Tenaya Therapeutics presents clinical, preclinical data on TN-301 program

Tenaya Therapeutics released new data for TN-301 at the 2023 Heart Failure Society of America Annual Scientific Meeting. TN-301 is Tenaya’s highly selective small molecule inhibitor of histone deacetylase 6 being developed for the potential treatment of heart failure with preserved ejection fraction. Results from the Phase 1 clinical trial of TN-301 were presented in an ePoster, Phase 1 Clinical Trial Of TN-301, A Highly Selective HDAC6 Inhibitor with Potential in HFpEF, Shows Target Engagement. Tenaya initiated the randomized, double-blind, placebo-controlled Phase 1 clinical trial in September 2022 to assess the safety and tolerability of escalating, oral doses of TN-301, as well as pharmacokinetics and pharmacodynamics measures. The Phase 1 trial enrolled a total of 72 healthy adult participants in two stages. In Stage 1, participants received single ascending doses of either TN-301 at doses ranging from 1mg – 700mg or placebo. Tubulin acetylation was previously established as a relevant PD marker of HDAC6 inhibition in preclinical studies and utilized in the Phase 1 clinical trial to confirm target engagement. Upon achieving evidence of target engagement at single doses of 5mg, participants were enrolled in Stage 2 and received multiple ascending doses of TN-301 at once daily doses of 25mg, 100mg and 300mg for 14 days. Key Findings: TN-301 was generally well tolerated across the broad range of doses studied, with no dose-limiting toxicities or serious adverse events observed. The most common adverse events observed were related to gastrointestinal disturbances. These occurred with similar frequency among those who received placebo or TN-301 and did not increase with TN-301 dose. All participants completed the study. PK results showed overall dose proportionality in both the SAD and MAD stages of the study with a half-life supportive of once-daily dosing. Robust HDAC6 inhibition was observed and increasing doses and exposures with TN-301 correlated with increasing PD effects. Plasma exposure and target engagement observed in this healthy participant study met or exceeded those required for maximal efficacy in preclinical studies. There were no changes in histone acetylation with TN-301, underscoring the selectivity of TN-301 for HDAC6 and potentially reducing the risk of off target effects observed with less selective HDAC6 inhibitors or pan-HDAC inhibition. Future studies of TN-301 in HFpEF patients may evaluate a range of doses starting at approximately 25 mg and higher. The ePoster titled, Co-Administration of Inhibitors of HDAC6 and SGLT2 in Murine HFpEF Models Results in Additive Improvements in Cardiac Structural and Functional Measures, describes an effort by Tenaya researchers to examine the effect of combining TYA-018 with empagliflozin in the company’s proprietary HFpEF mouse model. This study compared healthy controls with those treated with TYA-018 and empagliflozin administered alone or in combination vs. untreated HFpEF mice. Key findings: Evidence of additive benefits at or nearing that of healthy controls were observed in all treatment groups at eight weeks, but more substantially with combination treatment, across multiple measures of diastolic function without negative consequences to ejection fraction. At a gene level, an extensive reversal of disease toward healthy controls was observed in TYA-018 and combination groups, but less so in the empagliflozin group. A gene set enrichment analysis of pathway and functional level HFpEF changes provided insights on the distinct impact of HDAC6 inhibition on disease pathophysiology compared to SGLT2 inhibition, with TYA-018 demonstrating a greater impact on improving metabolism, oxidative stress and inflammation.