Clinical Trials

Inclusion Criteria:

• Adults, ages 18 to 65 years, at the time of informed consent.
• Provide signed, written informed consent.
• Confirmed Pathogenic (P) or Likely Pathogenic (LP) PKP2 mutation documented by central laboratory genotyping at Screening.
• Diagnosed with ARVC and meet the 2010 Modified Task Force Criteria for ARVC as definitely affected, at Screening.
• Functioning transvenous ICD with remote interrogation capabilities implanted at least 12 months prior to Screening.
• Mean PVCs ≥ 500 per 24 hours on a Screening 7-day ambulatory cardiac monitor.
• Biplane LVEF ≥ 50% by local ECHO, at Screening.
• New York Heart Association (NYHA) Functional Class I-III, at Screening.
• Has been on stable doses of standard of care medications for at least 6 weeks prior to dosing.
• Able to comply with trial procedures and restrictions.
• Body weight  < 100 kg, at Screening.
• AAV9 neutralizing antibody titer, at Screening:
  • For Cohorts 1 and 2, titer ≤ 1:10;
  • For expansion Cohorts 1a and 2a, higher titers (≤ 1:20, ≤ 1:40, or ≤ 1:80) may be permitted by the Investigator and the Tenaya Medical Monitor as long as there is no emerging evidence to indicate that these titers impact the efficacy or safety of TN-401.
• No contraindication to protocol-mandated procedures, including cardiac biopsy and IS (medications known to have strong drug-drug interactions with sirolimus are not permitted).
• Normal or near normal liver function tests (LFTs), at Screening and Pre-dose:
  • ALT < 1.5 × ULN;
  • TB ≤ ULN;
  • INR ≤ ULN.
• Normal Complete Blood Count as follows, at Screening and Pre-dose:
  • Hemoglobin ≥ 11 g/dL;
  • WBC count ≥ 3.8 × 10^3 /μL and ≤ 10.4 × 10^3 /μL;
  • Platelet count150 × 10^3 /μL.
• Persons of Childbearing Potential (POCBP) must have a negative pregnancy test at Screening and Pre-dose and agree to use effective methods of birth control for 12 months after Day -1 (Section 13.2).
• Patients engaging in vaginal intercourse with a POCBP must agree to use condoms and abstain from sperm donation for 12 months after Day -1.
• Willingness to abstain from alcohol intake until completion of IS medications. 

Exclusion Criteria: 

• Any known allergy or hypersensitivity to the IMP or its constituents.
• Ongoing amiodarone use. Amiodarone use must be completely discontinued at least 3 months prior to Screening.
• Initiation of flecainide 3 months prior to Screening and maintained on a stable dose.
• History of prior myocardial infarction, documented obstructive coronary artery disease (> 70% occlusion in 1 or more epicardial arteries), percutaneous coronary intervention or coronary artery bypass graft.
• A documented P/LP mutation in a desmosomal or arrhythmia-related gene in addition to PKP2.
• History of any prior VT ablation or a planned VT ablation within 6 months of Screening.
• Escalation of anti-arrhythmic therapy within 6 weeks prior to Screening.
• Signs or symptoms of RV failure requiring therapy or evidence of severe RV dysfunction.
• NYHA Class IV heart failure.
• Clinically significant renal disease (e.g., estimated glomerular filtration rate [eGFR] 160 mmHg or diastolic blood pressure [DBP] > 100 mmHg), autoimmune disorder (e.g., systemic lupus erythematosus), immunosuppressive disorder, active psychiatric illness, or other clinically significant disorder at Screening, as determined by the Investigator.
• Evidence of any active infections. Patients with mild local infections (e.g., onychomycosis, mild tinea pedis, gingivitis, etc.) that do not promote a significant systemic inflammatory reaction and are not expected to increase the risk of IS or of participating in the trial, may be enrolled per Investigator judgment. A viral illness within 6 weeks of the planned dose is exclusionary; however, the patient may be rescreened once they have recovered from the illness.
• Scheduled or anticipated major surgery, including heart transplantation, during the Screening period through 52 weeks following investigational gene therapy infusion (Stage 1).
• History of hepatitis C virus (HCV), hepatitis B virus (HBV) or Human Immunodeficiency Virus (HIV) or current treatment with an antiviral therapy for HCV, HBV or HIV-1/HIV-2, or a positive test result for HCV, HIV-1/HIV-2 or laboratory evidence of HBV at Screening defined as:
  • Positive test result for HCV antibodies or HCV RNA at Screening;
  • HBV surface antigen (HBsAg), HBV surface antibody (HBsAb) and/or HBV core antibody (HBcAb) test results consistent with the current Centers for Disease Control and;Prevention (CDC) interpretation of prior, current, or active hepatitis B infection;
  • HIV-1/HIV-2 positive result based on antigen/antibody test.
• Latent tuberculosis infection defined as positive interferon gamma release assay (IGRA), by QuantiFERON-TB Gold testing at Screening.
• History of clinically significant liver disease, liver transplant, genetic liver disease, cirrhosis, nonalcoholic steatohepatitis, or other liver condition that would preclude participation in the trial, as determined by the Investigator or Tenaya Medical Monitor.
• History of, or known genetic predisposition to, TMA, hemolyticuremic syndrome, or complement dysregulation.
• History of clinically significant malignant disease within 10 years. Patients who have been successfully treated for nonmetastatic malignancies such as cutaneous squamous cell or basal cell carcinoma or cervical carcinoma in situ, may be included in the trial.
• History of drug or alcohol abuse.
• Known allergy or hypersensitivity to corticosteroids or their excipients.
• Medical need for ongoing treatment with immunosuppressants (e.g., corticosteroids, eculizumab, sirolimus, tacrolimus, etc.).
• Participation in another interventional drug or device clinical trial within the last 3 months or planned participation during this trial.
• Previous treatment with an AAVbased gene therapy. 23. Patients who are pregnant or nursing.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/15/23. Questions regarding updates should be directed to the study team contact.