A Trial to Learn if ALN-PNP is Safe and Well Tolerated in Adult Healthy Participants

Study Overview
=================
Brief Summary
-----------------
The primary objective of the study is to evaluate the safety and tolerability of single doses of ALN-PNP in healthy adult participants. The secondary objectives of the study are to: Characterize single dose pharmacokinetics (PK) of ALN-PNP and potential major metabolite(s) in adult participants Assess the immunogenicity of ALN-PNP following single dose administrations Explore the effects of ALN-PNP on circulating blood lipid profile

Official Title
-----------------
A Phase 1, Randomized, Double-blind, Placebo-Controlled, Single Ascending Dose Study of the Safety, Tolerability, and Pharmacokinetics of ALN-PNP, an siRNA Targeting PNPLA3, in Healthy Adult Participants

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: ALN-PNP
* Drug: Placebo (PB)


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: For Japanese cohorts ONLY; the Japanese participant must: Be Japanese, born in Japan, and have both biologic parents and 4 biologic grandparents who are ethnically Japanese and born in Japan Have maintained a Japanese lifestyle, with no significant change since leaving Japan, including having access to Japanese food and adhering to a Japanese diet Be living <10 years outside of Japan Has a body mass index between 18 and 32 kg/m^2, inclusive, at the screening visit Is judged by the investigator to be in good health, as described in the protocol 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 Key Exclusion Criteria: 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 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 Hospitalized for any reason within 30 days of the screening visit Using the Modification of Diet in Renal Disease equation, has a glomerular filtration rate as described in the protocol at the screening visit Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or total bilirubin above the upper limit of normal (ULN) range. Is a current smoker or former smoker, including e-cigarettes, who stopped smoking within 3 months prior to the screening visit Has a history of alcohol or drug abuse per investigator opinion 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 NOTE: Other protocol defined inclusion / exclusion criteria apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALN-PNP Dose 1 or PB<br>8 participants, randomized 6:2 | Drug: ALN-PNP<br>* Solution for subcutaneous (SC) injection<br>Drug: Placebo (PB)<br>* matching placebo, solution for SC injection<br>|
| Experimental: ALN-PNP Dose 2 or PB<br>8 participants, randomized 6:2 | Drug: ALN-PNP<br>* Solution for subcutaneous (SC) injection<br>Drug: Placebo (PB)<br>* matching placebo, solution for SC injection<br>|
| Experimental: ALN-PNP Dose 3 or PB<br>8 participants, randomized 6:2 | Drug: ALN-PNP<br>* Solution for subcutaneous (SC) injection<br>Drug: Placebo (PB)<br>* matching placebo, solution for SC injection<br>|
| Experimental: ALN-PNP Dose 4 or PB<br>8 participants, randomized 6:2 | Drug: ALN-PNP<br>* Solution for subcutaneous (SC) injection<br>Drug: Placebo (PB)<br>* matching placebo, solution for SC injection<br>|
| Experimental: ALN-PNP Dose 5 or PB<br>8 participants, randomized 6:2 | Drug: ALN-PNP<br>* Solution for subcutaneous (SC) injection<br>Drug: Placebo (PB)<br>* matching placebo, solution for SC injection<br>|
| Experimental: Optional ALN-PNP Dose 5 or PB<br>8 participants, randomized 6:2 This is an optional cohort, if there is a need for additional dose characterization of ALN-PNP. | Drug: ALN-PNP<br>* Solution for subcutaneous (SC) injection<br>Drug: Placebo (PB)<br>* matching placebo, solution for SC injection<br>|
| Experimental: JPN ALN-PNP Dose 4 or PB<br>8 Japanese participants only, randomized 6:2 | Drug: ALN-PNP<br>* Solution for subcutaneous (SC) injection<br>Drug: Placebo (PB)<br>* matching placebo, solution for SC injection<br>|
| Experimental: JPN ALN-PNP Dose 5 mg or PB<br>8 Japanese participants only, randomized 6:2 | Drug: ALN-PNP<br>* Solution for subcutaneous (SC) injection<br>Drug: Placebo (PB)<br>* matching placebo, solution for SC injection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs) | A TEAE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. | Through end of study, approximately Day 169 | 
| Incidence of TEAEs by severity | The severity of AEs will be graded according to the following scale: Mild: Does not interfere in a significant manner with the participant normal functioning level. It may be an annoyance. Prescription drugs are not ordinarily needed for relief of symptoms, but may be given because of personality of the participant. Moderate: Produces some impairment of functioning but is not hazardous to health. It is uncomfortable or an embarrassment. Treatment for symptom may be needed. Severe: Produces significant impairment of functioning or incapacitation and is a definite hazard to the participant's health. Treatment for symptom may be given and/or participant hospitalized. | Through end of study, approximately Day 169 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of ALN-PNP and potential major metabolite(s) in plasma over time |  | Through end of study, approximately Day 169 | 
| Incidence of ALN-PNP antidrug-antibodies (ADA) over time |  | Through end of study, approximately Day 169 | 
| Titer of ALN-PNP ADA over time |  | From dosing, at Day 1 to study end at Day 169 | 
| Change from baseline in low-density lipoprotein (LDL) in adult participants |  | Through end of study, approximately Day 169 | 
| Change from baseline in high-density lipoprotein (HDL) in adult participants |  | Through end of study, approximately Day 169 | 
| Change from baseline in triglyceride (TG) in adult participants |  | Through end of study, approximately Day 169 | 
| Change from baseline in apolipoprotein B (ApoB) in adult participants |  | Through end of study, approximately Day 169 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Liver steatosis, Fibrosis, Hepatocytes, Non-alcoholic fatty liver disease, NAFLD, Non-alcoholic steatohepatitis, NASH