Tenaya’s Hypertrophic Cardiomyopathy Gene Therapy TN-201 Well-Tolerated in Early Clinical Data
The data comes from 3 patients treated at the trial’s low dose.
Milind Desai, MD, MBA
Tenaya Therapeutics’ TN-201, an investigational adeno-associated virus (AAV)-vector based gene therapy, has been well-tolerated and shown early signs of efficacy in data reported from the phase 1b MyPeak-1 clinical trial (NCT05836259) evaluating it for the treatment of hypertrophic cardiomyopathy (HCM) caused by mutations in the MYBPC3 gene.1
The data comes from 3 patients treated at the trial’s low dose (3x1013 vg/kg), 1 of whom has 52 weeks of follow-up (patient 1), 1 of whom has 40 weeks of follow-up (patient 2), and 1 of whom has 12 weeks of follow-up (patient 3). In these patients there were no cardiac toxicities, complement activation-associated adverse effects, or thrombotic microangiopathy (TMA)-related events reported. Isolated elevations in liver enzymes associated with treatment were observed, but were managed with corticosteroids; no other signs of liver damage were seen in association with these elevations. A single grade 1 case of mild, asymptomatic enzyme elevation was managed with a corticosteroid bolus in a hospital and thus was considered to be a serious adverse event (SAE). Generally, AEs that occurred during the study were mild, transient, or reversible and the majority of AEs associated with treatment were typical of AAV vector-based gene therapy or immunosuppressive regimens. Two SAEs deemed unrelated to TN-201 occurred. Tenaya noted that all 3 patients remain on study and that patient 1 and patient 2 have tapered off their immunosuppressive regimens.
With regard to signs of efficacy, at 8 weeks posttreatment cardiac transduction was seen in patients 1 and 2 at levels above those considered effective in mouse model research. Furthermore, patients 1 and 2 showed levels of TN-201-derived mRNA at 8 weeks posttreatment that were considered similar to those that have been observed in other clinical-stage gene therapies for cardiac disease; although, it was noted that these levels were lower than what was observed in preclinical research. In patient 1, TN-201 mRNA expression showed an increase of 50% at 52 weeks posttreatment. In additon, patient 1 showed a 3% increase in total levels MyBP-C, the disease-targeted protein encoded by TN-201, at 52 weeks posttreatment compared to 8 weeks posttreatment.
Tenaya also reported that NT-proBNP, a circulating biomarker of heart muscle strain, was “stable overall” in the treated patients. Furthemore, in patient 2, levels of heart muscle injury biomarker cardiac troponin I normalized. New York Heart association classification improvements were seen in patient 1 and patient 2.
“The initial patients enrolled in the MyPEAK-1 Phase 1b/2 clinical study are like many we see in our clinic: relatively young adults whose HCM is keeping them from having an adequate quality of life, including being able to perform activities of daily living and whose disease is progressing in spite of treatment interventions, putting them at significant risk of dire complications,” Milind Desai, MD, MBA, an investigator on the MyPeak-1 trial, the director of the Hypertrophic Cardiomyopathy Center, and the vice chair of the Heart Vascular Thoracic Institute at the Cleveland Clinic, said in a statement.1 “The goal of gene therapy is to halt or even reverse the steady decline in MYBPC3-associated HCM by addressing the underlying genetic cause of disease. Initial data from this first-in-human clinical trial of TN-201 demonstrate tolerability and early evidence of protein expression support additional investigation to build on these findings.”
In October 2024, Tenaya was cleared by the independent Data and Safety Monitoring Board (DSMB) for MyPEAK-1 to move onto a higher dose cohort, which will treat patients at a dose of 6x1013 vg/kg.2 At the time of that announcement, Tenaya noted that it had begun enrollment activities for that cohort. Alongside the announcement of the DSMB’s decision, Tenaya also noted that it has made some modifications to MyPeak-1's protocol. These include the addition of a biopsy taken at baseline and greater flexibility with regard to timing for the 2 posttreatment biopsies that were already part of the protocol; the extension of eligibility to patients who have obstructive HCM and patients who do not have an implantable cardioverter defibrillator device; and raising the total possible number of participants for the dose expansion portion of the study to 24 patients.
“TN-201’s emerging safety profile, excellent uptake into cardiomyocytes, and evidence of transgene RNA and protein expression provide important de-risking of the program as we proceed with enrollment of the higher dose cohort,” Whit Tingley, MD, PhD, Tenaya’s chief medical officer, added to the statement.1 “In addition, we haveobserved encouraging early hints of disease stability and improvement among certain clinical measures of disease, offering further reason to believe in TN-201’s promise. Longer-term follow up for all patients in the lower dose cohort and results from the higher dose cohort will further inform our understanding of TN-201 gene therapy’s potential in MYBPC3-associated HCM.”
CGTLive has previously spoken with Desai about TN-201 and the design of the MyPEAK-1 study. In an October 2023 interview, Desai expressed optimism, but emphasized the uncharted territory that lies ahead.
“At this point in time, we are just, with bated breath, looking for how this is going to evolve,” Desai told CGTLive. “This is such a new frontier in cardiovascular medicine, especially in the HCM space, that we have to ride it out. The science is there. The process has been operationalized. Now we have to wait and see the downstream ramifications of it. Based on animal data, the expectation is that this technology works, but we still have to prove it in humans."
