Announcement • May 16
Tenaya Therapeutics Presents Interim Data From Ridge-1 Phase 1b/2 Clinical Trial Of TN-401 Gene Therapy For PKP2-Associated ARVC
Tenaya Therapeutics, Inc. presented interim data from the ongoing RIDGE-1 Phase 1b/2 clinical trial of TN-401 gene therapy at the American Society of Gene and Cell Therapies 2026 Annual Meeting. In adults with arrhythmogenic right ventricular cardiomyopathy (ARVC), caused by mutations in the plakophilin-2 (PKP2) gene, treatment with a single infusion of TN-401 at either the 3E13 vg/kg (Cohort 1) or 6E13 vg/kg (Cohort 2) dose resulted in consistent and deep reductions in premature ventricular contractions (PVCs) in all six Cohort 1 and 2 patients. TN-401 was well tolerated at both dose levels, and post-dose biopsies provided evidence of robust transduction and TN-401-specific expression for the first five patients for whom data was available at the time of cut off. The dose-escalating RIDGE-1 clinical trial is designed to assess the safety, tolerability and activity of a one-time dose of TN-401 gene therapy. Data reported include electrophysiology, biopsy and safety results from a total of six patients who received a single infusion of TN-401 at a dose of 3E13vg/kg or 6E13vg/kg. As of the April 2026 data cut off, available follow up included assessments out to 20-52 weeks post-dose. Two additional patients have subsequently been dosed in the 6E13 vg/kg expansion cohort and will be included in future RIDGE-1 readouts. Electrophysiology data was collected at regular time intervals post-treatment using an ambulatory monitoring device worn for seven days. Exploratory endpoints, including electrocardiographic (ECG) changes, heart structure and function, and symptom burden were also collected as part of the RIDGE-1 trial. Treatment with TN-401 resulted in dramatic improvements in electrical stability, as measured by PVCs and non-sustained ventricular tachycardias (NSVTs). All six patients demonstrated meaningful reductions in arrhythmia burden as measured by PVCs, with a mean reduction of 60% for Cohort 1 and 67% for Cohort 2. Two patients with a high rate of NSVTs at baseline experienced substantial decreases, apparent as early as Week 20. Patient 2 had a NSVT burden of 78 counts per 24-hours, which dropped to zero and remained stable at Week 52. At baseline, Patient 5 had a NSVT count of 43 per 24 hours, which dropped to 4 per 24 hours at Week 20. Four patients had low NSVT burden at baseline and remained low. PVC COUNT Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 At screening 2,462 618 2,666 1,571 7,819 8,634 Most recent assessment 1,707 99 1,518 1,064 1,412 2,543 Percent change -31% -84% -43% -32% -82% -71%. Other measures of clinical response including ECG changes (QRS duration and T wave inversions), heart structure and function and New York Heart Association (NYHA) class were in the normal range or remained stable during the post-dose follow-up period. Biopsy samples were collected from the right ventricular septum at eight weeks for the first four patients and at 22 weeks for Patient 5, with results from 52-week biopsies available for Cohort 1 patients. Biopsy sample analysis from Patient 6 was not completed as of the data cut off. The totality of the biopsy data provides evidence that TN-401 is being transduced within the heart muscle cells, achieving transcription into messenger RNA and resulting in PKP2 protein. Mean TN-401 DNA levels were 3.4 vg/dg and 3.8 vg/dg in Cohorts 1 and 2, respectively. These levels were measured as early as 8 weeks post dose. At Week 8 for the first four patients, TN-401 mRNA expression ranged from 1.0E+04 - 2.9E+05 copies per microgram TN-401 mRNA was 7.1E+04 at Week 22 for Patient 5. Measures of PKP2 protein levels in heart muscle cells from baseline to the most recent timepoints ranged from -4% to +15% as measured by liquid chromatography mass spectrometry normalized to myosin heavy chain, a sarcomere protein only found in cardiomyocytes. Measurements of PKP2 protein levels are impacted by the varied composition of cardiac tissue in an ARVC heart. Safety is monitored throughout the RIDGE-1 trial, including one-week of inpatient observation and close monitoring of lab values throughout post-dose immunosuppressive tapering. As of the April data cut, all patients have successfully tapered off immunosuppressives. TN-401 has been generally well tolerated at both doses. The prophylactic immune suppression regimen of sirolimus and prednisone successfully managed immune responses, with similar dosing and duration of immunosuppressive medications utilized at both dose levels. Adverse events (AEs) associated with TN-401 treatment were asymptomatic and self-resolved or responded to treatment. The most frequent AEs attributed to TN-401 were transient elevations in troponins and/or transaminase. Among these, there was a Grade 3 liver enzyme elevation in Cohort 2 due to a medication error and interruption to steroid treatment. There was no clinical thrombotic microangiopathy (TMA), no ventricular arrhythmias related to TN-401, and no other cardiotoxicities associated with TN-401. All patients remain on study and no dose-limiting toxicities have occurred. The independent Data Safety Monitoring Board endorsed continuing the expansion portion of the study as planned. The European Medicines Agency (EMA) has granted TN-401 PRIority MEdicine (PRIME) designation. The designation recognizes the potential of TN-401 to address significant unmet medical needs in patients with PKP2-associated ARVC. The PRIME program enables the EMA to offer early and proactive support to sponsors in an effort to optimize the generation of robust safety and efficacy data in order to accelerate assessment of medicines applications.
