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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called TN-201 for individuals with hypertrophic cardiomyopathy (HCM), a condition where the heart muscle thickens excessively. Researchers aim to determine the safety of TN-201 and its effects, particularly in those with specific gene mutations that can cause disease. The trial includes two groups receiving different doses to identify the optimal treatment amount. It targets individuals with the MYBPC3 gene mutation who experience symptoms like shortness of breath or chest pain and have a certain level of heart function. As a Phase 1 trial, this research seeks to understand how TN-201 works in people, offering participants the chance to be among the first to receive this new treatment.

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 TN-201 is likely to be safe for humans?

Research shows that TN-201, a gene therapy, appears safe in early tests. In animal studies, TN-201 extended life by two months compared to untreated subjects, suggesting the treatment did not cause harm.

Independent safety boards reviewed TN-201 and reported positive safety findings. Experts have examined the data and consider the treatment generally safe for trials.

This trial is in the early stages, focusing mainly on human safety. So far, no major safety issues have emerged, which is promising. However, more information is needed to fully understand its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for hypertrophic cardiomyopathy, which often include beta-blockers, calcium channel blockers, or surgical interventions, TN-201 is unique because it uses gene therapy to address the root cause of the disease. This investigational treatment targets the underlying genetic mutations responsible for hypertrophic cardiomyopathy, potentially offering a more precise and long-lasting solution. Researchers are excited about TN-201 because it has the potential to significantly improve heart function and quality of life for patients by directly modifying the genetic material in heart cells. This approach could transform the management of the condition by reducing symptoms and slowing disease progression in a way that current treatments cannot.

What evidence suggests that TN-201 might be an effective treatment for hypertrophic cardiomyopathy?

Research shows that TN-201 is a gene therapy designed to treat hypertrophic cardiomyopathy (HCM) by delivering a healthy MYBPC3 gene to heart cells. Animal studies demonstrated that TN-201 can extend life by about two months compared to those not receiving the treatment, suggesting it might improve heart function over time. In this trial, participants will join different cohorts to receive varying doses of TN-201. Additionally, many patients with MYBPC3-related HCM are likely to benefit from TN-201, as only a few have pre-existing immunity to the therapy's delivery method. Although human data remains in the early stages, this technology shows promise for addressing the root cause of HCM in affected individuals. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

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 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 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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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 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]

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]

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]

Citations

1. tenayatherapeutics.com tenayatherapeutics.com/tn-201/

TN-201 Our TN-201 cardiac-selective gene therapy candidate is designed to deliver a working MYBPC3 gene to cardiomyocytes via a one-time infusion. Hypertrophic ...

2. nature.com nature.com/articles/s41467-025-57481-7

AAV9-mediated MYBPC3 gene therapy with optimized ... For TN-201-treated animals, median survival was 16 months (i.e. 2 months lifespan extension from vehicle), and all animals died by 19 months of ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41020222/

High rate of seroeligibility among MYBPC3-associated ... Conclusion: Pre-existing immunity to AAV9 was absent or low in most MYBPC3-associated HCM patients, with only a small proportion exceeding ...

4. investors.tenayatherapeutics.com investors.tenayatherapeutics.com/news-releases/news-release-details/tenaya-therapeutics-reports-promising-early-data-mypeaktm-1

1 Phase 1b/2 Clinical Trial of TN-201 for Treatment of ... TN-201 is being developed for the potential treatment of MYBPC3-associated hypertrophic cardiomyopathy (HCM), a condition caused by insufficient levels of ...

5. onlinejcf.com onlinejcf.com/article/S1071-9164(23)00859-X/fulltext

MyPeak-1: A Phase 1b Study to Evaluate Safety and ... TN-201 is an AAV9-based gene therapy designed to deliver the MYBPC3 transgene to cardiomyocytes to restore MyBP-C protein levels to ameliorate disease following ...

6. investors.tenayatherapeutics.com investors.tenayatherapeutics.com/news-releases/news-release-details/tenaya-receives-positive-safety-reviews-independent-dsmbs

Tenaya Receives Positive Safety Reviews from Independent ... TN-201 is an adeno-associated virus serotype 9 (AAV9)-based gene therapy designed to deliver a working MYBPC3 gene to heart muscle cells via a ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05836259

Study Details | NCT05836259 | Multi-center, Open-label, ... This is a first-in-human, non-randomized, open-label study designed to evaluate the safety, tolerability, and pharmacodynamics (PD) of TN-201 in adult patients