Tenaya Therapeutics announces publication of preclinical HDAC6 inhibitor data

Tenaya Therapeutics announced the publication of preclinical research related to Tenaya’s small molecule inhibitors of histone deacetylase 6, 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, a form of heart failure that effects more than three million people in the U.S. alone. 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 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 participants. 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 cardiomyopathy, researchers set out to assess the potential of HDAC6 inhibition in HFpEF using multiple models of HFpEF, including a proprietary high fat diet and moderate transverse aortic constriction murine model that replicated the metabolic and mechanical stress seen in patients with HFpEF. For preclinical studies, Tenaya researchers used TYA-018, an HDAC6 inhibitor structurally and functionally similar to the company’s clinical candidate, TN-301. Key Findings Treatment with TYA-018 as a single agent resulted in direct effects on the heart, and systemic benefits. TYA-018 showed comparable benefit to empagliflozin in the murine HFpEF model. Gene expression analysis provided insights on TYA-018’s distinct mechanism of action. HDAC6 inhibition was shown to restore hypertrophy, fibrosis and mitochondrial energy production. TYA-018 demonstrated greater impact on markers of oxidative stress, inflammation and metabolism as compared to SGLT2 inhibition. The combination of TYA-018 and empagliflozin resulted in additive benefits, exceeding the efficacy observed with either agent alone with measurements of cardiac function nearing that of healthy controls. The selective effects of HDAC6 inhibition were reaffirmed through genetic deletion studies, in which treatment of Hdac6 knockout mice did not display any of the beneficial effects that wild-type HFpEF mice did following treatment.