LY3849891 for Non-alcoholic Fatty Liver Disease

Recruiting at 17 trial locations

Overseen By Madhavi Rudraraju

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Eli Lilly and Company

Disqualifiers: Alcohol abuse, Cirrhosis, Heart attack, Cancer, others

Compensation: Varies

Number of Visits: 25

176 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and effects of a drug called LY3849891, an experimental treatment, on individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). Researchers will assess whether the drug can reduce liver inflammation and how the body processes it. Participants should have a specific gene type (PNPLA3 I148M) and certain liver fat levels, and may have controlled type 2 diabetes.

As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in humans.

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 there any evidence suggesting that LY3849891 is likely to be safe for humans?

Research has shown that the safety of LY3849891, a new treatment targeting a liver protein, remains uncertain in humans. This treatment is still in the early testing stages. Early trials typically focus on the body's response to the drug, so information on side effects and tolerance is limited.

As LY3849891 is in this early phase, researchers continue to assess its safety. Participants in these trials help researchers understand how the treatment might affect people and identify potential side effects. Prospective participants should discuss any concerns with the study team to understand what to expect. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for fatty liver disease?

Researchers are excited about LY3849891 for non-alcoholic fatty liver disease because it offers a new approach compared to current treatments like lifestyle changes and off-label use of medications such as vitamin E and pioglitazone. Unlike these options, LY3849891 is administered subcutaneously and focuses on delivering targeted doses directly into the body. This novel method of delivery could potentially improve efficacy and patient compliance by offering a more direct treatment that might work faster and more effectively than the current standard of care.

What evidence suggests that LY3849891 might be an effective treatment for MASLD?

Research has shown that treatments targeting the PNPLA3 gene, such as LY3849891, might help reduce liver fat in non-alcoholic fatty liver disease. This gene is linked to liver issues, and a genetic treatment called siRNA has shown promising results in early tests. Similar treatments have significantly reduced liver fat, suggesting that LY3849891 could also be effective. Although more research is needed, these early findings indicate that LY3849891 might help manage liver conditions related to this gene. ^{1 2 6 7 8}

Who Is on the Research Team?

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)

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

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.

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?

Group I: LY3849891 (Part B) Experimental Treatment 1 Intervention

Repeated doses of LY3849891 administered SC

Group II: LY3849891 (Part A) Experimental Treatment 1 Intervention

Single ascending doses of LY3849891 administered subcutaneously (SC)

Group III: Placebo (Part A) Placebo Group 1 Intervention

Placebo administered SC

Group IV: Placebo (Part B) Placebo Group 1 Intervention

Placebo administered SC

Who Is Running the Clinical Trial?

Eli Lilly and Company

Lead Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

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

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker. Baselli, GA., Dongiovanni, P., Rametta, R., et al.[2021]

The study enhances the detection of the pathogenic PNPLA3 rs738409 variant associated with nonalcoholic fatty liver disease by improving the PCR-RFLP method, ensuring more reliable identification of alleles.

By incorporating a second restriction enzyme digest, the new method provides a safer and more secure way to differentiate between pathogenic and nonpathogenic alleles, reducing the risk of false negatives in diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Secure and optimized detection of PNPLA3 rs738409 genotype by an improved PCR-restriction fragment length polymorphism&#160;method. Enssle, J., Weylandt, KH.[2021]

A new NAFLD liver fat score was developed using data from 470 subjects, which accurately predicts non-alcoholic fatty liver disease and liver fat content with high sensitivity (86%) and specificity (71%).

The addition of genetic information from the PNPLA3 gene only slightly improved prediction accuracy, indicating that clinical and laboratory data are the primary drivers for diagnosing NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Kotronen, A., Peltonen, M., Hakkarainen, A., et al.[2022]

A meta-analysis of 28 studies involving 6,216 patients and 8,218 controls found a strong association between the PNPLA3 gene rs738409 polymorphism and an increased risk of non-alcoholic fatty liver disease (NAFLD).

The analysis showed that individuals with the GG genotype had a 2.42 times higher risk of developing NAFLD compared to those with the CC genotype, indicating that this genetic variant significantly influences susceptibility to the disease across different populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Association between patatin-like phospholipase domain-containing protein 3 gene rs738409 polymorphism and non-alcoholic fatty liver disease susceptibility: a meta-analysis]. Wu, P., Shu, Y., Guo, F., et al.[2022]

The PNPLA3 I148M genetic polymorphism is linked to increased PNPLA3 expression in liver biopsies from NASH patients, correlating with higher fibrosis stages and α-SMA levels, indicating its role in disease progression.

High glucose levels and palmitic acid treatment in hepatocytes enhance PNPLA3 expression and promote fibrogenic activity in hepatic stellate cells, suggesting that metabolic conditions significantly influence liver fibrosis development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH. Bruschi, FV., Tardelli, M., Herac, M., et al.[2022]

In a study of 1550 Japanese patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), those carrying the PNPLA3 CG/GG genotypes had a significantly higher risk of liver-related events, including hepatocellular carcinoma (HCC) and liver-related deaths, compared to those with the CC genotype.

The study found that integrating the PNPLA3 genotype with the FIB-4 index provides a better risk stratification for NAFLD, highlighting the importance of genetic factors in predicting disease outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The greater impact of PNPLA3 polymorphism on liver-related events in Japanese non-alcoholic fatty liver disease patients: A multicentre cohort study. Seko, Y., Yamaguchi, K., Shima, T., et al.[2023]

NAFLD patients with the PNPLA3 148M allele may not respond effectively to omega-3 carboxylic acids for reducing liver fat, while those with the 148I allele show moderate benefits from this treatment.

Lifestyle changes are more effective for reducing liver fat in patients homozygous for the PNPLA3 148M allele compared to those with the wild-type allele, suggesting that personalized treatment strategies based on genetic testing could improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PNPLA3 I148M and response to treatment for hepatic steatosis: A systematic review. Boeckmans, J., Gatzios, A., Schattenberg, JM., et al.[2023]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease. Wang, JZ., Cao, HX., Chen, JN., et al.[2020]

Citations

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Among patients with simple steatosis, a notable 20% of them would develop metabolic dysfunction–associated steatohepatitis (MASH), a more advanced stage of ...

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7,8. These data provide the basis for reducing triglyceride content as a likely effective strategy to treat the entire spectrum of FLD. Another ...

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LY3849891 for Non-alcoholic Fatty Liver Disease

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 ...

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Recent clinical trials targeting PNPLA3 with siRNA and antisense oligonucleotides have shown promising results, including significant reductions ...

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This study is researching an experimental drug called ALN-PNP. This study is focused on participants who are known to have nonalcoholic fatty liver disease ...

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Study Details | nct05648214 | A Trial to Learn if ALN-PNP ...

What side effects may happen from taking the study drug; How the study drug works to change liver fat content in NAFLD; How much study drug and study drug ...

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pmc.ncbi.nlm.nih.gov

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Targeting PNPLA3 to Treat MASH and MASH Related ...

The PNPLA3 148M protein is causatively linked to the development of liver steatosis, inflammation and fibrosis in experimental studies and is therefore an ...

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Phase 1 Trials of PNPLA3 siRNA in I148M Homozygous ...

In phase 1 trials, JNJ-75220795, a hepatocyte-targeted GalNAc-conjugated PNPLA3 siRNA, reduced liver fat in PNPLA3 I148M homozygous patients.