Clinical trial NCT05648214: 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)
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Healthy Volunteers
Non-alcoholic Fatty Liver Disease (NAFLD)
Keywords: Liver steatosis
Fibrosis
Hepatocytes
Non-alcoholic steatohepatitis (NASH)
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2022-12-13
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Part A: Sequential ascending dose Part B: Parallel
Primary purpose: TREATMENT

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


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 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

Primary outcomes:
measure: Incidence of treatment-emergent adverse events (TEAEs)
timeFrame: Up to Day 253
measure: Incidence of TEAEs by severity
timeFrame: Up to Day 253
Secondary outcomes:
measure: Concentration of ALN-PNP and potential major metabolite(s) in plasma over time
timeFrame: Up to Day 253
measure: Incidence of ALN-PNP antidrug-antibodies (ADA) over time
timeFrame: Up to Day 253
measure: Titer of ALN-PNP ADA over time
timeFrame: Up to Day 253
measure: Change in low-density lipoprotein (LDL) over time
timeFrame: Baseline up to Day 169
measure: Change in high-density lipoprotein (HDL) over time
timeFrame: Baseline up to Day 169
measure: Change in triglyceride (TG) over time
timeFrame: Baseline up to Day 253
measure: Change in apolipoprotein B (ApoB) over time
timeFrame: Baseline up to Day 253
measure: Change in liver fat fraction by magnetic resonance imaging proton density fat fraction (MRI-PDF) over time
timeFrame: Baseline up to Day 253
measure: Change in low-density lipoprotein cholesterol (LDL-C) over time
timeFrame: Baseline up to Day 253
measure: Change in high-density lipoprotein cholesterol (HDL-C) over time
timeFrame: Baseline up to Day 253
measure: Change in lipoprotein (a) (Lp[a]) over time
timeFrame: Baseline up to Day 253
measure: Change in apolipoprotein A1 (ApoA1) over time
timeFrame: Baseline up to Day 253
Other outcomes:
Locations:
city: Glendale
country: United States
facility: California Clinical Trials Medical Group
state: California
city: Los Angeles
country: United States
facility: Velocity Clinical research
state: California
city: Miami
country: United States
facility: Genoma Research Group ,Inc
state: Florida
city: Miami
country: United States
facility: Med Research of Florida,LLC
state: Florida
city: Marrero
country: United States
facility: Tandem Clinical Research
state: Louisiana
city: Houston
country: United States
facility: Pioneer Research Solutions
state: Texas
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References: