176 Participants Needed

LY3849891 for Non-alcoholic Fatty Liver Disease

Recruiting at 16 trial locations
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Madhavi Rudraraju profile photo
Overseen ByMadhavi Rudraraju
Age: 18+
Sex: Any
Trial Phase: Phase 1
Sponsor: Eli Lilly and Company

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is testing a new medication called LY3849891 in people with fatty liver disease who have a specific genetic variant. The study will check how the drug affects liver fat and how the body processes it using blood tests and imaging.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is LY3849891 (PNPLA3 siRNA) safe for humans?

The safety of LY3849891 (PNPLA3 siRNA) in humans is not yet known, as the research primarily focuses on its potential to treat non-alcoholic fatty liver disease in mice.12345

What makes the drug LY3849891 unique for treating non-alcoholic fatty liver disease?

LY3849891 is unique because it uses a small interfering RNA (siRNA) approach to specifically target and reduce the levels of a mutant protein (PNPLA3 I148M) associated with non-alcoholic fatty liver disease, offering a precision medicine approach that differs from other treatments which do not target this genetic variant.14678

What data supports the effectiveness of the drug LY3849891 for treating non-alcoholic fatty liver disease?

Research shows that targeting the PNPLA3 I148M genetic variant with specific siRNA can prevent disease symptoms in mice, suggesting a precision medicine approach could be effective for treating non-alcoholic fatty liver disease in humans.13569

Who Is on the Research Team?

C1

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Principal Investigator

Eli Lilly and Company

Are You a Good Fit for This Trial?

This trial is for adults with nonalcoholic fatty liver disease who are overweight or obese, may or may not have type 2 diabetes (with HbA1c <8%), and carry the PNPLA3 I148M gene variant. Women must be non-childbearing due to surgery or menopause. Participants should not have a history of significant alcohol/substance abuse, active cancer in the last 5 years, uncontrolled high blood pressure, severe kidney issues, type 1 diabetes, MRI contraindications like metal implants, or serious heart conditions.

Inclusion Criteria

I carry the PNPLA3 I148M gene variant.
Participants must have liver fat content ≥10% as determined by MRI-PDFF
Participants must have a body mass index (BMI) within the range ≥25 and <50 kg/m² inclusive
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Exclusion Criteria

I do not have any implants or conditions that prevent me from having an MRI.
Participants must not have known or suspected alcohol abuse (>14 units/week for women and >21 units/week for men) or active substance abuse
I have not had active cancer in the last 5 years.
See 5 more

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Single ascending doses of LY3849891 or placebo administered subcutaneously

Up to 26 weeks
12 visits (in-person)

Treatment Part B

Repeated doses of LY3849891 or placebo administered subcutaneously

Up to 26 weeks
13 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 weeks

What Are the Treatments Tested in This Trial?

Interventions

  • LY3849891
Trial Overview The study tests LY3849891's safety and effects on liver fat in participants with a specific genetic background related to fatty liver disease. It involves two parts: one where doses increase to find safe levels and another where repeated doses are given over up to 32 weeks. Effects will be measured using blood tests and MRI scans of the liver.
How Is the Trial Designed?
4Treatment groups
Experimental Treatment
Placebo Group
Group I: LY3849891 (Part B)Experimental Treatment1 Intervention
Group II: LY3849891 (Part A)Experimental Treatment1 Intervention
Group III: Placebo (Part A)Placebo Group1 Intervention
Group IV: Placebo (Part B)Placebo Group1 Intervention

Find a Clinic Near You

Who Is Running the Clinical Trial?

Eli Lilly and Company

Lead Sponsor

Trials
2,708
Recruited
3,720,000+
Dr. Daniel Skovronsky profile image

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks profile image

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Published Research Related to This Trial

A targeted small interfering RNA (siRNA) was developed to specifically knock down the mutant PNPLA3 I148M protein associated with nonalcoholic fatty liver disease (NAFLD), showing high selectivity and efficacy in reducing its levels in mouse models.
In mice expressing the PNPLA3 I148M variant, treatment with the siRNA prevented disease symptoms linked to nonalcoholic steatohepatitis (NASH), highlighting the potential for precision medicine in treating NAFLD in individuals with this genetic variant.
Identification and Optimization of a Minor Allele-Specific siRNA to Prevent PNPLA3 I148M-Driven Nonalcoholic Fatty Liver Disease.Murray, JK., Long, J., Liu, L., et al.[2022]
Patients with the G-allele variant of PNPLA3 (rs738409) show better responses to lifestyle changes, dipeptidyl peptidase-4 inhibitors, and bariatric surgery for treating non-alcoholic fatty liver disease (NAFLD), leading to significant reductions in liver fat and improved insulin sensitivity.
In contrast, those with the C-allele variant benefit more from omega-3 fatty acids and statins, suggesting that genetic differences influence treatment effectiveness and highlighting the need for personalized medicine in NAFLD management.
PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease.Wang, JZ., Cao, HX., Chen, JN., et al.[2020]
In a study of 125 obese individuals, the PNPLA3 I148M genetic variant was found to significantly influence liver gene expression, particularly in patients with severe non-alcoholic fatty liver disease (NAFLD), highlighting its role in the disease's pathology.
The gene interleukin-32 (IL32) was identified as a key biomarker for NAFLD, showing strong correlation with disease severity and improved diagnostic performance when combined with traditional liver enzyme tests, suggesting it could be a valuable non-invasive marker for assessing NAFLD.
Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker.Baselli, GA., Dongiovanni, P., Rametta, R., et al.[2021]

Citations

Identification and Optimization of a Minor Allele-Specific siRNA to Prevent PNPLA3 I148M-Driven Nonalcoholic Fatty Liver Disease. [2022]
PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease. [2020]
Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker. [2021]
Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH. [2022]
PNPLA3 I148M and response to treatment for hepatic steatosis: A systematic review. [2023]
The greater impact of PNPLA3 polymorphism on liver-related events in Japanese non-alcoholic fatty liver disease patients: A multicentre cohort study. [2023]
[Association between patatin-like phospholipase domain-containing protein 3 gene rs738409 polymorphism and non-alcoholic fatty liver disease susceptibility: a meta-analysis]. [2022]
Secure and optimized detection of PNPLA3 rs738409 genotype by an improved PCR-restriction fragment length polymorphism&#160;method. [2021]
Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. [2022]
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