Part A: Optional Cohort	Drug: Placebo (PB); Administered per the protocol; Drug: ALN-PNP; Administered per the protocol
Experimental: Part A: JPN Cohorts	Drug: Placebo (PB); Administered per the protocol; Drug: ALN-PNP; Administered per the protocol
Experimental: Part C: Cohorts	Drug: Placebo (PB); Administered per the protocol; Drug: ALN-PNP; Administered per the protocol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of Treatment-Emergent Adverse Events (TEAEs)	Up to Day 337
Severity of TEAEs	Up to Day 337

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Low-Density Lipoprotein (LDL)	Part A	Baseline up to Day 169
Change in High-Density Lipoprotein (HDL)	Part A	Baseline up to Day 169
Change in liver fat fraction by Magnetic Resonance Imaging derived Proton-Density Fat Fraction (MRI-PDFF)	Part B and Part C	Baseline up to Day 253
Concentration of ALN-PNP and potential major metabolite(s) in plasma		Up to Day 337
Incidence of Anti-Drug Antibodies (ADAs) to ALN-PNP		Up to Day 337
Magnitude of ADAs to ALN-PNP		Up to Day 337
Change in TriGlyceride (TG)		Baseline up to Day 337
Change in Apolipoprotein B (ApoB)		Baseline up to Day 337
Change in Low-Density Lipoprotein Cholesterol (LDL-C)	Part B and Part C	Baseline up to Day 337
Change in High-Density Lipoprotein Cholesterol (HDL-C)	Part B and Part C	Baseline up to Day 337
Change in Lipoprotein (a) (Lp[a])	Part B and Part C	Baseline up to Day 337
Change in Apolipoprotein A1 (ApoA1)	Part B and Part C	Baseline up to Day 337
Change in small dense Low-Density Lipoprotein (sdLDL)	Part C	Baseline up to Day 337

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2022
• Primary Completion (Estimated): August 10, 2027
• Study Completion (Estimated): August 10, 2027

Study Registration Dates

• First Submitted: December 5, 2022
• First Submitted That Met QC Criteria: December 5, 2022
• First Posted (Actual): December 13, 2022

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: April 13, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Fibrosis; Liver steatosis; Hepatocytes; Non-Alcoholic Steatohepatitis (NASH); Non-Alcoholic Fatty Liver Disease (NAFLD); Metabolic dysfunction-Associated Steatohepatitis (MASH)
• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Liver Diseases; Pathological Conditions, Signs and Symptoms; Fibrosis; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: ALN-PNP-HV-2227

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