Phase 1 Clinical Trial of TN-301, A Highly Selective HDAC6 Inhibitor with Potential in HFPEF, Shows Target Engagement

Introduction TN-301 is a highly selective, orally available histone deacetylase 6 (HDAC6) inhibitor being developed for the potential treatment of heart failure with preserved ejection fraction (HFpEF). Studies in preclinical models show reversal of HFpEF disease by selective HDAC6 inhibition. This First-in-Human (FiH) Phase 1 clinical trial evaluates the safety and biological activity of TN-301 at a broad range of single doses and multiple daily doses over 2 weeks in healthy adult participants. Hypothesis Multiple preclinical models of HFpEF suggest that selective HDAC6 inhibition has direct and systemic effects on multiple pathways linked to HFpEF pathogenesis, including mitochondrial dysfunction, fibrosis and inflammation, while avoiding undesirable effects of non-selective HDAC inhibitors. This FiH study is designed to identify a dose range for further development and to demonstrate potential clinical utility through use of relevant biomarkers. Methods The double-blinded, randomized clinical trial plans to enroll 72 participants in 6 single-ascending dose (SAD) and 3 multiple-ascending dose (MAD) cohorts, each comprised of 8 participants (6 active, 2 placebo). MAD cohorts are dosed once daily for 14 consecutive days. Endpoints include safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) assessments. A key PD biomarker of HDAC6 inhibition is the level of acetylated tubulin in PMBCs. Results Comprehensive synthesis of unblinded safety, tolerability, PK, and PD results, including additional planned cohorts, are anticipated by the time of presentation. As of the submission of this abstract, 48 participants have been randomized into the SAD stage and received TN-301 or placebo per protocol at oral doses from 1-700mg. An additional 16 participants have been treated in 2 MAD cohorts at 25mg and 100mg. Among these participants, there were no SAEs, DLTs or premature withdrawals due to tolerability. Interim analysis showed a slightly more than dose-proportional PK profile with a half-life consistent with once-daily dosing. Plasma concentrations were attained that corresponded with those observed in mouse models that demonstrated robust PD affects and reversal of HFpEF phenotype. Target engagement was demonstrated at doses >5mg and was sustained above baseline throughout the dosing interval in the MAD cohorts at steady state. Conclusion Initial data from this FiH clinical trial of TN-301 in healthy adult participants demonstrated clear evidence of target engagement. To date, TN-301 has been generally well tolerated with PK consistent with once-daily dosing. TN-301 represents a promising new therapeutic candidate for the potential treatment of HFpEF and other indications.