TN-201 for Hypertrophic Cardiomyopathy

(MyPEAK-1 Trial)

Recruiting at 8 trial locations

Overseen By Matt Pollman, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Tenaya Therapeutics

Disqualifiers: High AAV9 antibody titer

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 53

Duration: 1 day

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new drug, TN-201, in adults with a specific genetic heart condition. It aims to see if the drug is safe and how it affects their health over several years.

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 treatment TN-201 for Hypertrophic Cardiomyopathy?

Research shows that gene therapy using adeno-associated virus (AAV) vectors, like those in TN-201, has been effective in preventing heart problems in mice with similar genetic heart conditions. Specifically, AAV9 has been shown to deliver genes effectively to heart cells, which is promising for treating hypertrophic cardiomyopathy. ^{1 2 3 4 5}

Is TN-201 safe for use in humans?

Research on similar treatments using AAV9 vectors, which are part of TN-201, shows they can be delivered safely to heart cells in animals without causing harmful side effects. These studies suggest that the treatment is generally safe, but human-specific safety data is not provided. ^{2 3 4 5 6}

How is the treatment TN-201 for Hypertrophic Cardiomyopathy different from other treatments?

TN-201 is unique because it uses a gene therapy approach with an AAV9 vector to deliver a specific gene directly to heart cells, aiming to correct the underlying genetic cause of Hypertrophic Cardiomyopathy, unlike traditional treatments that mainly manage symptoms. ^{4 5 6 7 8}

Eligibility Criteria

This trial is for adults with symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM) linked to MYBPC3 mutation. Participants must have certain heart function markers like NT-proBNP levels of at least 300pg/ml and a left ventricular ejection fraction of 50% or more, as well as an implantable cardiac defibrillator.

Inclusion Criteria

Your heart pumps blood out normally.

Your NT-proBNP level is higher than 300pg/ml.

I have a thickened heart muscle that isn't blocking blood flow.

Exclusion Criteria

You have a high level of AAV9 neutralizing antibodies in your blood.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single ascending dose of TN-201 Gene Therapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

52 weeks

Regular visits over 52 weeks

Long-term follow-up

Participants are followed for 5 years to assess long-term safety and efficacy

5 years

Treatment Details

Interventions

• TN-201

Trial Overview The study is testing TN-201, a new treatment for nHCM. It's the first time this drug is being given to humans. The trial will look at how safe it is, how well people can tolerate it, and what effects it has on the body.

Participant Groups

Group I: Cohort 2 Experimental Treatment 1 Intervention

Dose for Cohort 2 will be 6E13 vg/kg

Group II: Cohort 1 Experimental Treatment 1 Intervention

Dose for Cohort 1 will be 3E13 vg/kg

TN-201 is already approved in United States, European Union for the following indications:

Approved in United States as TN-201 for:

• None approved yet; under investigation for MYBPC3-associated hypertrophic cardiomyopathy (HCM)

Approved in European Union as TN-201 for:

• None approved yet; under investigation for MYBPC3-associated hypertrophic cardiomyopathy (HCM)

Who Is Running the Clinical Trial?

Tenaya Therapeutics

Lead Sponsor

Trials

4

Recruited

450+

Findings from Research

Inhibition of mAKAPβ expression in stressed cardiomyocytes showed cardioprotective effects, and deleting the mAKAP gene in mice prevented harmful heart changes after a heart attack, indicating its potential as a therapeutic target for ischemic cardiomyopathy.

The newly developed AAV9sc.shmAKAP gene therapy effectively reduced mAKAPβ levels in the heart and prevented heart failure after myocardial infarction, demonstrating long-term benefits in heart function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting mAKAPβ expression as a therapeutic approach for ischemic cardiomyopathy. Martinez, EC., Li, J., Ataam, JA., et al.[2023]

The study demonstrated that using viral-mediated antisense oligoribonucleotides (AONs) can effectively increase the expression of a beneficial mRNA variant and reduce harmful mRNAs in a mouse model of hypertrophic cardiomyopathy (HCM).

