Hypertrophic Cardiomyopathy Gene Therapy Receives IND Clearance


Tenaya Therapeutics expects the dosing of the first patient in the planned phase 1b trial in Q3 2023.

Tenaya Therapeutics’ 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, has received clearance of its investigational new drug application (IND) by the FDA.1

TN-201 is meant to provide a functional copy of MYBPC3 with the intention of halting or reversing disease progression via restoration of MYBPC3 protein production to normal levels. The planned phase 1b clinical trial will aim to enroll 6 or more adult patients with New York Heart Association class II or III symptomatic MYBPC3-associated nonobstructive HCM who have an implantable cardioverter defibrillator. The study will evaluate safety, markers of cardiac transduction and transgene expression in right ventricular biopsy samples, changes in circulating cardiac biomarkers, imaging biomarkers (via echocardiogram and changes in exercise capacity), symptom burden, and quality of life. Initial participants in the trial will receive a dose of 3x1013 vg/kg. It was noted that this starting dose was selected based on preclinical research that showed it to be associated with near-maximal efficacy. Based on an independent safety review of results from the dosing of the first cohort, a dose of 6x1013 vg/kg may be administered to subsequent participants, or enrollment at the initial dose may be expanded.

Tenaya Therapeutics expects the dosing of the first patient in the trial to occur in the third quarter of 2023 and initial data to be reported in 2024. The company also announced that it has already completed manufacturing of clinical trial material at an amount expected to be sufficient to support the trial’s estimated enrollment. 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.

“We look forward to initiating our phase 1b clinical trial of TN-201 in symptomatic adults living with the nonobstructive form of hypertrophic cardiomyopathy later this year,” Whit Tingley, MD, PhD, chief medical officer, Tenaya Therapeutics, said in a statement regarding the news.1 “HCM patients whose disease is caused by MYBPC3 mutations are at increased risk for early disease onset and rapid disease progression, but the clinical management for nonobstructive HCM is limited to nonspecific medications intended to reduce symptoms. TN-201 is being developed by Tenaya to correct the underlying genetic cause of HCM after a single dose, offering the hope of restoring normal contractility and preventing the serious complications associated with this disease.”

In addition to TN-201, Tenaya Therapeutics is also developing TN-401, an investigational AAV-based gene therapy intended to treat arrhythmogenic right ventricular cardiomyopathy (ARVC) via delivery of a functional copy of plakophilin-2 (PKP2), the disease-targeted gene in approximately 40% of patients with ARVC.2 In November of last year, TN-401 was granted orphan drug designation by the FDA. Preclinical efficacy and safety data for TN-401 were presented at the American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting, May 16–19, 2022, in Washington, D.C.3 The results included the finding that TN-401 significantly increased lifespan in a cardiac specific PKP2 knock-out mouse model. While IND-enabling studies for TN-401 remain ongoing, Tenaya Therapeutics has announced that it expects to submit an IND application to the FDAin the second half of this year.1

“Tenaya had a momentous year in 2022 in which we filed two INDs, transitioned into a clinical-stage company, launched operations of our Genetic Medicines Manufacturing Center - where we successfully produced clinical drug supply for TN-201 - and significantly extended our cash runway,” Faraz Ali, chief executive officer, Tenaya Therapeutics, added to the statement.1 “We are pleased to start 2023 with clearance of the IND for our TN-201 gene therapy program and look forward to dosing patients with MYBPC3-associated HCM in our Phase 1b study in the coming months... Taken altogether, we are making tremendous strides on our mission and are solidifying our leadership position in the field of precision medicine therapies for heart disease.”

1. Tenaya Therapeutics announces TN-201 IND clearance and anticipated 2023 milestones. News release. Tenaya Therapeutics, Inc. January 9, 2023. https://investors.tenayatherapeutics.com/news-releases/news-release-details/tenaya-therapeutics-announces-tn-201-ind-clearance-and 
2. 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. https://investors.tenayatherapeutics.com/news-releases/news-release-details/tenaya-therapeutics-receives-orphan-drug-designation-us-food-and 
3. 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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