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Highly selective small molecule HDAC6 inhibitor effectively reverses heart failure and heart failure Improving diastolic cardiac function alone or in combination SGLT2 inhibitors in mouse disease models

SOUTH SAN FRANCISCO, Calif., Feb. 26, 2024 (Globe Newswire) — Tenaya Therapeutics, Inc. (NASDAQ: TNYA) is a clinical-stage biotechnology company that discovers potential curative therapies to address problems, Our mission is to develop and provide. Tenaya, which researches the root causes of heart disease, today announced preclinical research related to his Tenaya small molecule inhibitors of histone deacetylase 6 (HDAC6), including TN-301, in the journal February 26, 2024. It was announced that it would be published in the Japanese issue. nature communications. Article titled “”Targeting HDAC6 to maintain ejection fraction and treat heart failure in mice” details the potential of HDAC6 inhibition in the treatment of heart failure with preserved ejection fraction (HFpEF), a type of heart failure that affects more than 3 million people in the United States alone.1.

Extensive preclinical studies described in nature communications showed inhibition of HDAC6.

  • In preclinical mouse models that recapitulate the pathology of HFpEF, many of the biological features of HFpEF, with direct effects on the heart such as diastolic relaxation, and systemic effects such as normalization of metabolic and inflammatory factors, have been demonstrated. succeeded in dealing with it.

  • Compared to empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor approved by the U.S. Food and Drug Administration for the treatment of HFpEF, it achieved similar or superior efficacy and a unique multimodal It has been shown to have a mechanism of action.

  • When used in combination with empagliflozin, additive benefits were shown compared to either drug alone, indicating the potential use of small molecule HDAC6 inhibitors, either alone or as combination therapy, in the treatment of HFpEF .

“With its combination of direct and systemic benefits on disease pathophysiology, HDAC6 inhibition shows great potential for the treatment of HFpEF, one of the greatest unmet needs in heart disease therapy.” said Dr. Tim Hoey, Chief Scientific Officer at Tenaya. . “Our extensive preclinical package is detailed in our latest publication. nature communicationsTogether with encouraging data from the TN-301 Phase 1 study, this provides a strong rationale for Tenaya’s HDAC6 inhibitor program as a promising treatment strategy for patients with HFpEF. ”

Last year, Tenaya completed a Phase 1 clinical trial in which TN-301 achieved promising safety, on-target engagement, and pharmacokinetic results across a wide range of doses tested in healthy participants. .2.

Tenaya’s highly selective small molecule inhibitors of the enzyme HDAC6 were discovered using the company’s modality-independent target discovery and validation capabilities. Unlike other members of the HDAC family, HDAC6 is localized to the cell cytoplasm, where it coordinates cellular processes through interactions with multiple substrates, including tubulin, and tubulin acetylation is associated with HDAC6. It has been identified as a reliable plasma biomarker of target binding.

We have previously reported on the cardioprotective properties of HDAC6 inhibition in a hereditary cardiomyopathy model.3Researchers used multiple models of HFpEF, including a unique high-fat diet (HFD) and moderate transverse aortic stenosis (mTAC) mouse model that mimicked the metabolic and mechanical stresses seen in HFpEF patients. We set out to evaluate the potential of HDAC6 inhibition in HFpEF. . In preclinical studies, Tenaya researchers used his HDAC6 inhibitor, TYA-018, which is structurally and functionally similar to the company’s clinical candidate TN-301.

Main findings

  • Treatment with TYA-018 as a single agent has both direct cardiac effects (reversal of diastolic and mitochondrial dysfunction, reduced hypertrophy, reduced fibroblast activation, and improved energy) and systemic effects. (improved exercise performance and glucose tolerance, and decreased inflammatory markers). ).

  • TYA-018 showed similar benefits to empagliflozin in the murine HFpEF model.

  • Gene expression analysis provided insight into the unique mode of action of TYA-018. Inhibition of HDAC6 was shown to restore hypertrophy, fibrosis, and mitochondrial energy production. TYA-018 demonstrated greater effects on markers of oxidative stress, inflammation, and metabolism compared to SGLT2 inhibition.

  • The combination of TYA-018 and empagliflozin provided additive benefits, exceeding the efficacy observed with either drug alone, with measures of cardiac function approaching that of healthy controls.

