Tenaya Therapeutics Publishes Preclinical Data Demonstrating TN-201 Enhances Cardiac Function and Survival in MYBPC3 Cardiomyopathy Models

Rhea-AI Summary

Tenaya Therapeutics (TNYA) has published positive preclinical data in Nature Communications for TN-201, its gene therapy candidate targeting MYBPC3-associated hypertrophic cardiomyopathy (HCM). The therapy demonstrated significant disease reversal in severe knock-out mice models.

Key findings show that TN-201 achieved:

• Dose-dependent increases in MyBP-C protein with improvements in cardiac function at doses as low as 1x10¹³ vg/kg
• Reversal of left ventricular hypertrophy
• Sustained increases in gene expression
• Decreased cardiac biomarkers associated with fibrosis and heart failure
• Extended survival in treated mice

The therapy is currently being evaluated in the MyPEAK™-1 Phase 1b/2 clinical trial at doses of 3x10¹³ vg/kg and 6x10¹³ vg/kg. Initial data from the first cohort will be presented at the upcoming American College of Cardiology Scientific Sessions, with high-dose cohort data expected in the second half of the year.

Positive

• Successful preclinical results published in prestigious Nature Communications journal
• Demonstrated disease reversal in severe knock-out mice model
• Achieved dose-dependent efficacy with near-maximal results at 3x10¹³ vg/kg
• Showed durable treatment effects lasting up to 20 months post-treatment
• Clinical trial progressing with both low and high-dose cohorts

Negative

• Results to preclinical stage, human efficacy yet to be proven
• Clinical data from first cohort still pending

Insights

Biotechnology/Gene Therapy Expert

Tenaya's Nature Communications publication provides compelling preclinical validation for TN-201's mechanism in treating MYBPC3-associated HCM. The data demonstrates several critical attributes essential for successful gene therapy development:

The dose-response relationship showing efficacy at 1x10¹³ vg/kg while maintaining a ceiling on protein expression is particularly noteworthy. This self-regulated expression mechanism—where transgene RNA increases proportionally with dose but protein doesn't exceed wild-type levels—represents an elegant safety feature addressing a common concern in gene therapy development.

The reversal of established disease in the knockout mouse model is scientifically significant. Many gene therapies can prevent disease progression, but demonstrating actual disease reversal in advanced cases suggests potential applicability across a broader patient spectrum than typically expected.

The 20-month durability in preclinical models is remarkable and distinguishes this program from many others. Long-term expression without apparent loss of efficacy addresses one of the fundamental challenges in gene therapy—ensuring sustained therapeutic effect after single administration.

I'm impressed by Tenaya's comprehensive approach using multiple model systems—knockout mice, iPSC-derived cardiomyocytes, and engineered heart tissue—creating a robust translational package that strengthens confidence in the clinical hypothesis. The normalization of calcium handling abnormalities directly addresses the pathophysiological mechanisms underlying the hypercontractility observed in HCM.

Clinical Development Expert

The preclinical data package for TN-201 strategically addresses key concerns regarding clinical translation for MYBPC3-associated HCM. The dose-finding approach is particularly well-designed: demonstrating near-maximal efficacy at 3x10¹³ vg/kg in preclinical models while evaluating both this dose and a higher 6x10¹³ vg/kg dose in the MyPEAK-1 trial creates a rational development path with built-in safety margins.

Demonstrating efficacy in both early-onset and advanced disease models provides crucial support for the current clinical strategy. This suggests potential applicability across various disease stages—a considerable advantage when designing inclusion criteria for pivotal trials and potentially expanding the addressable patient population.

The upcoming data presentations represent significant potential catalysts. Initial human data from the first cohort at ACC will provide preliminary validation of transduction efficiency and safety in humans. The high-dose cohort data expected in H2 2025 will be particularly important for dose selection in potential registrational studies.

