Evaluation of Safety and Tolerability of TX200-TR101 in Prophylaxis Against Renal Transplant Rejection in Living Donor Recipients

The primary objective of this study is to evaluate the **short-term safety and tolerability** of TX200-TR101, an autologous antigen-specific chimeric antigen receptor T regulatory cell therapy, in living donor renal transplant recipients. This assessment is conducted from the day of TX200-TR101 infusion up to 28 days post-infusion. The clinical relevance of this objective lies in its potential to provide critical safety data for TX200-TR101, which is being investigated for its role in the prophylaxis against renal transplant rejection.

Secondary objectives include:

• Evaluating the effect of TX200-TR101 on acute graft-related outcomes, including the type, severity, and timing of biopsy-confirmed acute rejection (BCAR), from the day of infusion through to Week 84.
• Assessing the long-term safety outcomes in terms of treatment-emergent adverse events (TEAEs) from the day of infusion through to Week 84.
• Evaluating the reduction of immunosuppression over time through to Week 84.
• Determining the localization of TX200-TR101 in the graft at Week 16.
• Evaluating the effect of TX200-TR101 on chronic graft-related outcomes from the day of infusion through to Week 84.

The clinical trial involves a total of **12 participants** who are being evaluated for the **prophylaxis against renal transplant rejection**. The study population comprises both male and female subjects, aged between **18 and 70 years**. Participants are individuals diagnosed with **end-stage renal disease (ESRD)** and are currently on the waiting list for a kidney transplant from a live donor. The trial includes single organ recipients, specifically those receiving a kidney. The health status of participants is monitored, ensuring normal or non-clinically significant abnormalities in the electrocardiogram (ECG) at the investigator's discretion. The trial population was selected based on their willingness and ability to provide informed consent, and women of childbearing potential are required to have a negative serum pregnancy test at screening and before transplantation. Participants are also required to use a highly effective method of contraception throughout the study duration. The trial includes a vulnerable population, indicating additional ethical considerations in the study design.

The clinical trial is designed as a **multicentre, open-label, single ascending dose, dose-ranging, Phase I/IIa study** to evaluate the safety and tolerability of an autologous antigen-specific chimeric antigen receptor T regulatory cell therapy, known as TX200-TR101, in living donor renal transplant recipients. The primary objective is to assess the short-term safety and tolerability of TX200-TR101 from the day of infusion up to 28 days post-infusion. The trial is expected to run from March 17, 2021, to March 4, 2026, with participants involved for a duration extending to Week 84 post-infusion.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of end-stage renal disease (ESRD), and readiness for kidney transplantation from a live donor. The screening will also ensure normal or non-clinically significant abnormalities in the electrocardiogram (ECG) and a negative serum pregnancy test for women of childbearing potential. Following the screening, participants will receive the TX200-TR101 infusion via **intravenous use** and will be monitored for the incidence and grade of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs), within the first 28 days.

Subsequent follow-up visits will occur through to Week 84, during which secondary endpoints will be evaluated. These include the incidence of biopsy-confirmed acute rejection (BCAR) episodes, opportunistic infections, and neoplasia, as well as the presence of CD4 positive cells with HLA-A2 CAR RNA transcripts in renal transplant biopsies. The study will also assess the cumulative dose of immunosuppression and the incidence of chronic graft dysfunction. The end-of-study visit will mark the conclusion of participant involvement, with data collected on the long-term safety and efficacy of the therapy.

Participants may be subject to early termination from the study if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial is not classified as low intervention, and it adheres to the guidelines set forth by the European Medicines Agency (EMA) for a Category 2 trial. The investigational product, TX200-TR101, is a **solution for infusion** and is classified as an orphan drug, emphasizing its role in addressing a rare medical condition, specifically the prophylaxis against renal transplant rejection.

The clinical trial involves the administration of **TX200-TR101**, an experimental medication designed as an autologous antigen-specific chimeric antigen receptor T regulatory cell therapy. This investigational product is formulated as a **solution for infusion** and is administered via the **intravenous route**. The study is structured as a multicentre, open-label, single ascending dose, dose-ranging, Phase I/IIa trial. The primary objective is to evaluate the short-term safety and tolerability of TX200-TR101 in living donor renal transplant recipients. The infusion of TX200-TR101 is conducted once, with the evaluation period extending up to 28 days post-infusion. The product is not a paediatric formulation and has been designated as an orphan drug, indicating its use in a rare condition.

TX200-TR101 is a **structurally diverse substance** categorized under cell therapy, developed by Sangamo Therapeutics France SAS. The trial does not specify a maximum daily dose or total dose amount, nor does it define a maximum treatment period, as the study focuses on a single administration. There are no additional non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, specified in the trial protocol. Participant compliance is monitored through the structured follow-up period post-infusion to assess safety and tolerability outcomes.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the incidence and grade of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs), within 28 days following the infusion of **TX200-TR101**. Secondary endpoints extend the evaluation period from the day of infusion through to Week 84 and include several parameters: the incidence of biopsy-confirmed acute rejection (BCAR) according to the Banff criteria, time to first BCAR episode, and the type and severity of any BCAR episodes. Additionally, the trial will monitor the incidence and grade of TEAEs, including SAEs, and the incidence of opportunistic infections such as BKV, EBV, and CMV reactivation, as well as the incidence of neoplasia.

Further secondary endpoints include the proportion of subjects receiving tacrolimus monotherapy at Week 84, the cumulative dose of immunosuppression through to Week 84, and the presence of CD4 positive cells that are also positive for HLA-A2 CAR RNA transcripts in the renal transplant biopsy at Week 16. The trial will also assess the incidence and severity of chronic graft dysfunction, as measured by estimated glomerular filtration rate (eGFR) and the Banff criteria for chronic rejection, including the Banff lesion score i-IFTA. The incidence of graft loss due to rejection and the incidence and semi-quantitative intensity of de novo donor-specific antibodies (DSA) will also be evaluated. These efficacy parameters will be collected and analyzed at specified timepoints throughout the study duration to determine the therapeutic impact of **TX200-TR101** in living donor renal transplant recipients.