Tenaya Therapeutics, Inc. announced the publication of preclinical research related to Tenaya's small molecule inhibitors of histone deacetylase 6 (HDAC6), including TN-301, in the February 26, 2024, issue of Nature Communications. The article, titled " Targeting HDAC6 to Treat Heart Failure with Preserved Ejection Fraction in Mice," details the potential of inhibiting HDAC6 for the treatment of Heart failure with preserved ejection fraction (HFpEF), a form of heart failure that effects more than three million people in the U.S. alone1. The extensive body of preclinical research described in Nature Communications showed that inhibition of HDAC6: Successfully addressed many of the biologic hallmarks of HFpEF, with direct effects on the heart such as diastolic relaxation and systemic benefits including normalization of metabolic and inflammatory factors, in a preclinical murine model that replicates the HFpEF disease state.

Achieved comparable or superior efficacy and was shown to have a distinctive multi-modal mechanism of action versus empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor approved by the U.S. Food and Drug Administration as a treatment for HFpEF. Showed additive benefits when combined with empagliflozin compared to either agent alone, indicating the potential for the use of a small molecule HDAC6 inhibitor alone or as a combination therapy for the treatment of HFpEF. Last year, Tenaya completed a Phase 1 clinical trial in which TN-301 achieved encouraging safety, target engagement and pharmacokinetic results across a wide range of doses tested in healthy participants2.

Tenaya's highly selective small molecule inhibitors of the enzyme HDAC6 were discovered using the company's modality-agnostic 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 was identified as a reliable plasma biomarker of HDAC6 target engagement. Having previously reported on the cardioprotective qualities of HDAC6 inhibition in a model of genetic cardiomyopathy3, researchers set out to assess the potential of HDAC6 inhibition in HFpEF using multiple models of HFpEF, including a proprietary high fat diet (HFD) and moderate transverse aortic constriction (mTAC) murine model that replicated the metabolic and mechanical stress seen in patients with HFpEF.

For preclinical studies, TN-301 has been shown to reverse many of the signs and symptoms of HFpEF, with evidence of improved cardiac function and improved glucose tolerance and reduced inflammation and fibrosis. Tenaya has completed a dose escalating Phase 1 clinical trial of TN-301 in healthy participants. TN-301 was well tolerated across a broad dose range with dose-proportional pharmacokinetics supportive of once-daily dosing and target engagement observed.

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-301 to demonstrate safety and/or efficacy in clinical testing; unexpected concerns that may arise as a result of the occurrence of adverse safety events or additional data analyses of clinical trials evaluating TN-301, both alone or in combination with other therapies; the timing, scope and likelihood of regulatory filings and approvals for TN-301; risks associated with the process of discovering, developing and commercializing the HDAC6 inhibitor.