A Single-Ascending and Repeated Dose Study of LY3849891 in Participants With Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

A Single-Ascending and Repeated Subcutaneous Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LY3849891 in Participants With Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Who Have the PNPLA3 I148M Genotype

The main purpose of this study is to evaluate the safety and tolerability of the study drug LY3849891 in participants with metabolic dysfunction-associated steatotic liver disease (MASLD) 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 MASLD and assessment of resolution of liver fibroinflammation. 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 visits in parts A and B.

Study Overview

• Status: Active, not recruiting
• Conditions: Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD); Metabolic Dysfunction-Associated Steatohepatitis (MASH)
• Intervention / Treatment: Drug: Placebo; Drug: LY3849891

• Study Type: Interventional
• Enrollment (Estimated): 176
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Hachiōji, Japan, 192-0071
    • P-One Clinic
  • Shinjuku-ku, Japan, 160-0004
    • Clinical Research Hospital Tokyo
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • FDI Clinical Research
• United States
  • Arizona
    • Chandler, Arizona, United States, 85225
      • Arizona Liver Health - Chandler
  • California
    • Orange, California, United States, 92868
      • Orange County Research Center
    • Rialto, California, United States, 92377
      • Inland Empire Clinical Trials, LLC
  • Florida
    • Brandon, Florida, United States, 33511
      • Synergy Healthcare LLC
    • Maitland, Florida, United States, 32751
      • Accel Research Sites - Maitland
    • Miami, Florida, United States, 33175
      • Advanced Pharma Clinical Research
    • Miami, Florida, United States, 33122
      • Evolution Clinical Trials, Inc
    • Miami Lakes, Florida, United States, 33016
      • Floridian Clinical Research
    • Orlando, Florida, United States, 32803
      • Charter Research - Winter Park
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • IU Health University Hospital
  • Texas
    • Houston, Texas, United States, 77079
      • Houston Research Institute
    • San Antonio, Texas, United States, 78229
      • Clinical Trials of Texas, Inc.
    • San Antonio, Texas, United States, 78229
      • Pinnacle Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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% in Part A and ≥8% for Part B 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% in Part A and <9% in Part B

• Male participants agree to use an effective method of contraception for the duration of the study and for 90 days after the last dose of study intervention
• 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 milliliter per minute per 1.73 square meter (ml/min/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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo (Part A); Placebo administered SC	Drug: Placebo; Administered SC
Placebo Comparator: Placebo (Part B); Placebo administered SC	Drug: Placebo; Administered SC
Experimental: LY3849891 (Part A); Single ascending doses of LY3849891 administered subcutaneously (SC)	Drug: LY3849891; Administered SC
Experimental: LY3849891 (Part B); Repeated doses of LY3849891 administered SC	Drug: LY3849891; Administered SC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Number of Participants with One or More Treatment Emergent Adverse Events (TEAEs) and Adverse Event(s) (AEs) Considered by the Investigator to be Related to Study Drug Administration	A summary of TEAEs and AEs, regardless of causality, will be reported in the Reported Adverse Events module	Predose up to 26 weeks post dose
Part B: Pharmacodynamics (PD): Mean change from baseline on liver inflammation and fibrosis measured by magnetic resonance imaging (MRI)	PD: Mean change from baseline on liver inflammation and fibrosis content measured by MRI	Baseline through 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: PD: Liver fat content measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF)	Part A: PD: Liver fat content measured by (MRI-PDFF)	Predose through Week 26
Part A: PK: Area Under the Concentration Versus Time Curve from Time Zero to Infinity (AUC(0-inf)) of LY3849891	Part A: PK: AUC(0-inf) of LY3849891	Predose through Week 26
Part A: Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of LY3849891	Part A: PK: Cmax of LY3849891	Predose through Week 26
Part A: PK: Time to Maximum Observed Concentration (Tmax) of LY3849891	Part A: PK: Tmax of LY3849891	Predose through Week 26
Part B: PD: Liver fat content changes at baseline and specified timepoints by MRI-PDFF	Part B: PD: Liver fat content changes at baseline and specified timepoints by MRI-PDFF	Predose through Week 24
Part B: PK: AUC(0-inf) of LY3849891 and its Metabolite	Part B: PK: AUC(0-inf) of LY3849891 and its metabolite	Predose through Week 24
Part B: Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of LY3849891 and its metabolite	Part B: PK: Cmax of LY3849891 and its metabolite	Predose through Week 24
Part B: PK: Tmax of LY3849891 and its metabolite	Part B: PK: Tmax of LY3849891 and its metabolite	Predose through Week 24

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Investigators: Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 8 AM - 8 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2022
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: May 24, 2022
• First Submitted That Met QC Criteria: May 24, 2022
• First Posted (Actual): May 27, 2022

Study Record Updates

• Last Update Posted (Actual): January 22, 2026
• Last Update Submitted That Met QC Criteria: January 20, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Magnetic resonance imaging; Hepatic fibrosis; Biomarkers; Liver fat
• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Liver Diseases; Fibrosis; Pathological Conditions, Signs and Symptoms; Fatty Liver; Liver Cirrhosis
• Other Study ID Numbers: 18214; J3W-MC-GZOA (Other Identifier: Eli Lilly and Company)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No