A Single-Ascending and Repeated Dose Study of LY3849891 in Participants With Nonalcoholic Fatty Liver Disease

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety and tolerability of the study drug LY3849891 in participants with nonalcoholic fatty liver disease who have the patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M genotype. Blood tests and magnetic resonance imaging of the liver will be performed to determine the effects of LY3849891 on fatty liver disease. Blood tests will also determine how long it takes the body to eliminate LY3849891. This is a 2-part study and may last up to 32 weeks for each participant and may include 12 and 13 visits in parts A and B, respectively.

Official Title
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A Single-Ascending and Repeated Subcutaneous Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LY3849891 in Participants With Nonalcoholic Fatty Liver Disease Who Have the PNPLA3 I148M Genotype

Conditions
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Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: LY3849891
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have a body mass index (BMI) within the range greater than or equal to (≥) 25 and less than (<) 50 kilogram per square meter (kg/m²) inclusive Participants must have liver fat content ≥10% as determined by MRI-PDFF Participants must be carriers of the PNPLA3 I148M allele Participants with or without type 2 diabetes mellitus (T2DM) o For participants with T2DM, hemoglobin A1c (HbA1c) <8% Male participants agree to use an effective method of contraception for the duration of the study Women not of childbearing potential may participate and include those who are: infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation), congenital anomaly such as Mullerian agenesis; or those who are postmenopausal Exclusion Criteria: Participants must not have known or suspected alcohol abuse (>14 units/week for women and >21 units/week for men) or active substance abuse Participants must not have evidence of cirrhosis or other forms of liver disease Participants must not have heart attack, stroke, or hospitalization for congestive heart failure in the past 3 months Participants must not have active cancer within the last 5 years Participants must not have uncontrolled high blood pressure Participants must not have renal impairment with estimated glomerular filtration rate (eGFR) <60 milliters/minute/1.73m² Participants must not have a diagnosis of type 1 diabetes Participants must not have 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) or other contraindications for MRI

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY3849891 (Part A)<br>Single ascending doses of LY3849891 administered subcutaneously (SC). | Drug: LY3849891<br>* Administered SC.<br>|
| Experimental: LY3849891 (Part B)<br>Repeated doses of LY3849891 administered SC. | Drug: LY3849891<br>* Administered SC.<br>|
| Placebo Comparator: Placebo (Part A)<br>Placebo administered SC. | Drug: Placebo<br>* Administered SC.<br>|
| Placebo Comparator: Placebo (Part B)<br>Placebo administered SC. | Drug: Placebo<br>* Administered SC.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants with One or More Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration | A summary of TEAEs and SAEs, regardless of causality, will be reported in the Reported Adverse Events module | Predose up to 26 weeks post dose | 
| Part B: Pharmacodynamics (PD): Relative change from baseline on liver fat content measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF) | PD: Relative change from baseline on liver fat content measured by MRI-PDFF | Baseline through 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A & B: Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of LY3849891 | Part A & B: PK: Cmax of LY3849891 | Predose through Week 26 | 
| Part A & B: Part A & B: PK: Area Under the Concentration Versus Time Curve (AUC) of LY3849891 | Part A & B: PK: AUC of LY3849891 | Predose through Week 26 | 
| Part A & B: PK: Time to Maximum Observed Concentration (Tmax) of LY3849891 | Part A & B: PK: Tmax of LY3849891 | Predose through Week 26 | 
| Part A & B: PD: Liver fat content at baseline and specified timepoints measured by MRI-PDFF | Part A & B: PD: Liver fat content at baseline and specified timepoints measured by MRI-PDFF | Predose through Week 26 | 
| Part B: PD: Alanine aminotransferase (ALT) measurements at baseline and specified time points | Part B: PD: ALT measurements at baseline and specified time points | Predose through Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-alcoholic steatohepatitis, Hepatic fibrosis, Biomarkers, Magnetic resonance imaging, Pharmacokinetics, Liver fat