Tenaya Therapeutics presented encouraging preclinical data evaluating TN-301, the company’s highly selective HDAC6 inhibitor, at the Muscular Dystrophy Association’s Clinical & Scientific Conference 2026 (MDA 2026). In in vitro and in vivo models of Duchenne muscular dystrophy (DMD), TN-301 improved muscle performance and corrected key drivers of DMD cardiomyopathy.
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TN-301 is Tenaya’s potent and highly selective small molecule HDAC6 inhibitor with a multi-modal mechanism of action, including reducing inflammation, metabolic and mitochondrial dysregulation and fibrosis, and improving autophagy, which may have potential benefit in rare or prevalent cardiac, metabolic, muscle and pulmonary diseases. In a Phase 1 safety study in healthy adults, TN-301 was generally well tolerated over a wide dose range and did not demonstrate serious adverse events or dose-limiting toxicities. Based on this profile, Tenaya has identified several potential indications of interest, supported by the company’s previously published preclinical results in heart failure with preserved ejection fraction (HFpEF) and genetic dilated cardiomyopathy.
DMD Cardiomyopathy and Muscle Degeneration
Today’s presentation at MDA 2026 adds to this body of research, highlighting TN-301’s potential in DMD cardiomyopathy and muscle degeneration. Tenaya plans to advance TN-301 toward clinical studies in patients, with HFpEF and DMD being among the most promising potential indications identified to date.
“DMD-related cardiomyopathy is the most common cause of death among individuals with DMD, and despite advances in care, there is a profound unmet need for treatments that can address both skeletal muscle atrophy and cardiac decline,” said Kathy Ivey, Ph.D., Senior Vice President, Research of Tenaya Therapeutics. “Recognizing that many of the drivers of DMD-related cardiomyopathy and skeletal muscle degeneration corresponded to TN-301’s multi-modal mechanism of action, we conducted a series of studies and found that TN-301 outperformed the approved agent, givinostat, achieving functional improvements in mdx mice that restored muscle performance to wild-type levels while also correcting key DMD-associated cardiomyocyte defects.”
The pan HDAC inhibitor, givinostat, is approved in the U.S. and EU for the treatment of DMD and has been shown to slow skeletal muscle decline in DMD patients as demonstrated clinically by the 4 Stair Climb (4SC) and North Star Ambulatory Assessment (NSAA). However, its use is limited by side effects including thrombocytopenia, and by QT prolongation risk – liabilities not observed clinically in the Phase 1 study of TN-301. To test the hypothesis that TN-301 may delay or reverse both skeletal muscle pathology and cardiomyopathy in DMD, Tenaya researchers conducted studies comparing TN-301 with givinostat. Key findings presented at MDA 2026 include:
TN-301 Vs. Givinostat
- TN-301 treatment at doses as low as 3 mg/kg improved grip strength to wild-type levels within five weeks, whereas mdx mice treated with givinostat (10 mg/kg, approximating clinical exposures) failed to reach wild-type performance.
- TN-301-mediated functional improvements were accompanied by reductions in circulating creatine kinase activity and favorable changes in gene expression, indicating reduced muscle cell injury.
- In cardiomyocytes derived from human DMD induced pluripotent stem cells, TN-301 corrected calcium handling abnormalities and mitochondrial dysfunction, while givinostat exacerbated these established drivers of DMD cardiomyopathy.
These positive preclinical data – as well as data from others using HDAC6 inhibitors in DMD disease models – collectively suggest that HDAC6 inhibition may be substantially driving the benefits observed to date with pan-HDAC inhibitors in DMD clinical studies.
What is TN-301?
TN-301 is Tenaya’s highly specific small molecule histone deacetylase (HDAC) 6 inhibitor, which has demonstrated promising preclinical potential for the treatment of heart failure with preserved ejection fraction (HFpEF) and Duchenne muscular dystrophy (DMD).
In a Phase 1 clinical trial of healthy volunteers, TN-301 was generally well tolerated across the broad range of doses studied, with dose-responsive pharmacokinetics and a half-life supportive of once-daily dosing. Notably, there were no changes in histone acetylation with TN-301, underscoring the >3000-fold selectivity of TN-301 for HDAC6 over other HDACs and supporting the potential to avoid the off-target effects observed with less selective HDAC6 or pan-HDAC inhibition.
HDAC6 inhibition exerts its benefits on the heart and other organs in the body by modifying cytoskeletal and other proteins to coordinate cellular processes through a multi-modal mechanism of action.
In preclinical studies, Tenaya’s HDAC6 inhibitors have been shown to reduce inflammation, oxidative stress, fibrosis, and metabolic dysregulation, as well as improve autophagy, protein quality control, mitochondrial metabolism, and lipid metabolism. Tenaya is committed to exploring opportunities to advance TN-301 into clinical studies of patients with cardiac, metabolic, muscular or pulmonary disorders where there is strong alignment between the activity of HDAC6 inhibition and the pathophysiology of disease.
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