As Duchenne muscular dystrophy (DMD) progresses, degeneration extends beyond skeletal muscle to involve the heart, leading to dilated cardiomyopathy, a major contributor to morbidity and mortality in DMD. Tenaya developed TN-301, a potent and highly selective HDAC6 inhibitor, which reverses measures of cardiomyopathy and diastolic dysfunction in mouse models of genetic cardiomyopathy and heart failure with preserved ejection fraction. TN-301 exhibits a multi-modal mechanism of action, including reducing inflammation, fibrosis and mitochondrial dysregulation. In a Phase 1 study in healthy adults, TN-301 did not demonstrate serious adverse events or dose limiting toxicities over a wide dose range after single or 14 days of oral dosing. HDAC6 inhibition was demonstrated in peripheral blood mononuclear cells and half-life supports once daily dosing.
Given preclinical and clinical evidence that HDAC inhibition can slow skeletal muscle decline in DMD, including the approval of a pan-HDAC inhibitor, givinostat, Tenaya hypothesized that TN-301 might delay or reverse both skeletal muscle pathology and cardiomyopathy in DMD. While givinostat has been shown to slow skeletal muscle decline, its use is limited by side effects including thrombocytopenia and QT prolongation risk – liabilities not observed clinically in a Ph1 study in healthy adults with TN-301 after oral dosing. Moreover, evidence of benefits of givinostat in DMD cardiomyopathy is lacking.
To test this hypothesis, Tenaya conducted a study in mdx mice comparing the effects of TN-301 and 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 and favorable changes in skeletal muscle histology and gene expression.
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. Ongoing studies are evaluating TN-301 in rodent models of DMD cardiomyopathy.
Together, these data support advancement of TN-301 as a potential DMD therapy with benefits for both skeletal and cardiac muscle and reduced liabilities compared to pan-HDAC inhibitors.