Tenaya’s Trial of Hypertrophic Cardiomyopathy Gene Therapy TN-201 Doses First Patient


The patient received the trial’s low dose of TN-201 at the Cleveland Clinic's Hypertrophic Cardiomyopathy Center, in Cleveland, Ohio.

Tenaya Therapeutics has dosed the first patient in the MyPeak-1 phase 1b clinical trial (NCT05836259) evaluating 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.1

The patient received the trial’s low dose of TN-201 (3x1013 vg/kg) at the Hypertrophic Cardiomyopathy Center at the Cleveland Clinic, in Cleveland, Ohio. Tenaya noted that it plans to treat 2 additional patients at this dose, after which initial safety data will be looked at by a data safety and monitoring board (DSMB). Pending the DSMB’s review, additional patients may be treated at both the low dose and the trial’s planned higher dose, 6x1013 vg/kg. 

MYBPC3 gene mutations are the most common genetic cause of HCM and people with MYBPC3-associated HCM are at increased risk for accelerated decline and serious complications associated with their condition,” Milind Desai, MD, MBA, a MyPeak-1 investigator and the director at the Cleveland Clinic Hypertrophic Cardiomyopathy Center and the vice chair of the Heart Vascular Thoracic Institute at the Cleveland Clinic, said in a statement.1 “TN-201, a gene therapy for MYBPC3-associated HCM, offers the potential of a 1-time treatment to correct the underlying genetic cause of disease and improve patient outcomes. We are pleased to participate in the first-in-human clinical trial of TN-201 to explore this new use of gene therapy treatment.”

The open-label, multicenter, dose-escalation study is currently recruiting adult patients with New York Heart Association Class II or III, nonobstructive HCM and an implantable cardioverter defibrillator. A minimum of 6 patients will be enrolled, though the study may ultimately treat up to 15 patients. Beyond the Hypertrophic Cardiomyopathy Center, which was the first location to begin recruiting patients for the trial, an additional 11 sites in the United States are planned to be part of the study; the trial may also ultimately treat patients in other countries. The company expects to first announce results from the trial next year.

“The initiation of the MyPeak-1 clinical trial of TN-201 – the first gene therapy for MYBPC3-associated HCM to be studied in humans and the first of Tenaya’s gene therapy candidates to reach clinical stage – is a significant milestone in our efforts to improve patients’ lives through the development of new treatments that target the genetic underpinnings of heart disease,” Whit Tingley, MD, PhD, the chief medical officer of Tenaya, added to the statement.1 “We are grateful for the support of study sites, referral centers, patient advocacy organizations, and patients and families who are actively engaged with Tenaya in our efforts to explore the potential of TN-201 as a novel treatment for MYBPC3-associated HCM. We look forward to continuing this close partnership as we enroll additional patients in the MyPeak-1 study and in subsequent studies.”

TN-201 is meant to provide a functional copy of MYBPC3 via an AAV vector, with the intention of halting or reversing disease progression via restoration of MYBPC3 protein production in heart muscle cells. The investigational new drug application for MyPeak-1 was cleared by the FDA in January 2023.2 At the time, Tenaya also announced that it had already completed manufacturing of clinical trial material at an amount expected to be sufficient to support the trial’s estimated enrollment. Notably, with the company stating in January that the dosing of the first patient was expected in the third quarter of 2023, Tenaya appears to be on track with its planned milestones for the study.

The development of TN-201 is also being supported by the ongoing MyCLIMB natural history study (NCT05112237) for pediatric patients with MYBPC3-associated HCM and a separate non-interventional study investigating seroprevalence to AAV9 antibodies in adults with MYBPC3-associated HCM. Although MyPeak-1 is currently only recruiting adult patients with nonobstructive HCM, Tenaya stated that it may eventually evaluate TN-201 for pediatric patients and patients with obstructive HCM.1 TN-201 has been granted orphan drug designation and fast track designation from the FDA and orphan medicinal product designation by the European Commission.

Tenaya’s pipeline also includes another gene therapy for a cardiovascular indication: TN-401, an investigational AAV-based gene therapy intended to treat arrhythmogenic right ventricular cardiomyopathy (ARVC).3 Although TN-401 remains in preclinical development, it notably received orphan drug designation from the FDA late last year. 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. In data presented at the American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting, May 16–19, 2022, in Washington, D.C., TN-401 was shown to significantly increase lifespans in a cardiac specific PKP2 knock-out mouse model (Pkp2-cKO).4

1. Tenaya Therapeutics doses first patient in the MyPeak-1 phase 1b clinical trial of TN-201 for the treatment of MYBPC3-associated hypertrophic cardiomyopathy. News release. Tenaya Therapeutics, Inc. October 5, 2023. Accessed October 5, 2023. https://investors.tenayatherapeutics.com/news-releases/news-release-details/tenaya-therapeutics-doses-first-patient-mypeak-1tm-phase-1b
2. Tenaya Therapeutics announces TN-201 IND clearance and anticipated 2023 milestones. News release. Tenaya Therapeutics, Inc. January 9, 2023. Accessed October 5, 2023. https://investors.tenayatherapeutics.com/news-releases/news-release-details/tenaya-therapeutics-announces-tn-201-ind-clearance-and
3. Tenaya Therapeutics receives orphan drug designation from the U.S. Food and Drug Administration for its gene therapy for genetic arrhythmogenic right ventricular cardiomyopathy. News release. Tenaya Therapeutics. November 28, 2022. Accessed October 5, 2023. https://investors.tenayatherapeutics.com/news-releases/news-release-details/tenaya-therapeutics-receives-orphan-drug-designation-us-food-and
4. Wu I, Greer-Short A, Zeng A, et al. Cardiac AAV:PKP2 gene therapy reduces ventricular arrhythmias, reverses adverse right ventricular remodeling, improves heart function, and extends survival in a PKP2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy. Presented at: American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting, May 16–19, 2022, Washington, D.C. and virtual. Abstract #630
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