The comprehensive biomarker analysis showing decreases in fibrosis and heart failure markers establishes valuable surrogate endpoints that could accelerate the development timeline. Coupled with functional cardiac improvements and evidence of structural remodeling, these create multiple potential endpoints for demonstrating clinical benefit.

TN-201's design focusing on cardiac-specific expression using a proprietary promoter addresses historical safety concerns with systemic AAV delivery, potentially creating a favorable risk-benefit profile necessary for regulatory success in this indication.

Robust Evidence of Disease Reversal in Severe Knock Out Mice Model Supports Tenaya’s Clinical Development Plan to Evaluate TN-201 as a Potential Treatment for Patients with MYBPC3-associated Hypertrophic Cardiomyopathy

SOUTH SAN FRANCISCO, Calif., March 24, 2025 (GLOBE NEWSWIRE) -- Tenaya Therapeutics, Inc. (Nasdaq: TNYA), a clinical-stage biotechnology company with a mission to discover, develop and deliver potentially curative therapies that address the underlying causes of heart disease, today announced the publications of positive preclinical data for TN-201, the company’s gene therapy candidate for Myosin-Binding Protein C3 (MYBPC3)-associated hypertrophic cardiomyopathy (HCM), in Nature Communications.

Variants in the MYBPC3 gene resulting in insufficient levels of MyBP-C protein are the most common genetic cause of HCM. TN-201 is Tenaya’s adeno-associated virus serotype 9 (AAV9)-based gene therapy designed to deliver a working MYBPC3 gene to heart muscle cells via a single intravenous infusion, increasing MyBP-C protein levels to address the underlying cause of MYBPC3-associated HCM with the aim of halting or even reversing disease. Preclinical results published in Nature Communications show that Tenaya’s MYBPC3 gene replacement therapy achieved dose-dependent increases in MyBP-C protein, improving multiple parameters of cardiac function at protein levels well below wild-type with doses as low as 1x10¹³ vg/kg. Of note, treatment with Tenaya’s MYBPC3 gene therapy reversed left ventricular hypertrophy, a hallmark of HCM, as evidenced by decreases in posterior wall thickness relative to vehicle and normalization of left ventricular mass relative to body weight. TN-201 is currently being evaluated at doses of 3x10¹³ vg/kg and 6x10¹³ vg/kg in Tenaya’s ongoing MyPEAK™-1 Phase 1b/2 clinical trial for the treatment of MYBPC3-associated HCM.

“The extensive body of preclinical data published in Nature Communications highlights the engineering, production and thorough testing that support TN-201’s clinical development and offers substantial evidence that our novel gene therapy approach to MYBPC3-associated HCM has the potential to change the treatment paradigm for patients suffering with this genetic heart condition,” said Kathy Ivey, Ph.D., Senior Vice President of Research of Tenaya Therapeutics.

“We are encouraged by TN-201’s consistency in achieving transduction and expression across our preclinical studies and the early findings from our first-in-human Phase 1b study of TN-201,” added Whit Tingley, M.D., Ph.D., Tenaya’s Chief Medical Officer. “The robust transduction and improvements in cardiac function observed in a model of severe disease, provide reason to believe in TN-201’s potential to achieve similar improvements in key parameters of human disease over time. We look forward to presenting additional data from our first cohort of patients in the MyPEAK-1 clinical trial at the upcoming American College of Cardiology Scientific Sessions, as well as sharing initial data from our high-dose cohort in the second half of this year.”

Key Preclinical Findings
The article, titled, “AAV9-Mediated MYBPC3 Gene Therapy with Optimized Expression Cassette Enhances Cardiac Function and Survival in MYBPC3 Cardiomyopathy Models,” describes the results from in vitro and in vivo preclinical studies.

Studies conducted in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) compared various cassette configurations and informed the final design of TN-201, which incorporates a full-length MYBPC3 gene with a proprietary cardiac promoter that maintains high specificity for heart cells.

