Tenaya Therapeutics Begins RIDGE™-1 Phase 1b Trial of TN-401 for PKP2-Associated ARVC

Tenaya Therapeutics, Inc., a clinical-stage biotechnology company, has announced the dosing of the first patient with TN-401 gene therapy in the RIDGE-1 Phase 1b clinical trial, held at the University of California, San Francisco. This trial represents a crucial step forward in the treatment of arrhythmogenic right ventricular cardiomyopathy (ARVC), particularly those cases caused by mutations in the plakophilin-2 (PKP2) gene.

ARVC, also known as arrhythmogenic cardiomyopathy (ACM), is a heart condition marked by arrhythmias and a high risk of heart failure, cardiac arrest, and sudden death. Mutations in the PKP2 gene result in insufficient protein levels that are vital for maintaining the structural and functional integrity of heart muscle cells. TN-401 aims to address this issue by delivering a functional version of the PKP2 gene into heart cells using an adeno associated virus serotype 9 (AAV9) capsid.

In preclinical studies, the introduction of a healthy PKP2 gene via TN-401 successfully integrated into heart cells, producing the missing protein and significantly slowing or reversing disease progression. The therapy showed promising results, including normalized heart rhythms and extended survival rates in treated models compared to untreated ones.

Dr. Vasanth Vedantham, a lead investigator for the RIDGE-1 trial, emphasized the significance of this treatment, noting that current ARVC management strategies involve significant lifestyle restrictions and chronic medications that don't address the genetic root of the disease. TN-401, on the other hand, seeks to remedy the underlying cause by delivering a fully functional PKP2 gene directly to the heart cells.

The RIDGE-1 Phase 1b clinical trial is a multi-center, open-label, dose-escalation study underway in the U.S. and the UK. This trial will assess the safety, tolerability, and preliminary efficacy of a single intravenous infusion of TN-401 and aims to enroll up to fifteen adults diagnosed with PKP2-associated ARVC. The initial dose being tested is 3E13 vg/kg, which showed near maximal efficacy in preclinical trials. The first three patients will receive this dose sequentially, with subsequent dose adjustments guided by a panel of independent safety reviewers.

Whit Tingley, Tenaya’s Chief Medical Officer, highlighted the importance of this first-in-human study, expressing gratitude for the support from various stakeholders. He pointed out that TN-401’s design, particularly its use of the AAV9 capsid, sets it apart and offers a promising therapeutic option for PKP2-associated ARVC. Preclinical studies demonstrated that TN-401 could restore PKP2 levels, reduce arrhythmia frequency and severity, and halt disease progression.

Currently, the RIDGE-1 trial is enrolling participants at six specialized ARVC care centers in the U.S. In addition, Tenaya has initiated a global natural history and seroprevalence study to collect data on ARVC patients with PKP2 mutations, which is being conducted at more than 20 clinical sites across the U.S., UK, and Europe.

PKP2 mutations are the leading cause of ARVC, accounting for about 40% of ARVC cases, with an estimated prevalence of over 70,000 people in the U.S. alone. These mutations result in the degradation of the desmosomal complex, crucial for the physical and electrical connectivity in heart muscle cells, leading to the replacement of cardiac muscle cells with fibrofatty tissue and unstable heart rhythms. Symptoms of ARVC include arrhythmias, palpitations, dizziness, and fainting and often manifest before age 40. Current treatments involve managing symptoms without addressing the genetic cause.

Tenaya Therapeutics continues to advance its mission of discovering and developing therapies for heart disease, with a diverse pipeline that includes TN-201 for hypertrophic cardiomyopathy, TN-401 for ARVC, TN-301 for heart failure, and various early-stage programs.