First Patient Dosed in RIDGE-1 Trial for Tenaya’s ARV Cardiomyopathy Gene Therapy TN-401
The patient’s dosing took place at the University of California, San Francisco, although the multicenter study is expected to eventually dose patients at other locations in the United States, United Kingdom, and Europe.
The first patient has been dosed in the phase 1b RIDGE-1 clinical trial (NCT06228924) evaluating Tenaya Therapeutics’ TN-401, an investigational adeno-associated virus (AAV)-based gene therapy, for the treatment of PKP2-associated arrhythmogenic right ventricular cardiomyopathy (ARVC).1
The patient’s dosing took place at the University of California, San Francisco, although the multicenter study is expected to eventually dose patients at other locations in the United States, United Kingdom, and Europe. The patient received a dose of 3x1013 vg/kg of TN-401, which in preclinical research was associated with “near-maximal efficacy”. Two more patients are expected to be treated at this dose level, sequentially, before potential dose escalation and/or expansion pending an independent safety review panel’s advice based on the results obtained.
The study is expected to enroll approximately 15 patients in total. To participate, patients are required to have an implantable cardioverter defibrillator and to undergo a premature ventricular contraction count during screening with results indicating that they have an elevated risk of experiencing arrhythmias. Tenaya anticipates reporting initial data from the trial next year.
TN-401 has demonstrated the ability to normalize heart rhythms, reverse disease progression, and extend survival in preclinical animal models. Untreated animal models were used for comparison in the preclinical work.
“People living with ARVC frequently experience dangerous arrhythmias and are at risk for developing heart failure, cardiac arrest and sudden death,” trial investigator Vasanth Vedantham, MD, PhD, a professor of medicine, cardiac electrophysiologist, and director of cardiovascular genetics at the University of California, San Francisco, said in a statement.1 “To minimize their risk, ARVC patients live with significant activity restrictions, take chronic medications, and require interventions that together negatively impact their quality of life but don’t address the underlying problem of a defective gene. PKP2 genetic mutations are the most common single gene cause of ARVC and unlike existing treatments for ARVC, TN-401 gene therapy seeks to directly address the underlying cause of disease by delivering a fully functional copy of PKP2 to the heart.”
The investigational new drug application enabling initiation of RIDGE-1 was originally cleared by the FDA in October 2023.2 Alongside RIDGE-1, Tenaya is also conducting RIDGE (NCT06311708), a natural history study that is currently enrolling participants and is focused on gathering information on AAV9 antibody seroprevalence and other data among the population of patients with PKP2-associated ARVC.
“Initiation of this first-in-human study of TN-401 is a significant milestone for Tenaya and we are grateful for the ongoing support received from our trial sites, advocacy organizations, patients and families in our efforts to advance a novel gene replacement therapy for PKP2-associated ARVC,” Whit Tingley, MD, PhD, Tenaya’s chief medical officer, added to the statement.1 “We believe TN-401 has best-in-class potential due to its differentiated construct, which utilizes an AAV9 capsid to deliver a fully functioning PKP2 gene directly to heart cells. We selected AAV9 capsid due to its extensive track record and in preclinical studies it outperformed other capsids and TN-401 restored PKP2 levels in a knockout model, leading to reductions in arrhythmia frequency and severity, and halted disease progression.”
In addition to developing TN-401, Tenaya is also developing TN-201, an investigational adeno-associated virus (AAV)-vector based gene therapy intended to treat hypertrophic cardiomyopathy (HCM) caused by mutations in the MYBPC3 gene.3 Notably, in October 2024, the company received clearance from the trial’s independent Data and Safety Monitoring Board (DSMB) to move onto a higher dose cohort for the MyPeak-1 phase 1b clinical trial (NCT05836259) evaluating TN-201.
“The MyPEAK-1 study of TN-201 is primarily intended to establish the safety profile of TN-201 gene therapy, and we are pleased to report that TN-201 has an appropriate tolerability profile at the 3x1013 vg/kg dose without unexpected adverse reactions,” Tingley said in a statement at the time.3 “The DSMB’s recommendation to proceed with dose escalation and endorsement to expand eligibility criteria are further positive early indicators for TN-201’s safety profile and enable Tenaya to explore the utility of TN-201 in different populations. We’ve implemented adjustments to the protocol, including the addition of a biopsy at baseline, broadening eligibility to include obstructive HCM patients and increasing the size of the overall MyPEAK-1 study.”
