A Trial to Learn if Having 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

Study Overview
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Brief Summary
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The study is researching an experimental drug called ALN-PNP. The study is focused on participants who are known to have non-alcoholic fatty liver disease (NAFLD), and a specific variant of the patatin-like phospholipase domain containing 3 (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 How ALN-PNP 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

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending 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

Conditions
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Nonalcoholic Steatohepatitis, Genetic Risk Factor

Intervention / Treatment
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* Drug: ALN-PNP Dose Level 1
* Drug: ALN-PNP Dose Level 2
* Drug: ALN-PNP Dose Level 3
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Participants from 18 (or country's legal age of adulthood) to 65 years of age, inclusive, at screening visit 1 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 Meets genotype criteria for the rs738409:G PNPLA3 risk allele: homozygotes or heterozygotes; p.I148M variant (PNPLA3 rs738409:G [p.I148M]) at screening visit 1 Liver fat content ≥8.5% as measured by MRI-PDFF at screening visit 3 Generally stable diet (based on participant's recall) for at least 3 months prior to the screening visit Key Exclusion Criteria: Evidence of other forms of known chronic liver disease, as defined in the protocol 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 Is taking a medication to treat a co-morbid condition that is not permitted during the study Has any laboratory parameter assessments a screening, as defined in the protocol History of Type 1 diabetes Bariatric surgery within approximately 5 years prior or planned during the study period Has lost or gained more than 4.0% body weight over the 3 months prior to or during the screening period 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 Was hospitalized (ie, >24 hours) for any reason within 30 days of the screening visit Note: Other protocol defined Inclusion/Exclusion Criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Participants who are homozygous for the PNPLA3 risk allele (G/G) Randomized 3:1 within three dose levels to ALN-PNP or placebo | Drug: ALN-PNP Dose Level 1<br>* Administered by subcutaneous (SC) injection, every 4 weeks (Q4W) x 4 doses<br>Drug: ALN-PNP Dose Level 2<br>* Administered SC, Q4w x 4 doses<br>Drug: ALN-PNP Dose Level 3<br>* Administered SC, Q4W x 4 doses<br>Drug: Matching Placebo<br>* Administered SC, Q4W x 4 doses<br>|
| Experimental: Cohort 2<br>Participants who are heterozygous for the PNPLA3 risk allele (C/G) Randomized 3:1 within three dose levels to ALN-PNP or placebo | Drug: ALN-PNP Dose Level 1<br>* Administered by subcutaneous (SC) injection, every 4 weeks (Q4W) x 4 doses<br>Drug: ALN-PNP Dose Level 2<br>* Administered SC, Q4w x 4 doses<br>Drug: ALN-PNP Dose Level 3<br>* Administered SC, Q4W x 4 doses<br>Drug: Matching Placebo<br>* Administered SC, Q4W x 4 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs) |  | Through End of Study (EOS), Up to 253 days | 
| Severity of TEAEs |  | Through EOS, Up to 253 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in liver fat fraction by Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) in participants with NAFLD |  | Baseline up to 169 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NASH, Nonalcoholic Fatty Liver Disease, NAFLD