ALN-PNP safety and tolerability in healthy adults and adults with MASLD

A Three-Part, Phase 1/2a, Randomized, Double-blind, Placebo-Controlled, Single and Multiple Dose Study of the Safety, Tolerability, and Pharmacokinetics of ALN-PNP, an siRNA Targeting PNPLA3, in Healthy Adults and Adult Participants With MASLD

This first-in-human trial tests whether the experimental drug ALN-PNP is safe and well tolerated in healthy adults and in adults with MASLD who carry a specific PNPLA3 gene variant.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 172 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Regeneron Pharmaceuticals (Industry-sponsored)
• Locations: 6 sites (Glendale, California and 5 other locations)
• Trial ID: NCT05648214 on ClinicalTrials.gov

What this trial studies

This randomized, placebo-controlled Phase 1/2 trial administers ALN-PNP to healthy volunteers (Part A) and to adults with MASLD who have a defined PNPLA3 variant (Parts B and C). The study measures safety, tolerability, pharmacokinetics, and anti-drug antibody formation after single and/or multiple doses, with blood sampling at scheduled time points. Part A includes specific enrollment criteria for Japanese cohorts, and Parts B and C focus on MASLD participants within defined age and BMI ranges. Placebo arms are included to compare adverse events and drug-related signals.

Who should consider this trial

Good fit: Ideal candidates are adults who are either healthy volunteers aged 18–55 (with additional criteria for Japanese cohorts) or adults with MASLD who meet the trial's age and BMI windows and carry the specified PNPLA3 variant.

Not a fit: People without MASLD, those with advanced liver disease or significant comorbidities, or those who do not carry the PNPLA3 variant are unlikely to receive direct benefit from this early safety-focused trial.

Why it matters

Potential benefit: If successful, ALN-PNP could lead to a new targeted therapy to reduce liver fat and potentially slow fibrosis in people with MASLD, particularly those with the PNPLA3 variant.

How similar studies have performed: This is the first-in-human trial of ALN-PNP, though other RNA-based and nanoparticle liver therapies have shown promising safety and efficacy signals in related liver conditions.

Eligibility 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 (BMI) 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 and Part C (Participants with MASLD):

1. Part B: From 18 to 65 years of age
2. Part C: From 18 to 75 years of age
3. 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
4. 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 (HCV) Ribonucleic Acid (RNA) test at the screening visit

Part B and Part C:

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. Has lost or gained more than 4.0% body weight over the 3 months prior to or during the screening period
5. Has known Human Immunodeficiency Virus (HIV) infection, evidence of current or chronic Hepatitis B Virus (HBV) infection, or current or chronic HCV infection, as defined in the protocol
6. Bariatric surgery within approximately 5 years (Part B) or 3 years (Part C) prior or planned during the study period

NOTE: Other protocol defined inclusion / exclusion criteria apply

Where this trial is running

Glendale, California and 5 other locations

• California Clinical Trials Medical Group — Glendale, California, United States (Completed)
• Velocity Clinical research — Los Angeles, California, United States (Recruiting)
• Genoma Research Group, Inc — Miami, Florida, United States (Recruiting)
• Med Research of Florida, LLC — Miami, Florida, United States (Recruiting)
• Tandem Clinical Research — Marrero, Louisiana, United States (Recruiting)
• Pioneer Research Solutions — Houston, Texas, United States (Recruiting)

Study contacts

• Study coordinator: Clinical Trials Administrator

Conditions Healthy Volunteers; Metabolic Dysfunction-Associated Steatotic Liver Disease; Liver steatosis; Fibrosis; Hepatocytes; Non-Alcoholic Steatohepatitis; Non-Alcoholic Fatty Liver Disease; Metabolic dysfunction-Associated Steatohepatitis