To test transduction and expression strength, additional analyses in human iPSC-derived cardiomyocytes showed transduction equivalent to 1 vector genome per diploid genome (vg/dg) resulted in near-wild type levels of MYBPC3 RNA and MyBP-C protein at 3x10¹³ vg/kg. Researchers observed proportional increases in transgene RNA at doses of 3x10¹³ and 1x10¹⁴ vg/kg, while MyBP-C protein levels did not exceed wild type levels, indicating that RNA overexpression does not result in overexpression of protein, suggesting an attractive safety feature of MYBPC3 gene therapy.

To measure the efficacy of TN-201, a mouse surrogate of TN-201 (mTN-201) was tested against vehicle in a homozygous Mybpc3-deficient murine model that mimics severe disease in humans. Treatment with mTN-201 in Mybpc3 knock-out mice at the time of disease onset or in a more challenging model of advanced disease resulted in:

• Sustained increases in Mybpc3 RNA and MYBPC3 protein expression
• Decreased cardiac biomarkers associated with fibrosis and heart failure
• Improved cardiac function, including improved ejection fraction and diastolic function
• Heart remodeling
• Extended survival
  

These results were dose dependent, with near-maximal efficacy achieved at doses of 3x10¹³ vg/kg, and durable, lasting out to 20 months post-treatment.

Additional experiments in human engineered heart tissue models that replicate the hypercontractility associated with MYBPC3-associated HCM demonstrated:

• Resolution of calcium handling abnormalities
• Enhanced diastolic activity

The complete article can be accessed at Nature Communications and within the Publications and Presentations section of Tenaya Therapeutics’ website.

About MYBPC3-Associated Hypertrophic Cardiomyopathy

Variants in the MYBPC3 gene are the most common genetic cause of hypertrophic cardiomyopathy (HCM), accounting for approximately 20% of the overall HCM population, or 120,000 patients, in the United States alone.⁽¹⁾ MYBPC3-associated HCM is a severe and progressive condition affecting adults, teens, children and infants. Mutations of the MYBPC3 gene result in insufficient expression of a protein, called MyBP-C, needed to regulate heart contraction. The heart becomes hypercontractile and the left ventricle thickens, resulting in symptoms such as chest pain, shortness of breath, palpitations and fainting. Patients whose disease is caused by MYBPC3 mutations are more likely than those with non-genetic forms of HCM to experience earlier disease onset and have high rates of serious outcomes, including heart failure symptoms, arrhythmias, stroke and sudden cardiac arrest or death.⁽²⁾ There are currently no approved therapeutics that address the underlying genetic cause of HCM.

About the MyPEAK-1 Phase 1b/2 Clinical Trial

The MyPEAK-1 Phase 1b/2 clinical trial (Clinicaltrials.gov ID: NCT05836259) is an ongoing, multi-center, open-label, dose-escalating study designed to assess the safety, tolerability and clinical efficacy of a one-time intravenous infusion of TN-201 gene replacement therapy. The trial is enrolling symptomatic (New York Heart Association Class II or III) adults who have been diagnosed with MYBPC3-associated HCM. MyPEAK-1 is testing doses of 3E13 vg/kg and 6E13 vg/kg in two cohorts of three patients each. MyPEAK-1 may enroll up to 24 MYBPC3-associated HCM adults with either nonobstructive or obstructive forms of HCM in planned dose expansion cohorts.

To learn more about gene therapy for HCM and participation in the MyPEAK-1 study, please visit HCMStudies.com.

