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

Regeneron Pharmaceuticals

Status and phase: Completed; Phase 1

Conditions: Nonalcoholic Steatohepatitis (NASH); Nonalcoholic Fatty Liver Disease (NAFLD); Genetic Risk Factor

Treatments: Drug: Placebo; Drug: ALN-PNP

Study type: Interventional

Funder types: Industry

Identifiers

NCT06024408

ALN-PNP-NASH-2255

Details and patient eligibility

About

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

Enrollment: 9 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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9 participants in 10 patient groups, including a placebo group

Part A: Placebo

Placebo Comparator group

Description:

Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1

Treatment:

Drug: Placebo

Part A: Low Dose

Experimental group

Description:

Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1

Treatment:

Drug: ALN-PNP

Part A: Mid Dose

Experimental group

Description:

Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1

Treatment:

Drug: ALN-PNP

Part A: High Dose

Experimental group

Description:

Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1

Treatment:

Drug: ALN-PNP

Part B: Placebo

Placebo Comparator group

Description:

Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1

Treatment:

Drug: Placebo

Part B : Low Dose

Experimental group

Description:

Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1

Treatment:

Drug: ALN-PNP

Part B: Mid Dose

Experimental group

Description:

Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1

Treatment:

Drug: ALN-PNP

Part B: High Dose

Experimental group

Description:

Participants who are homozygous for the PNPLA3 rs738409:G risk allele will be randomized 1:1:1:1

Treatment:

Drug: ALN-PNP

Part C: Placebo (Optional)

Placebo Comparator group

Description:

Sponsor may elect to enroll participants who are heterozygous for the PNPLA3 rs738409:G risk allele and may be randomized 1:1

Treatment:

Drug: Placebo

Part C: High Dose (Optional)

Experimental group

Description:

Sponsor may elect to enroll participants who are heterozygous for the PNPLA3 rs738409:G risk allele and may be randomized 1:1

Treatment:

Drug: ALN-PNP