LY3849891 for Non-alcoholic Fatty Liver Disease
Recruiting in Palo Alto (17 mi)
+16 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Eli Lilly and Company
Disqualifiers: Alcohol abuse, Cirrhosis, Heart attack, Cancer, others
Trial Summary
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.
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.
12345Is 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.
12367What 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.
15789Eligibility Criteria
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
+4 more
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.
+5 more
Trial Timeline
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
Participant Groups
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.
4Treatment groups
Experimental Treatment
Placebo Group
Group I: LY3849891 (Part B)Experimental Treatment1 Intervention
Repeated doses of LY3849891 administered SC
Group II: LY3849891 (Part A)Experimental Treatment1 Intervention
Single ascending doses of LY3849891 administered subcutaneously (SC)
Group III: Placebo (Part A)Placebo Group1 Intervention
Placebo administered SC
Group IV: Placebo (Part B)Placebo Group1 Intervention
Placebo administered SC
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Orange County Research CenterTustin, CA
Orange County Research CenterOrange, CA
Arizona Liver Health - ChandlerChandler, AZ
Evolution Clinical Trials, IncMiami, FL
More Trial Locations
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Who Is Running the Clinical Trial?
Eli Lilly and CompanyLead Sponsor
References
Identification and Optimization of a Minor Allele-Specific siRNA to Prevent PNPLA3 I148M-Driven Nonalcoholic Fatty Liver Disease. [2022]Human genome wide association studies confirm the association of the rs738409 single nucleotide polymorphism (SNP) in the gene encoding protein patatin like phospholipase domain containing 3 (PNPLA3) with nonalcoholic fatty liver disease (NAFLD); the presence of the resulting mutant PNPLA3 I148M protein is a driver of nonalcoholic steatohepatitis (NASH). While Pnpla3-deficient mice do not display an adverse phenotype, the safety of knocking down endogenous wild type PNPLA3 in humans remains unknown. To expand the scope of a potential targeted NAFLD therapeutic to both homozygous and heterozygous PNPLA3 rs738409 populations, we sought to identify a minor allele-specific small interfering RNA (siRNA). Limiting our search to SNP-spanning triggers, a series of chemically modified siRNA were tested in vitro for activity and selectivity toward PNPLA3 rs738409 mRNA. Conjugation of the siRNA to a triantennary N-acetylgalactosamine (GalNAc) ligand enabled in vivo screening using adeno-associated virus to overexpress human PNPLA3I148M versus human PNPLA3I148I in mouse livers. Structure-activity relationship optimization yielded potent and minor allele-specific compounds that achieved high levels of mRNA and protein knockdown of human PNPLA3I148M but not PNPLA3I148I. Testing of the minor allele-specific siRNA in PNPLA3I148M-expressing mice fed a NASH-inducing diet prevented PNPLA3I148M-driven disease phenotypes, thus demonstrating the potential of a precision medicine approach to treating NAFLD.
PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease. [2020]Non-alcoholic fatty liver disease (NAFLD) has now become the leading cause of chronic liver disease with its growing incidence worldwide. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C > G reflects one of the critical genetic factors that confers high-risk to NAFLD. However, the role of PNPLA3 polymorphism in NAFLD treatment remains uncertain. Here, the present review reveals that NAFLD patients with G-allele at PNPLA3 rs738409 (PNPLA3 148M variant) are sensitive to therapies of lifestyle modification, dipeptidyl peptidase-4 inhibitors, and bariatric surgery. They exhibit much significant reduction of liver fat content, in concurrence with weigh loss and abolished insulin resistance, as compared to those of C-allele carriers. In contrast, patients bearing PNPLA3 rs738409 C-allele (PNPLA3 148I variant), instead of G-allele, demonstrate greater beneficial effects by omega-3 poly-unsaturated fatty acids and statin intervention. Improved adipose tissue-liver interaction and decrease in intrahepatic triglyceride efflux may contribute to the PNPLA3 rs738409 related diversities in therapeutic efficacy. Therefore, PNPLA3 rs738409 underlies the response to a variety of treatments, which warrants a personalized, precise medicine in NAFLD on the basis of genotype stratification.
Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker. [2021]Label="OBJECTIVE">Efforts to manage non-alcoholic fatty liver disease (NAFLD) are limited by the incomplete understanding of the pathogenic mechanisms and the absence of accurate non-invasive biomarkers. The aim of this study was to identify novel NAFLD therapeutic targets andbiomarkers by conducting liver transcriptomic analysis in patients stratified by the presence of the PNPLA3 I148M genetic risk variant.
Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH. [2022]The genetic PNPLA3 polymorphism I148M has been extensively associated with higher risk for development and progression of NAFLD towards NASH.
PNPLA3 I148M and response to treatment for hepatic steatosis: A systematic review. [2023]It is unclear whether the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C-to-G single nucleotide polymorphism, resulting in the substitution of isoleucine to methionine at position 148 (I148M), impedes regression of hepatic steatosis when treating non-alcoholic fatty liver disease (NAFLD).
The greater impact of PNPLA3 polymorphism on liver-related events in Japanese non-alcoholic fatty liver disease patients: A multicentre cohort study. [2023]PNPLA3 rs738409 has been associated with an increased risk of liver-related events in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the epidemiology of NAFLD and the impact of PNPLA3 on prognosis in Japan.
[Association between patatin-like phospholipase domain-containing protein 3 gene rs738409 polymorphism and non-alcoholic fatty liver disease susceptibility: a meta-analysis]. [2022]To explore the association between patatin-like phospholipase domain-containing protein 3(PNPLA3) gene rs738409 polymorphism and the susceptibility of non-alcoholic fatty liver disease(NAFLD).
Secure and optimized detection of PNPLA3 rs738409 genotype by an improved PCR-restriction fragment length polymorphism method. [2021]The PNPLA3 reference single-nucleotide polymorphism rs738409 has been identified as a predisposing factor for nonalcoholic fatty liver disease. A simple method based on PCR and restriction fragment length polymorphism (RFLP) analysis had been published to detect the nonpathogenic allele PNPLA3 rs738409 variant. The presence of the pathogenic variant was deduced by the indigestibility of the corresponding PCR product with BtsCI recognizing the nonpathogenic allele. However, one cannot exclude that an enzymatic reaction does not occur for other, more trivial, reasons. For safe and secure detection of the pathogenic PNPLA3 rs738409, we have further developed the PCR-restriction fragment length polymorphism method by adding a second restriction enzyme digest, clearly identifying the correct PNPLA3 alleles and in particular the pathogenic variant.
Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. [2022]Our aims were to develop a method to accurately predict non-alcoholic fatty liver disease (NAFLD) and liver fat content based on routinely available clinical and laboratory data and to test whether knowledge of the recently discovered genetic variant in the PNPLA3 gene (rs738409) increases accuracy of the prediction.