Clinical trial NCT06024408: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Nonalcoholic Fatty Liver Disease (NAFLD)
Nonalcoholic Steatohepatitis (NASH)
Genetic Risk Factor
Keywords: Homozygous
Heterozygous
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2023-09-06
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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

Primary outcomes:
measure: Incidence of treatment-emergent adverse events (TEAEs)
timeFrame: Up to 253 days
measure: Severity of TEAEs
timeFrame: Up to 253 days
Secondary outcomes:
measure: Change in liver fat fraction by magnetic resonance imaging proton density fat fraction (MRI-PDFF) in participants with NAFLD
timeFrame: Baseline up to 253 days
measure: Change in low-density lipoprotein cholesterol (LDL-C) in participants with NAFLD
timeFrame: Baseline up to 253 days
measure: Change in high-density lipoprotein cholesterol (HDL-C) in participants with NAFLD
timeFrame: Baseline up to 253 days
measure: Change in triglycerides (TG) in participants with NAFLD
timeFrame: Baseline up to 253 days
measure: Change in lipoprotein a (Lp(a)) in participants with NAFLD
timeFrame: Baseline up to 253 days
measure: Change in apolipoprotein A1 (ApoA1) in participants with NAFLD
timeFrame: Baseline up to 253 days
measure: Change in apolipoprotein B (ApoB) in participants with NAFLD
timeFrame: Baseline up to 253 days
measure: Concentration of ALN-PNP and potential major metabolite(s) in plasma over time
timeFrame: Up to 253 days
measure: Incidence of anti-drug antibodies (ADAs) to ALN-PNP
timeFrame: Up to 253 days
measure: Titer of anti-drug antibodies (ADAs) to ALN-PNP
timeFrame: Up to 253 days
Other outcomes:
Locations:
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Chungcheong Buk-do
city: Seongnam-si
country: Korea, Republic of
facility: CHA Bundang Medical Center
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References: