Lepodisiran for Cardiovascular Disease

Recruiting at 1054 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Eli Lilly and Company

Disqualifiers: Recent MI, Uncontrolled hypertension, Severe renal failure, others

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing lepodisiran, a medication given as an injection under the skin. It targets people with high levels of lipoprotein(a) who have cardiovascular disease or are at risk of heart attack or stroke. The medication works by lowering lipoprotein(a) levels to reduce the risk of these cardiovascular events.

Will I have to stop taking my current medications?

The trial information does not specify whether 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 Lepodisiran for cardiovascular disease?

Research shows that small interfering RNA (siRNA) drugs, like Lepodisiran, have been effective in treating various conditions by silencing specific genes. For example, siRNA drugs have been approved for other diseases and are being developed for conditions like high cholesterol, which is related to heart disease. This suggests potential for Lepodisiran in cardiovascular treatment. ^{1 2 3 4 5}

What safety data exists for Lepodisiran and similar siRNA treatments?

While specific safety data for Lepodisiran is not provided, siRNA-based treatments, in general, have been developed with chemical modifications to improve their stability and effectiveness. However, these modifications can sometimes increase the risk of unintended effects by changing the RNA's natural structure and activity. ^{1 2 3 6 7}

What makes the drug Lepodisiran unique for treating cardiovascular disease?

Lepodisiran is unique because it uses small interfering RNA (siRNA) technology to specifically target and silence genes involved in cardiovascular disease, offering a novel approach compared to traditional treatments. This method allows for precise targeting of disease-related genes, potentially leading to more effective and personalized treatment options. ^{1 8 9 10 11}

Research Team

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

Principal Investigator

Eli Lilly and Company

Eligibility Criteria

This trial is for adults with high levels of lipoprotein(a), a type of fat in the blood, who either have cardiovascular disease or are at risk for heart attacks or strokes. Details on specific inclusion and exclusion criteria were not provided.

Inclusion Criteria

Have Lipoprotein(a) [Lp(a)] ≥175 nanomoles per liter (nmol/L)

I am 18 or older with a history of heart or blood vessel disease.

I am 55 or older with a high risk of a first heart event due to certain heart conditions or high cholesterol.

Exclusion Criteria

I have had or plan to have a procedure to remove bad cholesterol from my blood recently or during the study.

I have not had a heart attack, stroke, or any major heart surgery in the last 3 months.

My high blood pressure is not under control.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive lepodisiran or placebo administered subcutaneously to evaluate the reduction of cardiovascular risk

4.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Lepodisiran (RNA-targeted therapy)

Trial Overview The study is testing Lepodisiran Sodium's ability to lower the risk of major adverse cardiovascular events compared to a placebo. Participants will receive the drug through an injection under their skin.

Participant Groups

Group I: Lepodisiran Sodium Experimental Treatment 1 Intervention

Lepodisiran sodium administered subcutaneously (SC).

Group II: Placebo 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

Findings from Research

Small interfering RNA (siRNA) therapeutics are gaining traction in the pharmaceutical market, with three approved drugs and several others in advanced clinical trials, primarily targeting rare diseases and conditions like hypercholesterolemia.

Inclisiran, an siRNA drug for hypercholesterolemia, has shown effectiveness in patients who do not respond adequately to standard statin therapy, highlighting the potential of siRNA to provide novel treatment options for broader populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The growth of siRNA-based therapeutics: Updated clinical studies. Zhang, MM., Bahal, R., Rasmussen, TP., et al.[2022]

Using a specially designed delivery system (PEI1.8-DA) for siRNA targeting SHP-1 significantly reduced cardiomyocyte apoptosis in heart tissue after ischemia-reperfusion injury, indicating a potential cardioprotective effect.

In rat models of myocardial infarction, treatment with the PEI1.8-DA/SHP-1 siRNA polyplexes led to a notable decrease in both myocardial apoptosis and infarct size, demonstrating the efficacy of this gene delivery method in improving heart repair.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-apoptotic cardioprotective effects of SHP-1 gene silencing against ischemia-reperfusion injury: use of deoxycholic acid-modified low molecular weight polyethyleneimine as a cardiac siRNA-carrier. Kim, D., Hong, J., Moon, HH., et al.[2013]

RNA interference (RNAi) is a powerful therapeutic strategy that allows for precise modulation of gene expression, with four siRNA medications already approved by the FDA, demonstrating its efficacy in clinical applications.

Current advancements aim to develop biologic RNAi agents that closely mimic natural RNA structures, potentially improving safety and reducing off-target effects associated with chemical modifications in RNAi drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies. Traber, GM., Yu, AM.[2023]

Local delivery of MMP2-targeted siRNA in balloon-injured carotid arteries of hypercholesterolemic rabbits resulted in a significant 79% reduction in MMP2 mRNA levels, indicating effective gene silencing.