About Tenaya Therapeutics
Tenaya Therapeutics is a clinical-stage biotechnology company committed to a bold mission: to discover, develop and deliver potentially curative therapies that address the underlying drivers of heart disease. Tenaya employs a suite of integrated internal capabilities, including modality agnostic target validation, capsid engineering and manufacturing, to generate a portfolio of genetic medicines aimed at the treatment of both rare genetic disorders and more prevalent heart conditions. Tenaya’s pipeline includes TN-201, a gene therapy for MYBPC3-associated hypertrophic cardiomyopathy (HCM), TN-401, a gene therapy for PKP2-associated arrhythmogenic right ventricular cardiomyopathy (ARVC), TN-301, a small molecule HDAC6 inhibitor intended for heart failure with preserved ejection fraction (HFpEF), and multiple early-stage programs in preclinical development.

⁽¹⁾ Sedaghat-Hemedani, et al., Clinical Research Cardiology, 2017
⁽²⁾ Ho, et al., Circulation 2018

Forward-Looking Statements

This press release contains forward-looking statements as that term is defined in Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Statements in this press release that are not purely historical are forward-looking statements. Words such as “potential,” “believe,” “look forward,” and similar expressions are intended to identify forward-looking statements. Such forward-looking statements include, among other things, the clinical, therapeutic and commercial potential of, and expectations regarding TN-201; the value of preclinical data to inform the potential of TN-201; the planned timing to report additional data from MyPEAK-1; statements regarding the continued development of TN-201; and statements made by Tenaya’s Senior Vice President of Research and Chief Medical Officer. The forward-looking statements contained herein are based upon Tenaya’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. These forward-looking statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, including but not limited to: the potential failure of TN-201 to demonstrate safety and/or efficacy in clinical testing; the potential for any MyPEAK-1 clinical trial results to differ from preclinical, interim, preliminary or expected results; availability of MyPEAK-1 data at the referenced times; the timing and progress of MyPEAK-1; Tenaya’s ability to enroll and maintain patients in clinical trials, including MyPEAK-1; risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics and operating as an early stage company; Tenaya’s continuing compliance with applicable legal and regulatory requirements; Tenaya’s ability to raise any additional funding it will need to continue to pursue its product development plans; Tenaya’s reliance on third parties; Tenaya’s manufacturing, commercialization and marketing capabilities and strategy; the loss of key scientific or management personnel; competition in the industry in which Tenaya operates; Tenaya’s ability to obtain and maintain intellectual property protection for its product candidates; general economic and market conditions; and other risks. Information regarding the foregoing and additional risks may be found in the section titled “Risk Factors” in Tenaya’s Annual Report on Form 10-K for the year ended December 31, 2024, and other documents that Tenaya files from time to time with the Securities and Exchange Commission. These forward-looking statements are made as of the date of this press release, and Tenaya assumes no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

Contact
Michelle Corral
Vice President, Investor Relations and Corporate Communications
Tenaya Therapeutics
IR@tenayathera.com

Investors
Anne-Marie Fields
Precision AQ (formerly Stern Investor Relations)
annemarie.fields@precisionaq.com

Media
Wendy Ryan
Ten Bridge Communications
wendy@tenbridgecommunications.com

FAQ

What are the key preclinical results for TNYA's TN-201 gene therapy?

TN-201 showed dose-dependent increases in MyBP-C protein, improved cardiac function, reversed left ventricular hypertrophy, and extended survival in mice models at doses as low as 1x10¹³ vg/kg.

What doses of TN-201 is TNYA testing in the MyPEAK-1 clinical trial?

Tenaya is evaluating TN-201 at doses of 3x10¹³ vg/kg and 6x10¹³ vg/kg in the Phase 1b/2 MyPEAK-1 clinical trial.

When will TNYA release the next clinical data for TN-201?

TNYA will present first cohort data at the upcoming American College of Cardiology Scientific Sessions and initial high-dose cohort data in H2 2025.

What disease does TNYA's TN-201 gene therapy target?

TN-201 targets MYBPC3-associated hypertrophic cardiomyopathy (HCM), the most common genetic cause of HCM.

How is TNYA's TN-201 gene therapy administered to patients?

TN-201 is administered as a single intravenous infusion using an AAV9-based delivery system to target heart muscle cells.