Tenaya's Phase 1b MyPeak-1 Trial is Testing the Waters in Gene Therapy for Hypertrophic Cardiomyopathy

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, is currently being assessed in the MyPeak-1 phase 1b clinical trial (NCT05836259).^1,2 It is intended to deliver a functional copy of MYBPC3 to cardiomyocytes and is the first known gene therapy to be developed for this indication.

The first-in-human trial, which is following an open-label, dose escalation and dose expansion design, will enroll an estimated 15 patients in total. The initial cohort (cohort 1) will treat 3 patients sequentially at a dose of 3x10¹³ vg/kg of TN-201. This dose was shown to have near maximal efficacy in preclinical mouse model research, with uniform transduction observed in cardiomyocytes in the left ventricle and restoration of MYBPC3 protein to normal levels reported. Pending a data safety monitoring board (DSMB)’s review of the results from cohort 1, a second cohort (cohort 2) may treat an additional 3 patients sequentially at a higher dose of 6x10¹³ vg/kg TN-201. Furthermore, the DSMB will monitor factors including adverse events (AEs) and laboratory and imaging data between each sequential patient within each cohort before dosing of the next patient goes forward. The trial also includes the option for 2 expansion cohorts, cohort 1a and cohort 2a, which may treat additional patients at the doses used in cohort 1 and cohort 2, respectively.

“This is a multicenter phase 1 trial, which means the fundamental objective of this is to understand safety and tolerability,” Milind Desai, MD, MBA, an investigator on the MyPeak-1 trial and the director of the Hypertrophic Cardiomyopathy Center and the vice chair of the Heart Vascular Thoracic Institute at the Cleveland Clinic, told CGTLive™ in October 2023. “[We are] also looking at an effective dose. We start with the lowest dose that we think is going to work and then dose escalation studies will go on [from there]. We are looking for specifically MYBPC3-positive nonobstructive HCM patients that are symptomatic. The other thing is also that at this point in time, since this is such a new technology—a new frontier, essentially—everybody that will be included will have a functioning implantable cardiac defibrillator in place.”

MyPeak-1 will take place at 11 centers throughout the United States, with locations in California, Georgia, Massachusetts, Minnesota, Ohio, Oregon, Pennsylvania, Texas, and Utah.^1,2 According to the clinicaltrials.gov page, which was most recently updated on August 2, 2023, the Cleveland Clinic in Cleveland, Ohio, is currently recruiting patients, but other locations are not yet recruiting. On October 5, 2023, Tenaya announced that the first patient was dosed at the trial's lower dose at the Hypertrophic Cardiomyopathy Center at the Cleveland Clinic. The company expects to announce initial results from the study next year.

The trial’s primary end point is safety and tolerability of TN-201, assessed via the number and severity of AEs during the study and the number of serious AEs related to the gene therapy. The secondary end point is the change from baseline to 52 weeks posttreatment on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, a patient reported outcomes measure that has been associated with clinical outcomes improvement for patients with symptomatic HCM. Exploratory end points include measurements of TN-201 transduction and expression of the transgene and MyBO-C protein via right ventricular septal biopsies taken at 8 and 52 weeks posttreatment; changes from baseline in biomarkers including N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I; echocardiography assessments of the changes from baseline in left ventricular mass, thickness, and volume, left atrium volume, and global longitudinal strain; the change from baseline on cardiopulmonary exercise testing; and the percentage of patients who experience a change from baseline in New York Heart Association (NYHA) Functional Class.

The study will include patients aged 18 to 65 years who have a confirmed truncating mutation in MYBPC3. In addition, patients must have a left ventricular ejection fraction of 50% or greater, NYHA functional class 2 or 3 symptoms while on standard of care medications, and NT-proBNP levels of 300 pg/ml or greater. Patients with an AAV9 neutralizing antibody titer of 1:10 or greater will be excluded from participation in the study. Three days before patients receive TN-201, they will be administered prophylactic immunosuppression with the intention of preventing an immune response to the gene therapy’s AAV9 vector. Patients will be followed up with in-hospital laboratory and immune-monitoring assessments every day for the first 7 days after receiving TN-201, which is administered as a one-time intravenous infusion.

The investigational new drug application enabling initiation of MyPeak-1 was originally cleared by the FDA in January 2023.³ 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. 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 noninterventional study investigating seroprevalence to AAV9 antibodies in adults with MYBPC3-associated HCM.

“MyPeak-1 is the first-in-human study of TN-201 and to our knowledge is the first clinical study of a gene therapy for sarcomeric HCM,” Jeff Haroldson PharmD, MBA, executive director and head of medical affairs, North America, at Tenaya, the first author of a poster detailing the study, and colleagues wrote.¹ “Upon establishing a safe and effective dose of TN-201, Tenaya Therapeutics plans to assess TN-201 in a broader range of MYPC3-HCM patients, including younger participants and patients with obstructive HCM, in future studies.”

REFERENCES
1. Haroldson J, Harrison W, Lombard L, et al. MyPeak-1: A Phase 1b Study to Evaluate Safety and Efficacy of TN-201, an Adeno-Associated Virus Serotype 9 (AAV9) Investigational Gene Therapy, in Adults with MYBPC3-Associated Hypertrophic Cardiomyopathy (HCM). Presented at: 2023 Hypertrophic cardiomyopathy medical society (HCMS) scientific sessions, held October 6 in Cleveland, Ohio.
2. 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 November 6, 2023. https://investors.tenayatherapeutics.com/news-releases/news-release-details/tenaya-therapeutics-doses-first-patient-mypeak-1tm-phase-1b
3. Tenaya Therapeutics announces TN-201 INDclearance and anticipated 2023 milestones. News release. Tenaya Therapeutics, Inc. January 9, 2023. Accessed November 6, 2023. https://investors.tenayatherapeutics.com/news-releases/news-release-details/tenaya-therapeutics-announces-tn-201-ind-clearance-and