A Trial to Learn if Receiving ALN-PNP siRNA is Safe and Well Tolerated, and How it Works in Adult Participants With Nonalcoholic Fatty Liver Disease (NAFLD) and a Genetic Risk Factor

A Three-Part, Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Dose Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ALN-PNP siRNA in Participants With Nonalcoholic Fatty Liver Disease (NAFLD) and a PNPLA3 Genetic Risk Factor

This study is researching an experimental drug called ALN-PNP. This study is focused on participants who are known to have nonalcoholic fatty liver disease (NAFLD), and a specific variant of the patatin-like phospholipase domain containing 3 (PNPLA3) gene.

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

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

• What side effects may happen from taking the study drug
• How the study drug works to change liver fat content in NAFLD
• How much study drug and study drug metabolites (byproduct of the body breaking down the study drug) are in your blood at different times
• Whether the body makes antibodies against the study drug (which could make the drug less effective or could lead to side effects)
• Better understanding of the study drug and NAFLD

Study Overview

• Status: Not yet recruiting
• Conditions: Nonalcoholic Steatohepatitis (NASH); Nonalcoholic Fatty Liver Disease (NAFLD); Genetic Risk Factor
• Intervention / Treatment: Drug: Placebo; Drug: ALN-PNP

• Study Type: Interventional
• Enrollment (Estimated): 104
• Phase: Phase 1

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:

1. Participants from 18 (or country's legal age of adulthood) to 65 years of age, inclusive, at screening visit 1
2. Body mass index (BMI) from 23.0 kg/m^2 to 40.0 kg/m^2, inclusive, for East Asians (including but not limited to South Koreans, Chinese, Taiwanese, and Japanese) and BMI from 27.0 kg/m^2 to 40.0 kg/m^2, inclusive, for any other ethnicity at screening visit 1
3. Meets genotype criteria for the rs738409:G PNPLA3 risk allele: homozygotes (for Part A and Part B) or heterozygotes (optional Part C); p.I148M variant (PNPLA3 rs738409:G [p.I148M]) at screening visit 1
4. Liver fat content ≥8.5% as measured by MRI-PDFF at screening visit 3
5. Generally stable diet (based on participant's recall) for at least 3 months prior to the screening visit

Key Exclusion Criteria:

1. Evidence of other forms of known chronic liver disease, as defined in the protocol
2. Has a contraindication to MRI examinations, such as persons with cardiac pacemaker and implants made out of metal (for example, cochlear implant, nerve stimulators, magnetic vascular clips, and metallic heart valve), severe claustrophobia, or other contraindications for MRI
3. Is taking a medication to treat a co-morbid condition that is not permitted during the study
4. Has any laboratory parameter assessments at screening, as defined in the protocol
5. History of Type 1 diabetes
6. Bariatric surgery within approximately 5 years prior or planned during the study period
7. Has lost or gained more than 4.0% body weight over the 3 months prior to or during the screening period
8. Has known human immunodeficiency virus (HIV) infection, evidence of current or chronic hepatitis B virus (HBV) infection, or current or chronic hepatitis C virus (HCV) infection, as defined in the protocol
9. Was hospitalized (ie, >24 hours) for any reason within 30 days of the screening visit

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

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Part A: Placebo; Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1	Drug: Placebo; Part A: Administered as single SC injection on day 1 Part B and Part C: Administered SC every 12 weeks (Q12W x2)
Experimental: Part A: Low Dose; Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1	Drug: ALN-PNP; Part A: Administered as single subcutaneous (SC) injection on day 1 Part B and Part C: Administered SC every 12 weeks (Q12W x2)
Experimental: Part A: Mid Dose; Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1	Drug: ALN-PNP; Part A: Administered as single subcutaneous (SC) injection on day 1 Part B and Part C: Administered SC every 12 weeks (Q12W x2)
Experimental: Part A: High Dose; Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1	Drug: ALN-PNP; Part A: Administered as single subcutaneous (SC) injection on day 1 Part B and Part C: Administered SC every 12 weeks (Q12W x2)
Placebo Comparator: Part B: Placebo; Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1	Drug: Placebo; Part A: Administered as single SC injection on day 1 Part B and Part C: Administered SC every 12 weeks (Q12W x2)
Experimental: Part B : Low Dose; Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1	Drug: ALN-PNP; Part A: Administered as single subcutaneous (SC) injection on day 1 Part B and Part C: Administered SC every 12 weeks (Q12W x2)
Experimental: Part B: Mid Dose; Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1	Drug: ALN-PNP; Part A: Administered as single subcutaneous (SC) injection on day 1 Part B and Part C: Administered SC every 12 weeks (Q12W x2)
Experimental: Part B: High Dose; Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1	Drug: ALN-PNP; Part A: Administered as single subcutaneous (SC) injection on day 1 Part B and Part C: Administered SC every 12 weeks (Q12W x2)
Placebo Comparator: Part C: Placebo (Optional); Sponsor may elect to enroll participants who are heterozygous for the PNPLA3 rs738409:G risk allele and may be randomized 1:1	Drug: Placebo; Part A: Administered as single SC injection on day 1 Part B and Part C: Administered SC every 12 weeks (Q12W x2)
Experimental: Part C: High Dose (Optional); Sponsor may elect to enroll participants who are heterozygous for the PNPLA3 rs738409:G risk allele and may be randomized 1:1	Drug: ALN-PNP; Part A: Administered as single subcutaneous (SC) injection on day 1 Part B and Part C: Administered SC every 12 weeks (Q12W x2)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of treatment-emergent adverse events (TEAEs)	Up to 253 days
Severity of TEAEs	Up to 253 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Concentration of ALN-PNP and potential major metabolite(s) in plasma over time	Up to 253 days
Incidence of anti-drug antibodies (ADAs) to ALN-PNP	Up to 253 days
Titer of anti-drug antibodies (ADAs) to ALN-PNP	Up to 253 days
Change in liver fat fraction by magnetic resonance imaging proton density fat fraction (MRI-PDFF) in participants with NAFLD	Baseline up to 253 days
Change in low-density lipoprotein cholesterol (LDL-C) in participants with NAFLD	Baseline up to 253 days
Change in high-density lipoprotein cholesterol (HDL-C) in participants with NAFLD	Baseline up to 253 days
Change in triglycerides (TG) in participants with NAFLD	Baseline up to 253 days
Change in lipoprotein a (Lp(a)) in participants with NAFLD	Baseline up to 253 days
Change in apolipoprotein A1 (ApoA1) in participants with NAFLD	Baseline up to 253 days
Change in apolipoprotein B (ApoB) in participants with NAFLD	Baseline up to 253 days

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Estimated): April 15, 2024
• Primary Completion (Estimated): May 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: August 16, 2023
• First Submitted That Met QC Criteria: September 5, 2023
• First Posted (Actual): September 6, 2023

Study Record Updates

• Last Update Posted (Estimated): January 25, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Homozygous; Heterozygous
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: ALN-PNP-NASH-2255

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, has made results publicly available (e.g., scientific publication, scientific conference, clinical trial registry), has the legal authority to share the data, and has 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
• product manufactured in and exported from the U.S.: Yes