Gene Therapy for Arrhythmogenic Cardiomyopathy

Not currently recruiting at 4 trial locations

Overseen By LEXEO Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Lexeo Therapeutics

Disqualifiers: Other cardiac abnormalities, NYHA Class IV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy called LX2020, designed to help individuals with arrhythmogenic cardiomyopathy (ACM), a heart condition that can cause irregular heartbeats. The trial's main goal is to assess the treatment's safety and tolerability. It involves administering different doses to groups to find the best balance between effectiveness and safety. Suitable candidates have been diagnosed with ACM, possess a specific genetic variant (PKP2), and experience frequent abnormal heartbeats. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

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 this treatment is likely to be safe for humans?

Studies have shown that LX2020, a gene therapy, is safe in animals. Tests with monkeys revealed no harmful effects, indicating the treatment did not cause any problems. This suggests potential safety for humans, though more information is needed. As a Phase 1/2 trial, this marks one of the first tests of LX2020 in humans. The main goal is to assess its safety and how well people tolerate the treatment. While early results are promising, the trial will provide a better understanding of its safety in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for arrhythmogenic cardiomyopathy, like beta-blockers or implantable cardioverter-defibrillators, focus on managing symptoms or preventing sudden cardiac death. But LX2020 offers a groundbreaking approach by using gene therapy to address the root cause of the condition. This treatment delivers a corrected version of the faulty gene responsible for the disease, potentially halting its progression. Researchers are excited because this could not only manage symptoms but also offer a long-term solution, transforming care for patients with this challenging heart disorder.

What evidence suggests that LX2020 might be an effective treatment for arrhythmogenic cardiomyopathy?

Research shows that LX2020, the investigational treatment in this trial, might help treat arrhythmogenic cardiomyopathy (ACM) by targeting the PKP2 gene, which significantly influences this heart condition. Studies in mice have found that LX2020 can improve heart function and reduce irregular heartbeats, especially at higher doses. Another study found that this treatment could extend the lifespan of mice with the same genetic condition. These results suggest that LX2020 might benefit people with PKP2-related ACM, but further research is needed to confirm this in humans. ^{1 2 3 6 7}

Who Is on the Research Team?

LEXEO Clinical Trials

Principal Investigator

Lexeo Therapeutics

Are You a Good Fit for This Trial?

This trial is for adults with a specific heart condition called Arrhythmogenic Cardiomyopathy (ACM) due to a PKP2 gene variant. Participants must meet certain diagnostic criteria, have frequent irregular heartbeats known as PVCs, and have had an ICD (a device that can prevent sudden death from cardiac arrest) implanted for at least 12 weeks. They should also have a left ventricular ejection fraction of 50% or higher.

Inclusion Criteria

Frequent premature ventricular complexes (PVCs)

I have been diagnosed with ACM according to the 2010 criteria.

Left ventricular ejection fraction ≥ 50%

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single ascending dose of LX2020 in multiple cohorts

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• LX2020

Trial Overview The trial is testing LX2020, which is a new gene therapy given through the veins. It's in early stages of testing (Phase 1/2), where researchers are trying to find out how safe it is and what doses are tolerable when given to humans for the first time.

How Is the Trial Designed?

Group I: LX2020 Experimental Treatment 1 Intervention

Single ascending dose of LX2020, with a starting dose of 2.0 x10\^13 gc/kg, in multiple cohorts

Who Is Running the Clinical Trial?

Lexeo Therapeutics

Lead Sponsor

Trials

5

Recruited

110+

Published Research Related to This Trial

Arrhythmogenic cardiomyopathy (AC) is linked to mutations in desmosomal proteins in about 50% of patients, highlighting the genetic basis of the disease.

Recent research indicates that changes in intercalated disk proteins and abnormal cell signaling pathways play a significant role in the development of AC, suggesting potential targets for future therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remodeling of cell-cell junctions in arrhythmogenic cardiomyopathy. Asimaki, A., Saffitz, JE.[2021]

Arrhythmogenic cardiomyopathy (AC) is a serious heart condition that can lead to dangerous heart rhythms and sudden cardiac death, particularly in young athletes, and is characterized by scarring in the heart muscle.

The disease has a genetic basis linked to mutations in cardiac desmosome genes, but also includes non-genetic factors, leading to a variety of symptoms and disease progression that varies with age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natural History of Arrhythmogenic Cardiomyopathy. Mattesi, G., Zorzi, A., Corrado, D., et al.[2020]

In a study of 168 patients with arrhythmogenic cardiomyopathy (AC), greater exercise exposure was linked to worse left ventricular (LV) function at the initial assessment, indicating that exercise may exacerbate LV dysfunction in these patients.

