Tenaya Therapeutics Updates TN-201 Gene Therapy for MYBPC3-Linked HCM

Tenaya Therapeutics, a biotechnology company based in South San Francisco, announced updates on their Phase 1b/2 MyPEAK-1 clinical trial for TN-201, a gene therapy for MYBPC3-associated hypertrophic cardiomyopathy (HCM). This condition is characterized by insufficient levels of myosin-binding protein C (MyBP-C) in heart muscle cells, leading to disease progression. TN-201 aims to increase MyBP-C protein levels by delivering a functional MYBPC3 gene to heart cells, potentially slowing or reversing HCM.

Whit Tingley, M.D., Ph.D., Tenaya's Chief Medical Officer, reported that the TN-201 therapy has shown appropriate tolerability at the 3E13 vg/kg dose, with no unexpected adverse reactions. An independent Data and Safety Monitoring Board (DSMB) has reviewed the safety data from the first cohort of three patients and recommended dose escalation to 6E13 vg/kg. The DSMB also endorsed broadening the trial's eligibility criteria, allowing Tenaya to explore TN-201's utility in different patient populations. The MyPEAK-1 trial will now include obstructive HCM patients and increase the study size.

The trial has completed the first cohort's dosing with no unexpected events or toxicities. The ongoing second cohort is now enrolling participants. Tenaya plans to report initial data from the first cohort in December 2024, focusing on safety, tolerability, cardiac biopsy analyses, and changes in cardiac biomarkers. The trial is also gathering data on TN-201's effects on imaging biomarkers, heart function, exercise capacity, functional status, and patient quality of life.

Tenaya has implemented several protocol changes to support future development. These include adding a baseline biopsy, increasing the number of cardiac biopsies, and allowing more flexible timing for post-dose biopsies. Additionally, the eligibility criteria now include participants without an implantable cardioverter defibrillator device (ICD) and both obstructive and nonobstructive HCM patients. The trial's potential enrollment has increased from nine to 24 adults.

In efforts to understand the pediatric burden of MYBPC3-associated HCM, Dr. Tingley presented data from a study conducted with the Sarcomeric Human Cardiomyopathy Registry (SHaRe). The study identified nearly 1,800 individuals with MYBPC3-associated HCM, with approximately 13% diagnosed before age 18. The cumulative lifetime risk of severe events for pediatric patients is high, with 50% experiencing significant morbidity by age 40. Both adult and pediatric patients with MYBPC3-associated HCM have high rates of serious complications, including heart failure and ventricular arrhythmias, underscoring the need for timely diagnosis and new genetic medicines.

Tenaya continues to characterize the pediatric MYBPC3-associated HCM population through the MyClimb natural history study, which has enrolled over 200 children and adolescents across 29 sites in the USA, Canada, Spain, and the United Kingdom.

The MyPEAK-1 Phase 1b/2 clinical trial is an ongoing, multi-center, open-label, dose-escalating study designed to assess the safety, tolerability, and clinical efficacy of a one-time intravenous infusion of TN-201 gene therapy. The trial is enrolling symptomatic adults with MYBPC3-associated HCM and testing doses of 3E13 vg/kg and 6E13 vg/kg in two cohorts of three patients each. Following DSMB safety assessments, dose expansion cohorts may enroll up to 24 MYBPC3-associated HCM adults with either nonobstructive or obstructive forms of the disease.

MYBPC3-associated hypertrophic cardiomyopathy is a severe and progressive condition affecting individuals of all ages. Variants in the MYBPC3 gene lead to insufficient MyBP-C protein expression, causing hypercontractility and left ventricle thickening. This results in symptoms such as chest pain, shortness of breath, palpitations, and fainting. Patients with MYBPC3 mutations are more likely to experience earlier disease onset and higher rates of serious outcomes, including heart failure, arrhythmias, stroke, and sudden cardiac arrest.

TN-201 is an adeno-associated virus serotype 9 (AAV9)-based gene therapy designed to deliver a functional MYBPC3 gene to heart muscle cells, potentially halting or reversing the disease with a single dose. It has received Fast Track, Orphan Drug, and Rare Pediatric Drug Designations from the U.S. FDA, and orphan medicinal product designation from the European Commission.

Tenaya Therapeutics is dedicated to discovering, developing, and delivering therapies that address the underlying causes of heart disease. Their pipeline includes TN-201 for MYBPC3-associated HCM, TN-401 for PKP2-associated arrhythmogenic right ventricular cardiomyopathy (ARVC), TN-301 for heart failure with preserved ejection fraction (HFpEF), and several early-stage programs in preclinical development.