Tenaya Therapeutics, Inc. announced that the U.S. Food and Drug Administration has provided clearance of its Investigational New Drug application to initiate clinical testing of TN-201. In addition, Tenaya shared anticipated 2023 program milestones and updated cash runway guidance. Tenaya received notification from the FDA indicating that, following review of the company's IND package, clinical testing of TN-201 may proceed.

TN-201 is Tenaya's first-in-class adeno-associated virus (AAV)-based investigational gene therapy product candidate for the treatment of hypertrophic cardiomyopathy (HCM) caused by mutations in the MYBPC3 gene, the most common genetic cause of HCM. TN-201 is designed to deliver a fully functional MYBPC3 gene to restore normal levels of MYBPC3 protein and thereby potentially halt disease progression and reverse the course of genetic HCM after a single treatment. The TN-201 Phase 1b clinical trial is a multi-center, open-label study to assess the safety, tolerability and clinical efficacy of a one-time intravenous infusion of TN-201.

The trial will seek to enroll at least six symptomatic (New York Heart Association class II or III) adults who have been diagnosed with MYBPC3-associated nonobstructive HCM and have an implantable cardioverter defibrillator. The trial protocol includes assessments of safety, markers of cardiac transduction and transgene expression in right ventricular biopsy samples, changes in circulating cardiac biomarkers, imaging biomarkers relevant to HCM as measured by echocardiogram and changes in exercise capacity, symptom burden and quality of life. Tenaya expects to assess two dose levels of TN-201, starting with 3E13 vg/kg, a dose associated with near-maximal efficacy in preclinical studies.

An independent safety review following the initial cohort will inform plans for dose escalation to 6E13 vg/kg, as needed, and/or enrollment of additional patients in the initial cohort. 2023 Anticipated Milestones and Recent Progress TN-201 – MYBPC3Gene Therapy Program for Genetic Hypertrophic Cardiomyopathy (HCM) Tenaya is conducting two non-interventional studies to support the development of TN-201: a study evaluating seroprevalence to AAV9 antibodies among adults with MYBPC3-associated HCM, and MyClimb, a natural history study of pediatric patients with MYBPC3-associated HCM for which the company has activated more than 15 sites in the U.S. and Europe and enrolled more than 80 subjects. Tenaya has produced sufficient clinical trial material at the company's Genetic Medicines Manufacturing Center to support the entire anticipated enrollment in the Phase 1b clinical trial.

Tenaya anticipates dosing the first patient in the Phase 1b clinical trial of TN-201 in the third quarter 2023. Initial data from the TN-201 Phase 1b clinical trial is anticipated in 2024. TN-301 – Small Molecule HDAC6 Inhibitor for Heart Failure with Preserved Ejection Fraction (HFpEF) Tenaya is conducting a Phase 1 clinical trial designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics, including target engagement, of escalating oral doses of TN-301, a highly selective small molecule inhibitor of HDAC6 being developed for the potential treatment of HFpEF.

The Phase 1 clinical trial began dosing healthy adult participants in September 2022 with single ascending doses (SAD) of TN-301 or a placebo. To date, no dose-limiting toxicities have been observed in the ongoing SAD portion of the study. Initial target engagement, measured by the biomarker of tubulin acetylation, has been achieved.

In preclinical studies, dose dependent tubulin acetylation measured in circulating blood cells was found to correlate to levels in the heart. The company expects to commence dosing in the multiple-ascending dose (MAD) stage of the Phase 1 trial in the first quarter 2023. Tenaya plans to present clinical data from both the SAD and MAD stages of the Phase 1 clinical trial in the second half 2023.

The company expects to also present additional preclinical data supporting the efficacy of TN-301, the mechanism of action (MOA) of HDAC6 inhibition, and comparisons with SGLT2 inhibitors at major conferences in 2023. TN-401 – PKP2Gene Therapy Program for Genetic Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Tenaya is preparing for the submission of an IND for TN-401, the company's second gene therapy candidate, being developed for the treatment of genetic ARVC. TN-401 IND-enabling studies and process development for manufacturing are currently underway.

Tenaya has initiated a global non-interventional study to collect treatment history and seroprevalence to AAV9 antibodies data among ARVC PKP2 gene mutation carriers. Tenaya plans to submit an IND application to the FDA in the second half 2023 to enable clinical development of TN-401. Clinical supply of TN-401 will be produced at Tenaya's cGMP Genetic Medicines Manufacturing Center to support the IND filing.

These efforts leverage significant learnings from related nonclinical, regulatory, clinical and manufacturing efforts for TN-201. Early-stage Research Efforts Tenaya plans to present and publish new preclinical data related to its research on new targets, novel AAV capsid engineering efforts and manufacturing process improvements throughout 2023. Tenaya continues to conduct research on numerous promising targets for potential therapeutic utility and is also pursuing platform enhancements that may further the company's ability to deliver on its mission of discovering and developing disease-modifying medicines for heart disease.