The progression of LV dysfunction over time was most significant in patients with the desmoplakin genotype, and this deterioration was a predictor of future ventricular tachyarrhythmias, highlighting the importance of monitoring LV function for risk assessment in AC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Left Ventricular Dysfunction in Arrhythmogenic Cardiomyopathy: Association With Exercise Exposure, Genetic Basis, and Prognosis. Lie, ØH., Chivulescu, M., Rootwelt-Norberg, C., et al.[2021]

Arrhythmogenic cardiomyopathy (ACM) is a hereditary heart disease that leads to dangerous heart rhythms and can result in sudden cardiac death, with its genetic basis becoming clearer due to advancements in genetic analysis techniques.

Various preclinical models, including gene-targeted animals and human stem cell-derived heart cells, are being used to better understand ACM's mechanisms and the relationship between specific genetic mutations and disease outcomes, which could help improve patient prognosis and treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arrhythmogenic Cardiomyopathy: from Preclinical Models to Genotype-phenotype Correlation and Pathophysiology. Fan, X., Yang, G., Duru, F., et al.[2023]

Arrhythmogenic cardiomyopathy, though rare, is primarily caused by single-gene mutations affecting desmosomal proteins, which are crucial for cell adhesion and mechanical stability in heart tissue.

Understanding the mechanisms behind the arrhythmogenic features of this disease could provide insights into lethal heart rhythms and sudden cardiac death in more prevalent heart conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pathobiology of arrhythmogenic cardiomyopathy. Saffitz, JE.[2012]

Inherited arrhythmias, caused by genetic mutations, pose a lifelong risk of sudden death and are linked to various conditions like long QT syndrome and hypertrophic cardiomyopathy.

Recent studies indicate that gene therapies may offer targeted treatment options for certain inherited arrhythmias, potentially improving outcomes where current therapies fall short.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for inherited arrhythmias. Bezzerides, VJ., Prondzynski, M., Carrier, L., et al.[2021]

Arrhythmogenic cardiomyopathy primarily affects young males, with a median diagnosis age of 38.2 years, and all patients experienced potentially fatal ventricular arrhythmias, highlighting the condition's serious nature.

Among the 13 patients studied, 84.6% are still alive, with treatment strategies including implantable cardioverter defibrillators (ICDs) for secondary prevention, ablation, and heart transplantation, indicating effective management options for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical profile and therapeutic strategies in patients with arrhythmogenic cardiomyopathy treated in a national reference institute]. Huerta Robles, R., Chávez Solsol, F., Muñoz Moreno, J., et al.[2023]

Citations

1. nature.com nature.com/articles/s41536-025-00401-6

Preclinical efficacy and safety of AAVrh10-based ... PKP2 (LX2020) to rescue cardiac (molecular and especially RV) deficits, arrhythmia burden and survival in PKP2 ACM mice, suggesting its ...

2. ahajournals.org ahajournals.org/doi/10.1161/res.135.suppl_1.We117

Abstract We117: Preclinical Evidence of Long-term Efficacy ... Long term LX2020 efficacy was observed at the same doses in PKP2-Hom mice with dose-dependent improvements in cardiac function, arrhythmia ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT07050160

NCT07050160 | Long-term Follow-up Study of Gene ... GRIT-PKP2 is a Phase 1/2 long-term follow-up (LTFU) study designed to evaluate the long-term safety and tolerability of LX2020 gene therapy for participants ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38288614/

AAV-Mediated Delivery of Plakophilin-2a Arrests Progression ... These preclinical data demonstrate the potential for AAVrh.74-PKP2a (RP-A601) as a therapeutic for PKP2-related arrhythmogenic right ventricular cardiomyopathy.

5. ir.rocketpharma.com ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-presents-preliminary-data-phase-1

News Release Details “These initial results represent the second gene therapy from our AAV cardiovascular portfolio to show positive clinical data, propelling us one step closer ...

6. ahajournals.org ahajournals.org/doi/10.1161/circ.148.suppl_1.18583

Abstract 18583: Preclinical Efficacy and Safety of ... Conclusions: Collectively, these data support the efficacy of LX2020 in restoring cardiac hPKP2 expression and rescuing the progressively ...

7. ir.lexeotx.com ir.lexeotx.com/news-releases/news-release-details/lexeo-therapeutics-granted-fda-fast-track-designation-and-orphan

Press Release LX2020 is an AAVrh10-based gene therapy candidate designed to intravenously deliver a functional PKP2 gene to cardiac muscle for the treatment of PKP2-ACM.