A Study of ALN-HSD in Healthy Adult Subjects and Adult Patients With Nonalcoholic Steatohepatitis (NASH)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of single ascending doses of ALN-HSD in healthy participants (Part A) and multiple doses of ALN-HSD in patients with NASH (Parts B and C).

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, 3-Part Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Dose ALN-HSD in Healthy Adult Subjects and Multiple Dose ALN-HSD in Adult Patients With Nonalcoholic Steatohepatitis (NASH)

Conditions
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Nonalcoholic Steatohepatitis, NASH

Intervention / Treatment
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* Drug: ALN-HSD
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A Only Has body mass index (BMI) ≥18 kg/m^2 and ≤28 kg/m^2 Has normal 12-lead electrocardiogram (ECG) Parts B and C Only: Has BMI ≥18 kg/m^2 and ≤40 kg/m^2 Has a diagnosis of NASH documented in the patient's medical history or a clinical suspicion of NASH based on defined study criteria Has screening liver biopsy with NASH activity score (NAS) score of ≥3 per NASH Clinical Research Network (CRN) criteria Exclusion Criteria: Parts A, B and C: Has any clinical safety laboratory result considered clinically significant and unacceptable by the Investigator Has known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection Has known history or evidence of drug abuse, within 12 months prior to screening Has evidence of other forms of known chronic liver disease Has recently received an investigational agent Has any uncontrolled or serious disease, medical or surgical condition that my interfere with participation or data interpretation Has excessive alcohol intake for ≥ 3 months during past year Has history of intolerance to SC injection(s) Has international normalized ratio (INR) >1.2 Has platelet count <140x10^9/L Part A Only Has systolic blood pressure (BP) >140 mmHg and diastolic >90 mmHg; Has used certain prescription drugs within last 14 days prior to screening Has used certain over the counter (OTC) medication within 7 days prior to screening Has estimated glomerular filtration rate (GFR) ≤60 mL/min/1.73m^2 at screening Parts B and C Only Has abnormal ECG Has changes in certain prescription medications defined in the protocol within the specified timeframe prior to screening Has GFR<45ml/min/1.73m^2

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: ALN-HSD<br>Participants will be administered a single dose of ALN-HSD. | Drug: ALN-HSD<br>* ALN-HSD will be administered by subcutaneous (SC) injection.<br>|
| Placebo Comparator: Part A: Placebo<br>Participants will be administered a single dose of ALN-HSD-matching placebo. | Drug: Placebo<br>* Normal saline (0.9% NaCl) matching volume of ALN-HSD doses will be administered SC.<br>|
| Experimental: Part B: ALN-HSD<br>Participants will be administered multiple doses of ALN-HSD. | Drug: ALN-HSD<br>* ALN-HSD will be administered by subcutaneous (SC) injection.<br>|
| Placebo Comparator: Part B: Placebo<br>Participants will be administered multiple doses of ALN-HSD-matching placebo. | Drug: Placebo<br>* Normal saline (0.9% NaCl) matching volume of ALN-HSD doses will be administered SC.<br>|
| Experimental: Part C: ALN-HSD<br>Participants will be administered multiple doses of ALN-HSD. | Drug: ALN-HSD<br>* ALN-HSD will be administered by subcutaneous (SC) injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts A and B: Frequency of Adverse Events |  | Part A: Up to 3.5 months; Part B: up to 12.5 months | 
| Part C: Change from Baseline of Liver Hydroxysteroid 17β Dehydrogenase 13 (HSD17B13) Messenger Ribonucleic Acid (mRNA) |  | Baseline and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Area Under the Plasma Concentration-time Curve (AUC) for ALN-HSD and Potential Metabolites |  | Part A: Day 1 predose and up to 48 hours postdose; Part B: Day 1 and Month 3 predose and up to 4 hours postdose | 
| Pat A: Maximum Plasma Concentration (Cmax) for ALN-HSD and Potential Metabolites |  | Part A: Day 1 predose and up to 48 hours postdose; Part B: Day 1 and Month 3 predose and up to 4 hours postdose | 
| Part A: Fraction Excreted in Urine (fe) of ALN-HSD and Potential Metabolites |  | Part A and B: Day 1 up to 24 hours postdose | 
| Part B: Plasma Concentrations of ALN-HSD and Potential Major Metabolite(s) |  | Predose and up to 9 months postdose | 
| Part B: Change from Baseline of Liver HSD17B13 mRNA | Hepatic HSD17B13 mRNA will be measured by quantitative reverse-transcription polymerase chain reaction using ribonucleic acid (RNA) isolated from liver biopsy. | Predose and up to 9 months postdose | 
| Part C: Frequency of Adverse Events |  | Up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatobiliary disorders, Non-alcoholic fatty liver disease, NAFLD, Fatty liver, RNAi therapeutic