  • The selective effects of HDAC6 inhibition were reconfirmed through gene deletion studies, where treatment of Hdac6 knockout mice did not show the same beneficial effects that wild-type HFpEF mice showed after treatment.

About HFpEF and TN-301
Heart failure with preserved ejection fraction (HFpEF) is a common debilitating syndrome characterized by stiffness of the heart muscle that prevents the left ventricle from relaxing properly during normal heart rhythms, leading to diastolic dysfunction and will be called. There are several cellular processes that are thought to underlie the pathophysiology of HFpEF, including increased fibrosis and inflammation and metabolic defects. HFpEF accounts for approximately 50% of all heart failure hospitalizations in the United States;Fourthere are few proven treatments.

TN-301 is Tenaya’s highly specific, potential first-in-class, small molecule histone deacetylase (HDAC) 6 inhibitor originally developed for the treatment of HFpEF. TN-301 has a multimodal mode of action, including modifying the cytoskeleton and other proteins to modulate cellular processes. Preclinical studies have shown that TN-301 reverses many of the signs and symptoms of his HFpEF, with evidence of improved cardiac function, improved glucose tolerance, and reduced inflammation and fibrosis. Tenaya has completed a dose-escalation Phase 1 clinical trial of TN-301 in healthy participants. TN-301 was well tolerated over a wide dose range, with dose-proportional pharmacokinetics and target engagement observed supporting once-daily dosing.

About Tenaya Therapeutics
Tenaya Therapeutics is a clinical-stage biotechnology company on a bold mission to discover, develop and deliver potentially curative therapies that address the root causes of heart disease. The company leverages its integrated and interconnected gene therapy, cell regeneration, and precision medicine platforms and unique core capabilities to develop a diverse range of treatments for rare genetic cardiovascular diseases and more common heart diseases. The company is promoting a pipeline of new treatments. Tenaya’s most advanced candidates include the gene therapy drug TN-201. MYBPC3– Associated hypertrophic cardiomyopathy (HCM), TN-401, gene therapy PKP2TN-301, a small molecule HDAC6 inhibitor originally developed for arrhythmia-associated right ventricular cardiomyopathy (ARVC) and heart failure with preserved ejection fraction (HFpEF). Tenaya also has multiple early-stage programs in preclinical development. For more information, please visit www.tenayatherapeutics.com.

1. Tsao et al., Circulation 2023
2. Bexon et al., HFSA 2023
3. Yang et al., Sci Trans Med 2022
4. Shah et al., JACC 2017

Forward-looking statements

This press release contains forward-looking statements as 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 “may”, “promising” 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 TN-301 alone and/or in combination with emerging standard treatments for the treatment of HFpEF. The forward-looking statements contained herein are based on Tenaya’s current expectations and involve assumptions that may never materialize or prove to be inaccurate. These forward-looking statements are not promises or guarantees and are subject to various risks and uncertainties, including, but not limited to: the occurrence of adverse safety events or unanticipated concerns that may arise as a result of additional data analysis from clinical trials evaluating TN-301 alone or in combination with other treatments; the timing, scope and likelihood of regulatory filings and approvals for TN-301; 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 ability to develop, initiate or complete preclinical studies and clinical trials and obtain approval for its product candidates; Tenaya will continue to comply with applicable legal and regulatory requirements. Tenaya’s ability to obtain additional financing needed to continue advancing its business and product development plans; Tenaya relies on third parties. Tenaya’s manufacturing, commercialization and marketing capabilities and strategies; loss of key scientific or administrative personnel; competition in the industries 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 risks and additional risks is contained in the section entitled “Risk Factors” in Tenaya’s filings with the Securities and Exchange Commission from time to time. These forward-looking statements are made as of the date of this press release and, except as required by law, Tenaya does not believe that future forward-looking statements, whether as a result of new information, future events or otherwise, will We undertake no obligation to update or revise any forward-looking statements.

contact address

Michelle Corral
Vice President of Investor Relations and Corporate Communications
Tenaya Therapeutics
IR@TenayaThera.com

Investor
Annmarie Fields
Stern IR
AnneMarie.Fields@SternIR.com

media
wendy ryan
tenbridge communications
wendy@tenbridgeecommunications.com



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