Lepodisiran for Cardiovascular Disease

Recruiting at 1249 trial locations

Overseen By Physicians interested in becoming principal investigators please contact

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Eli Lilly and Company

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 4.5 years

16700 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called lepodisiran, an experimental drug, to determine if it can lower the risk of heart attacks and strokes in people with high lipoprotein(a), a type of cholesterol linked to heart disease. The study explores different methods of administering the drug to find the most effective approach. Participants who have experienced cardiovascular issues or are at risk, and have high lipoprotein(a) levels, might be suitable candidates. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment for heart disease.

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.

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

Previous studies have shown that lepodisiran is well-tolerated by patients. Research indicates it effectively lowers lipoprotein(a) levels in the blood, reducing the risk of heart problems. In one trial, patients experienced a significant decrease in lipoprotein(a) without major safety issues. However, researchers are still studying its long-term safety and effects on heart-related events. Although this adds some uncertainty, the treatment has not shown serious side effects so far. As it advances through further research stages, more detailed safety information will become available. ^{1 2 3 4 5}

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

Lepodisiran is unique because it offers a novel approach to treating cardiovascular disease. Unlike traditional treatments that often focus on managing symptoms or reducing cholesterol levels, Lepodisiran targets the underlying causes by inhibiting a specific protein involved in disease progression. This drug is administered subcutaneously, which might improve patient compliance compared to oral medications. Researchers are excited about Lepodisiran because its innovative mechanism of action has the potential to provide more effective and longer-lasting results than current therapies.

What evidence suggests that lepodisiran might be an effective treatment for cardiovascular disease?

Research has shown that lepodisiran, which participants in this trial may receive, can significantly lower lipoprotein(a) [Lp(a)], a factor linked to heart disease risk. Studies have found that lepodisiran can reduce Lp(a) levels by up to 97%. The reduction depends on the dose; higher doses result in a greater effect. The effect lasts for several months. Specifically, previous patients experienced significant drops in Lp(a) levels between 60 to 180 days after just one dose. This suggests that lepodisiran could help reduce heart disease risk in people with high Lp(a). ^{1 2 3 4 6}

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 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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Lepodisiran

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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]

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]

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 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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40162643/

Lepodisiran - A Long-Duration Small Interfering RNA ... Conclusions: Lepodisiran reduced mean serum concentrations of lipoprotein(a) from 60 to 180 days after administration. (Funded by Eli Lilly; ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40968429/

Lepodisiran: Effects on Lipoprotein(a) and Cardiovascular ... Results: Lepodisiran demonstrated a dose-dependent and sustained reduction in Lp(a) levels, achieving a maximum reduction of up to 97% at the ...

3. consultqd.clevelandclinic.org consultqd.clevelandclinic.org/lepodisirans-large-durable-lpa-reductions-in-phase-2-trial-boost-anticipation-of-phase-3-results

Phase 2 Lepodisiran Trial Boosts Interest in Phase 3 Results A single 400-mg dose lowered Lp(a) levels by 94% from day 60 to day 180 in a phase 2 trial of this therapy for elevated lipoprotein(a).

4. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2811935

Lepodisiran, an Extended-Duration Short Interfering RNA ... Lepodisiran was well tolerated and produced dose-dependent, long-duration reductions in serum lipoprotein(a) concentrations in this phase 1 trial.

5. nejm.org nejm.org/doi/abs/10.1056/NEJMoa2415818

Lepodisiran — A Long-Duration Small Interfering RNA ... Lepodisiran reduced mean serum concentrations of lipoprotein(a) from 60 to 180 days after administration. (Funded by Eli Lilly; ALPACA ...

6. wjgnet.com wjgnet.com/1949-8462/full/v17/i8/109657.htm

Lepodisiran: From genetic targeting to cardiovascular ... Long-term safety and major adverse cardiovascular events (MACE) outcome data remain pending. Pelacarsen. Pelacarsen, an antisense ...