In light of the IND clearance, Tenaya now intends to go forward with plans for a phase 1b clinical trial (RIDGE-1) that will seek to recruit up to 15 adult patients.
Tenaya Therapeutics’ TN-401, an investigational adeno-associated virus (AAV)-based gene therapy intended to treat PKP2-associated arrhythmogenic right ventricular cardiomyopathy (ARVC), has received clearance of its investigational new drug (IND) application from the FDA.1
In light of the IND clearance, Tenaya now intends to go forward with plans for a phase 1b clinical trial (RIDGE-1) that will seek to recruit up to 15 adult patients with PKP2-associated ARVC in order to explore safety and efficacy of the gene therapy. 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. The multicenter, open-label trial will initially dose patients at 3x1013 vg/kg but may later utilize a higher dose for patients in a separate cohort pending the recommendation of a panel of independent safety reviewers based on results from the first 3 patients treated.
The study includes outpatient assessments through 52 weeks following the one-time treatment with TN-401, which is administered via a single intravenous infusion, and an additional 4-year, long-term follow-up period after that. In addition to safety, end points for RIDGE-1 include markers of cardiac transduction and transgene expression as determined via ventricular biopsy, events of sustained or non-sustained ventricular tachycardia, patient-reported outcomes, premature ventricular contraction changes, circulating plasma biomarkers, and imaging biomarkers of disease, as assessed via echocardiogram. TN-401 is intended to deliver a functional copy of plakophilin-2 (PKP2), the disease-targeted gene in approximately 40% of patients with ARVC, via an AAV9 vector, in a single dose.
“People with arrhythmogenic cardiomyopathy report high levels of fear and stress and must withstand burdensome physical and lifestyle restrictions in an effort to manage the frequent abnormal heart rhythms and constant risk of sudden cardiac arrest associated with their disease,” Whit Tingley, MD, PhD, Tenaya’s chief medical officer, said in a statement.1 “TN-401 is intended to address the genetic mutation most frequently underlying ARVC. The initial dose for TN-401 in the RIDGE-1 study was associated with near maximal efficacy in our preclinical studies. With clinical site and patient community engagement well underway, we look forward to rapidly advancing TN-401 into the clinic.”
In November of last year, TN-401 was granted orphan drug designation by the FDA.2 Earlier, in May of 2022, Tenaya had presented promising preclinical results related to TN-401 at the American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting, May 16-19, 2022, in Washington, DC, in a poster authored by Jane Yang, PhD, a senior scientist at Tenaya Therapeutics, and others.3
“A single dose of cardiac AAV:PKP2 gene delivery significantly improves life span of Pkp2-cKO ARVC mice by restoring expression of desmosome components; preventing and reversing adverse right ventricular remodeling; maintaining and improving ventricular functions; preventing cardiac fibrosis, and reducing ventricular arrhythmia event frequency and severity,” lead author Yang and colleagues wrote in the poster.3 “Additional studies on AAV:PKP2 gene therapy efficacy show a dose-dependency in disease modification and survival benefit. Safety evaluation of AAV:PKP2 in wild-type mice shows no adverse effects on cardiac function and no changes in tissues examined. Our preclinical results demonstrate that cardiac AAV:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.”
Tenaya has noted that manufacturing activities necessary to supply RIDGE-1 with sufficient TN-401 product are completed.1 Alongside RIDGE-1, Tenaya will also be conducting RIDGE, a natural history study focused on gathering information on AAV9 antibody seroprevalence and other data among the population of patients with PKP2-associated ARVC. RIDGE is already enrolling participants.
The IND clearance is one of a series of recent milestones for Tenaya. Just earlier this month, the company dosed the first patient in the MyPeak-1 phase 1b clinical trial (NCT05836259) evaluating TN-201, its investigational AAV-vector based gene therapy intended to treat hypertrophic cardiomyopathy caused by mutations in the MYBPC3 gene.4