The treatment also led to a substantial decrease in MMP2 activity over time, with reductions of 53%, 50%, and 46% at 24, 48, and 72 hours, respectively, demonstrating the potential of siRNA as a therapeutic approach for cardiovascular diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local matrix metalloproteinase 2 gene knockdown in balloon-injured rabbit carotid arteries using nonviral-small interfering RNA transfection. Hlawaty, H., San Juan, A., Jacob, MP., et al.[2012]

RNA interference (RNAi) is a promising new therapeutic strategy for treating coronary heart disease (CHD) by using small interfering RNA (siRNA) to specifically silence disease-related genes.

Optimizing delivery systems for siRNA could significantly improve treatment efficiency, potentially leading to innovative therapies for CHD in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New aspects of gene-silencing for the treatment of cardiovascular diseases. Koenig, O., Walker, T., Perle, N., et al.[2021]

The study developed polymeric nanoparticles that can safely deliver both miRNA-124a and atorvastatin (ATOR) to inflamed arterial cells, showing no toxicity across a wide concentration range.

The combination of ATOR and miRNA-124a significantly reduced inflammation and oxidative stress in cells, outperforming single-loaded nanoparticles in preventing LDL accumulation and maintaining cell morphology, indicating a promising strategy for treating atherosclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Therapeutics for Atherosclerosis Treatment Using Polymeric Nanovectors. Leal, BH., Velasco, B., Cambón, A., et al.[2022]

RNA interference (RNAi) is emerging as a powerful tool for both validating gene function in research and as a promising new approach for developing therapies, particularly for targeting proteins that traditional drugs cannot.

The review highlights advancements in designing chemically modified small interfering RNAs (siRNAs) to enhance their therapeutic potential while addressing challenges like immunogenicity and off-target effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene silencing by chemically modified siRNAs. Engels, JW.[2013]

The study demonstrated that a fusion protein (F5-P) can effectively deliver Polo-like kinase 1 (PLK1) siRNAs to Her2(+) breast cancer cells, leading to reduced cell proliferation and increased apoptosis without triggering an interferon response.

Intravenous administration of F5-P/PLK1-siRNA complexes not only concentrated in breast cancer tumors but also significantly slowed tumor growth and metastasis while prolonging survival in animal models, indicating a promising therapeutic approach with minimal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast cancer growth and metastasis. Yao, YD., Sun, TM., Huang, SY., et al.[2023]

Lipid nanoparticles (LNPs) significantly enhance the delivery and effectiveness of antisense oligonucleotides (ASOs) and single-stranded siRNAs (ss-siRNAs) in reducing PTEN gene expression in the livers of mice, compared to unformulated drugs.

The study found that an unformulated ss-siRNA could reduce PTEN mRNA levels in a dose-dependent manner, but required much higher doses than the formulated ss-siRNA, highlighting the efficiency of LNPs in gene silencing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipid nanoparticles improve activity of single-stranded siRNA and gapmer antisense oligonucleotides in animals. Prakash, TP., Lima, WF., Murray, HM., et al.[2022]

The novel liposome-entrapped siRNA (LEsiRNA) nanoparticles effectively deliver anti-cancer siRNA to tumors in mice, resulting in a significant reduction in tumor growth and Survivin expression.

These nanoparticles are designed for in vivo use, showing accumulation in tumors through MR imaging and confirming delivery via fluorescence microscopy, highlighting their potential as a targeted therapy for cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel multifunctional nanoparticle mediates siRNA tumour delivery, visualisation and therapeutic tumour reduction in vivo. Kenny, GD., Kamaly, N., Kalber, TL., et al.[2022]

Atu027, a siRNA-lipoplex targeting PKN3, effectively inhibits tumor growth and lymph node metastasis in preclinical models of prostate and pancreatic cancers, demonstrating its potential as a treatment for advanced solid tumors.

The systemic administration of Atu027 leads to specific silencing of PKN3 in the vasculature, impairing endothelial cell functions like tube formation and migration, which are crucial for tumor growth and metastasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. Aleku, M., Schulz, P., Keil, O., et al.[2008]

References

1. England pubmed.ncbi.nlm.nih.gov

The growth of siRNA-based therapeutics: Updated clinical studies. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Anti-apoptotic cardioprotective effects of SHP-1 gene silencing against ischemia-reperfusion injury: use of deoxycholic acid-modified low molecular weight polyethyleneimine as a cardiac siRNA-carrier. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Local matrix metalloproteinase 2 gene knockdown in balloon-injured rabbit carotid arteries using nonviral-small interfering RNA transfection. [2012]

5. Switzerland pubmed.ncbi.nlm.nih.gov

New aspects of gene-silencing for the treatment of cardiovascular diseases. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Combined Therapeutics for Atherosclerosis Treatment Using Polymeric Nanovectors. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Gene silencing by chemically modified siRNAs. [2013]

8. United States pubmed.ncbi.nlm.nih.gov

Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast cancer growth and metastasis. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Lipid nanoparticles improve activity of single-stranded siRNA and gapmer antisense oligonucleotides in animals. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Novel multifunctional nanoparticle mediates siRNA tumour delivery, visualisation and therapeutic tumour reduction in vivo. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. [2008]