A Trial to Learn if ALN-PNP is Safe and Well Tolerated in Healthy Adults and Adult Participants With Non-Alcoholic Fatty Liver Disease (NAFLD)

• ClinicalTrials.gov Identifier: NCT05648214
• Recruitment Status: Recruiting
• First Posted: December 13, 2022
• Last Update Posted: March 8, 2024
• Sponsor: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Regeneron Pharmaceuticals

Study Description

Brief Summary:

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.

Part A is focused on healthy participants. Part B of the study is focused on participants who are known to have NAFLD 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.

Part A is looking at several other research questions, including:

• What side effects may happen from taking the study drug
• How much study drug is 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)
• 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 B 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

Condition or disease	Intervention/treatment	Phase
Healthy Volunteers; Non-alcoholic Fatty Liver Disease (NAFLD)	Drug: ALN-PNP - Part A; Drug: ALN-PNP - Part B; Drug: Placebo (PB)	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 96 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Part A: Sequential ascending dose Part B: Parallel
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Two-Part, Phase 1, Randomized, Double-blind, Placebo-Controlled, Single Dose Study of the Safety, Tolerability, and Pharmacokinetics of ALN-PNP, an siRNA Targeting PNPLA3, in Healthy Adults and Adult Participants With NAFLD
• Actual Study Start Date: December 27, 2022
• Estimated Primary Completion Date: September 10, 2025
• Estimated Study Completion Date: September 10, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A: ALN-PNP Dose 1 or PB; 8 Participants, Randomized 6:2	Drug: ALN-PNP - Part A; Administered by subcutaneous (SC) single ascending dose (SAD); Drug: Placebo (PB); Administered by SC injection
Experimental: Part A: ALN-PNP Dose 2 or PB; 8 Participants, Randomized 6:2	Drug: ALN-PNP - Part A; Administered by subcutaneous (SC) single ascending dose (SAD); Drug: Placebo (PB); Administered by SC injection
Experimental: Part A: ALN-PNP Dose 3 or PB; 8 Participants, Randomized 6:2	Drug: ALN-PNP - Part A; Administered by subcutaneous (SC) single ascending dose (SAD); Drug: Placebo (PB); Administered by SC injection
Experimental: Part A: ALN-PNP Dose 4 or PB; 8 Participants, Randomized 6:2	Drug: ALN-PNP - Part A; Administered by subcutaneous (SC) single ascending dose (SAD); Drug: Placebo (PB); Administered by SC injection
Experimental: Part A: ALN-PNP Dose 5 or PB; 8 Participants, Randomized 6:2	Drug: ALN-PNP - Part A; Administered by subcutaneous (SC) single ascending dose (SAD); Drug: Placebo (PB); Administered by SC injection
Experimental: Part A: Optional ALN-PNP Dose 5 or PB; 8 Participants, Randomized 6:2 This is an optional cohort, if there is a need for additional dose characterization of ALN-PNP.	Drug: ALN-PNP - Part A; Administered by subcutaneous (SC) single ascending dose (SAD); Drug: Placebo (PB); Administered by SC injection
Experimental: Part A: JPN ALN-PNP Dose 4 or PB; 8 Japanese Participants only, Randomized 6:2	Drug: ALN-PNP - Part A; Administered by subcutaneous (SC) single ascending dose (SAD); Drug: Placebo (PB); Administered by SC injection
Experimental: Part A: JPN ALN-PNP Dose 5 or PB; 8 Japanese Participants only, Randomized 6:2	Drug: ALN-PNP - Part A; Administered by subcutaneous (SC) single ascending dose (SAD); Drug: Placebo (PB); Administered by SC injection
Placebo Comparator: Part B: Placebo; Up to 32 Participants Randomized 1:1:1:1 resulting in 8 participants per arm	Drug: Placebo (PB); Administered by SC injection
Experimental: Part B: ALN-PNP Dose 3; Up to 32 Participants Randomized 1:1:1:1 resulting in 8 participants per arm	Drug: ALN-PNP - Part B; Administered by SC parallel single dose
Experimental: Part B: ALN-PNP Dose 4; Up to 32 Participants Randomized 1:1:1:1 resulting in 8 participants per arm	Drug: ALN-PNP - Part B; Administered by SC parallel single dose
Experimental: Part B: ALN-PNP Dose 5; Up to 32 Participants Randomized 1:1:1:1 resulting in 8 participants per arm	Drug: ALN-PNP - Part B; Administered by SC parallel single dose

Outcome Measures

Primary Outcome Measures :

1. Incidence of treatment-emergent adverse events (TEAEs) [ Time Frame: Up to Day 253 ]
2. Incidence of TEAEs by severity [ Time Frame: Up to Day 253 ]

Secondary Outcome Measures :

1. Concentration of ALN-PNP and potential major metabolite(s) in plasma over time [ Time Frame: Up to Day 253 ]
2. Incidence of ALN-PNP antidrug-antibodies (ADA) over time [ Time Frame: Up to Day 253 ]
3. Titer of ALN-PNP ADA over time [ Time Frame: Up to Day 253 ]
4. Change in low-density lipoprotein (LDL) over time [ Time Frame: Baseline up to Day 169 ]
   Part A
5. Change in high-density lipoprotein (HDL) over time [ Time Frame: Baseline up to Day 169 ]
   Part A
6. Change in triglyceride (TG) over time [ Time Frame: Baseline up to Day 253 ]
7. Change in apolipoprotein B (ApoB) over time [ Time Frame: Baseline up to Day 253 ]
8. Change in liver fat fraction by magnetic resonance imaging proton density fat fraction (MRI-PDF) over time [ Time Frame: Baseline up to Day 253 ]
   Part B
9. Change in low-density lipoprotein cholesterol (LDL-C) over time [ Time Frame: Baseline up to Day 253 ]
   Part B
10. Change in high-density lipoprotein cholesterol (HDL-C) over time [ Time Frame: Baseline up to Day 253 ]
    Part B
11. Change in lipoprotein (a) (Lp[a]) over time [ Time Frame: Baseline up to Day 253 ]
    Part B
12. Change in apolipoprotein A1 (ApoA1) over time [ Time Frame: Baseline up to Day 253 ]
    Part B

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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 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 (Participants with NAFLD):

1. From 18 to 65 years of age
2. Body mass index (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
3. 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 ribonucleic acid (RNA) test at the screening visit

Part B:

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. Bariatric surgery within approximately 5 years prior or planned during the study period
5. Has lost or gained more than 4.0% body weight over the 3 months prior to or during the screening period
6. 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

NOTE: Other protocol defined inclusion / exclusion criteria apply

Contacts and Locations

Contacts

Contact: Clinical Trials Administrator; 844-734-6643; clinicaltrials@regeneron.com

Locations

United States, California

California Clinical Trials Medical Group; Recruiting

Glendale, California, United States, 91206

Sponsors and Collaborators

Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Trial Management; Regeneron Pharmaceuticals

More Information

• Responsible Party: Regeneron Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT05648214
• Other Study ID Numbers: ALN-PNP-HV-2227
• First Posted: December 13, 2022
• Last Update Posted: March 8, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (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, 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.
• 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
• URL: https://vivli.org/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Regeneron Pharmaceuticals:

Liver steatosis; Fibrosis; Hepatocytes; Non-alcoholic steatohepatitis (NASH)

Additional relevant MeSH terms:

Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Digestive System Diseases