Tenaya Therapeutics Releases Preclinical Data in Scientific Translational Medicine Detailing Discovery of HDAC6 Inhibitor for Treatment of Heart Failure

Tenaya Therapeutics, Inc.

Tenaya’s Precision Medicine Platform Used to Identify HDAC6 Target Using Phenotypic Screening and Machine Learning Algorithms

Tenaya TN-301’s HDAC6 Inhibitor Proceeds to Clinic for HFpEF, with IND Filing on Track for 2H 2022

SOUTH SAN FRANCISCO, Calif., July 06 10, 2022 (GLOBE NEWSWIRE) — Tenaya Therapeutics, Inc. (NASDAQ: TNYA), a biotechnology company whose mission is to discover, develop and deliver curative therapies that address the underlying causes of heart disease, the publication announced. of preclinical research in the July 6 issue of Science Translational Medicine. The article, titled “Phenotypic screening with deep learning identifies HDAC6 inhibitors as cardioprotective in a BAG3 mouse model of dilated cardiomyopathy,” describes the discovery of histone deacetylase 6 (HDAC6) as a promising therapeutic target. This insight led to the development of the company’s lead small molecule candidate, TN-301, a highly selective HDAC6 inhibitor originally developed for the potential treatment of heart failure with preserved ejection fraction (HFpEF).

“While cardiovascular disease remains the leading cause of death worldwide, innovation in therapeutic discovery has suffered from the challenge of identifying targets with validation in human tissues that can attack the mechanisms underlying the diseases. The success of our approach using human cell-based disease models together with machine learning algorithms to discover promising new therapeutic targets for heart disease gives reason to believe that this methodology may be broadly applicable to the ‘accelerating the target and drug discovery of other disease-modifying therapies,” said Timothy Hoey, Ph.D., Chief Scientific Officer of Tenaya Therapeutics. “The research presented in this article highlights the selectivity targeted and exquisite cardioprotective qualities of our HDAC6 inhibitors. We look forward to advancing TN-301, the first product candidate in our pipeline to be discovered and validated using this approach, in clinical studies.”

Main research results
The publication in Science Translational Medicine Details Tenaya’s precision medicine platform’s distinct approach of applying phenotypic screening and deep learning to human pluripotent stem cell (iPSC-CM)-derived cardiomyocyte disease models. Tenaya has developed and validated a BAG3 knockdown human iPSC-CM model of Dilated Cardiomyopathy (DCM), a genetic cardiomyopathy that can lead to an enlarged heart and heart failure in humans, for target identification and screening new candidates for cardiovascular diseases. In BAG3-deficient human iPSC-CM models, inhibition of HDAC6 has been shown to protect against damage to the sarcomere, one of the basic building blocks of cardiac muscle present in all cardiomyocyte cells. Tenaya then developed a series of novel HDAC6 inhibitors through medicinal chemistry efforts that include TYA-018 and TN-301, which are structurally and functionally similar. TYA-018 is used in preclinical studies of Tenaya in vitro and live studies on HDAC6 inhibition, while TN-301 is undergoing clinical studies.

To further validate the inhibition potential of HDAC6, Tenaya translated his first in vitro results to a BAG3 cardiomyocyte knockout mouse model of DCM. BAG3 loss-of-function mutations have been linked to DCM and, in preclinical animal models, result in a steady loss of heart function leading to death from heart failure that mimics the progressive decline seen in human disease, providing a relevant model by which to study the results of the targeted intervention.

When assessed in a BAG3 knockout mouse model of DCM, HDAC6 inhibition with TYA-018:

  • Highly selective enzyme inhibition demonstrated, with over 2500-fold preference for HDAC6 over other HDAC family members

  • Reduced sarcomeric damage, improved cardiac dilation and conferred protection of left ventricular function against rapidly progressive decline.

  • Improved cardiac energetics, mitochondrial membrane potential and reserve respiratory capacity, which contribute to the maintenance of improved cardiac function.

To study the mechanism of action of HDAC6 inhibition in these in in vitro and in long live DCM models provided additional insights which later led to the finding that HDAC6 inhibition can be highly effective in the setting of HFpEF with a multi-model mechanism of action. Based on extensive preclinical evaluation, Tenaya will seek to initially develop TN-301 for the potential treatment of HFpEF. Tenaya is on track to submit an Investigational New Drug (IND) application to the United States Food and Drug Administration (FDA) in the second half of 2022.

About TN-301 and HFpEF
TN-301 is a highly specific small molecule HDAC6 inhibitor originally developed for the potential treatment of HFpEF. HFpEF accounts for about 50% of all heart failure, but there are few proven treatment options. This disease involves systemic inflammation, left ventricular hypertrophy, fibrosis, and diastolic dysfunction resulting in high morbidity and mortality in those affected. In preclinical studies, TN-301 has been shown to have a multimodal mechanism of action and to reverse many signs and symptoms of HFpEF in several relevant models, with evidence of reduced inflammation and fibrosis, overall improvement in metabolism and improvements. in left ventricular function and diastolic filling and pressures. Tenaya plans to submit an IND application to study TN-301 in human clinical studies to the FDA in the second half of 2022.

About Tenaya Precision Medicine Platform
Tenaya’s precision medicine platform uses human iPSC-CMs as proprietary disease models combined with the analysis of human genetics and the use of machine learning algorithms for the identification of new targets, validation of known targets and high throughput screening for drug discovery. This platform is intended to overcome the shortcomings of traditional drug development efforts that rely more on knowledge from animal models to identify targets and develop therapies for human heart disease. This platform has potentially broad utility for identifying targets and therapies in a modality-independent manner – including gene therapy, small molecules and biologics – for genetic and non-genetic forms of heart disease. .

About Tenaya Therapeutics
Tenaya Therapeutics is a biotechnology company committed to a bold mission: to discover, develop and deliver curative therapies that address the underlying drivers of heart disease. Founded by leading cardiovascular scientists from the Gladstone Institutes and the University of Texas Southwestern Medical Center, Tenaya develops therapies for rare genetic cardiovascular disorders, as well as more prevalent heart diseases, through three distinct but interdependent products: gene therapy, cell regeneration and precision medicine. For more information, visit www.tenayatherapeutics.com.

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 statements are forward-looking statements. Words such as “looking into the future”, “believe”, “will”, “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements include, among others, Tenaya’s clinical development plans for TN-301; the therapeutic potential of TN-301 as a treatment for HFpEF; expectations regarding the timing of IND filing for TN-301 and the broad potential of Tenaya’s precision medicine platform for identifying targets and therapies. The forward-looking statements contained herein are based on 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 timing, scope and likelihood of regulatory filings and approvals; the timing, progress and results of clinical studies for TN-301; the possibility that results of a clinical trial will differ from preclinical, interim, preliminary, primary or expected results; risks associated with the process of discovering, developing and commercializing safe and effective drugs for human therapeutic use and operating as a start-up company; Tenaya’s ability to develop, initiate or complete preclinical studies and clinical trials, and obtain approvals, for any of its product candidates; Tenaya’s ability to raise any additional financing it needs to pursue its business and product development plans; adverse impacts of the COVID-19 pandemic on Tenaya’s manufacturing and operations, including preclinical studies and planned clinical trials; Tenaya’s dependence on third parties; Tenaya’s sales and marketing capabilities and strategy; 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 can be found in the section titled “Risk Factors” in documents 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 undertakes no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except if required by law.

michelle corral
Vice President, Investor Relations and Corporate Communications
Therapeutic Tenaya
[email protected]

wendy ryan
Ten-bridge communications
[email protected]

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