Tenaya Therapeutics Reports Promising Early Results for TN-401 Gene Therapy in Rare Heart Disease
核心洞察
Tenaya Therapeutics announced positive interim data from the RIDGE-1 Phase 1b/2 trial of TN-401 gene therapy for PKP2 (搜索)-associated arrhythmogenic right ventricular cardiomyopathy (搜索) (ARVC).
The therapy demonstrated a favorable safety profile at the 3E13 vg/kg dose with no dose-limiting toxicities and showed robust transduction with increased PKP2 (搜索) protein levels in two of three patients.
Clinically meaningful reductions in arrhythmia burden were observed, with PVC counts decreasing by 46% and 89% in the first two patients with over six months of follow-up.
Tenaya Therapeutics has reported encouraging interim results from its RIDGE-1 Phase 1b/2 clinical trial evaluating TN-401, an investigational AAV9-based gene therapy for adults with PKP2 (搜索)-associated arrhythmogenic right ventricular cardiomyopathy (搜索) (ARVC). The data, announced December 11, 2025, demonstrate a promising safety profile and early evidence of clinical benefit in the first cohort of patients.
Safety Profile and Tolerability
TN-401 was well tolerated at the 3E13 vg/kg dose level across three patients in Cohort 1, with no dose-limiting toxicities observed. Adverse events were generally mild, asymptomatic and manageable, and deemed unrelated to TN-401 treatment. Among treatment-related adverse events, there was one transient, asymptomatic Grade 1 elevation in cardiac troponin levels, categorized as a serious adverse event only due to inpatient monitoring requirements.
Notably, no incidents of thrombotic microangiopathy or cardiotoxicities were observed, and no implantable cardioverter-defibrillator shocks or arrhythmias associated with TN-401 have occurred to date. All patients have successfully tapered off immunosuppressive medications. Enrollment and dosing of three additional patients at the higher 6E13 vg/kg dose (Cohort 2) has been completed with no new serious adverse events related to TN-401 reported.
Robust Gene Expression and Protein Production
Cardiac biopsies demonstrated robust transduction and expression in all patients within the first eight weeks post-treatment. Patients 1 and 2 showed consistent evidence of cardiac transduction with TN-401 DNA levels of 3.4 vg/dg and 5.0 vg/dg respectively. High TN-401 mRNA expression levels, ranging from 1.4x10⁴ to 2.9x10⁵ copies per microgram of RNA, were detected across all three Cohort 1 patients as early as eight weeks.
Most significantly, post-treatment PKP2 (搜索) protein levels increased by a mean of 10% from baseline to Week 8 in Patients 1 and 2, as measured using rigorous liquid chromatography-mass spectrometry methods normalized to myosin heavy chain. These protein level increases were also confirmed through multiplexed immunofluorescent imaging, which provided visual evidence of protein increases and colocalization of other proteins associated with intracellular stability and electrical signaling.
Clinical Improvements in Arrhythmia Burden
The trial demonstrated clinically meaningful improvements in electrical instability for the first two patients with greater than six months of follow-up. Patient 1 experienced a 46% decrease in premature ventricular contraction (PVC) counts by Week 40, while Patient 2 showed an even more dramatic 89% reduction in PVC counts by Week 32.
Patient 2 also exhibited a substantial reduction in non-sustained ventricular tachycardia (NSVT) burden, dropping from 78 counts per 24-hour period at baseline to zero by Week 32, where it remained stable. Patient 1 maintained low NSVT counts throughout the follow-up period. Other clinical measures including QRS duration, T wave inversions, heart function, and New York Heart Association class remained stable or within normal ranges for all three patients.
Addressing an Unmet Medical Need
PKP2 (搜索) mutations represent the most common genetic cause of ARVC, occurring in approximately 40% of the overall ARVC population. The prevalence of PKP2-associated ARVC (搜索) is estimated at more than 70,000 people in the United States alone. In this condition, PKP2 gene mutations result in insufficient expression of proteins needed for proper functioning of the desmosomal complex that maintains physical connections and electrical signaling between heart muscle cells.
"We are excited by the strength of the data for TN-401 at this relatively early timepoint in the RIDGE-1 trial," said Whit Tingley, M.D., Ph.D., Tenaya's Chief Medical Officer. "Less than a year after dosing, initial data indicate a promising safety profile, consistent transduction of the gene therapy in cardiomyocytes and RNA and protein expression, and meaningful reductions in PVCs and NSVTs, well-established risk factors for dangerous sustained arrhythmias."
Trial Design and Regulatory Status
The RIDGE-1 Phase 1b/2 clinical trial is a multi-center, open-label, dose escalation study being conducted in the United States and United Kingdom. The trial is designed to assess the safety, tolerability and preliminary clinical efficacy of a one-time intravenous infusion of TN-401 and will seek to enroll up to fifteen adults diagnosed with PKP2-associated ARVC (搜索) who have an implantable cardioverter-defibrillator and are at increased risk for arrhythmias.
TN-401 has received Orphan Drug and Fast Track Designations from the U.S. Food and Drug Administration. The therapy uses AAV9 as the delivery vector, selected based on its extensive clinical and commercial safety record and demonstrated ability to target heart muscle cells. Tenaya's development of TN-401 is supported in part by a grant from the California Institute for Regenerative Medicine.