Injection of the AONs into newborn mice not only abolished cardiac dysfunction but also prevented left ventricular hypertrophy, indicating a potential therapeutic approach for HCM, although the effects were temporary and need further optimization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice. Gedicke-Hornung, C., Behrens-Gawlik, V., Reischmann, S., et al.[2021]

A single systemic administration of AAV9-Mybpc3 gene therapy in 1-day-old mice successfully prevented cardiac hypertrophy and dysfunction for up to 34 weeks, indicating its long-term efficacy in treating neonatal hypertrophic cardiomyopathy (HCM).

The therapy not only increased levels of Mybpc3 mRNA and cMyBP-C protein but also reduced the accumulation of harmful mutant mRNAs, suggesting a dual mechanism of action that addresses both the genetic deficiency and the effects of mutant genes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice. Mearini, G., Stimpel, D., Geertz, B., et al.[2014]

The AAV9 capsid effectively targets the heart after intravenous administration in both newborn and adult mice, showing potential for gene delivery specifically to cardiac tissues.

Using the alpha-MHC promoter allows for focused gene expression in the heart, while the desmin promoter enables broader expression in both cardiac and skeletal muscles, enhancing the safety and control of gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tissue specific promoters improve specificity of AAV9 mediated transgene expression following intra-vascular gene delivery in neonatal mice. Pacak, CA., Sakai, Y., Thattaliyath, BD., et al.[2020]

Two novel AAV capsid variants, AAV2-THGTPAD and AAV2-NLPGSGD, were identified as more effective than the standard AAV2 and AAV9 in delivering gene therapy specifically to heart cells, showing improved transduction efficiency in a mouse model of cardiac hypertrophy.

These variants also demonstrated reduced immunogenicity, meaning they are less likely to be neutralized by the immune system, which enhances their potential for safe and effective cardiac-directed gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV capsid engineering identified two novel variants with improved in vivo tropism for cardiomyocytes. Rode, L., Bär, C., Groß, S., et al.[2023]

The study successfully delivered two types of adeno-associated virus (AAV9sc) biologics to the heart of swine, demonstrating effective targeting of cardiomyocytes without causing toxic effects, which is crucial for future heart failure treatments.

Quantitative PCR showed that the delivery of viral genomes was proportional to the dose, with significant expression of the transgenes in the heart, indicating that these biologics could potentially be effective in treating heart conditions in a preclinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Distribution of cardiomyocyte-selective adeno-associated virus serotype 9 vectors in swine following intracoronary and intravenous infusion. Li, J., Kelly, SC., Ivey, JR., et al.[2023]

Engineered adeno-associated viral (AAV) vectors showed increased specificity for skeletal muscle and reduced targeting to the liver, enhancing their potential for safe and effective gene delivery in muscle disorders.

In mouse models of X-linked myotubular myopathy and Duchenne muscular dystrophy, the best-performing vectors (AAVMYO2 and AAVMYO3) significantly improved survival, muscle strength, and function, indicating their therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders. El Andari, J., Renaud-Gabardos, E., Tulalamba, W., et al.[2022]

The adenoviral vector Ad-mlcLuc, controlled by the heart-specific myosin light chain-2 promoter, successfully targets gene expression specifically to cardiomyocytes, demonstrating its potential for gene therapy in heart muscle diseases.

In both in vitro and in vivo studies, Ad-mlcLuc showed significant activity in cardiac muscle cells while exhibiting minimal expression in non-target tissues, indicating a safer approach for gene delivery to the heart.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heart muscle-specific gene expression using replication defective recombinant adenovirus. Rothmann, T., Katus, HA., Hartong, R., et al.[2006]

References

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

Targeting mAKAPβ expression as a therapeutic approach for ischemic cardiomyopathy. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice. [2014]

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

Tissue specific promoters improve specificity of AAV9 mediated transgene expression following intra-vascular gene delivery in neonatal mice. [2020]

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

AAV capsid engineering identified two novel variants with improved in vivo tropism for cardiomyocytes. [2023]

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

Distribution of cardiomyocyte-selective adeno-associated virus serotype 9 vectors in swine following intracoronary and intravenous infusion. [2023]

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

Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Heart muscle-specific gene expression using replication defective recombinant adenovirus. [2006]