Evaluation of Tegoprubart Versus Tacrolimus in Prophylaxis of Renal Allograft Rejection in Kidney Transplant Recipients

The primary objective of this study is to assess the **graft function** at 12 months post-transplant in participants treated with tegoprubart compared to those treated with tacrolimus. This evaluation is clinically relevant as it aims to determine the efficacy of tegoprubart in maintaining renal allograft function, which is crucial for the long-term success of kidney transplantation and the prevention of renal allograft rejection.

Secondary objectives include:

• Assessing the safety and tolerability of immunomodulation with tegoprubart in combination with rabbit anti-thymocyte globulin (rATG), mycophenolate mofetil (MMF) or mycophenolate sodium (MPS), and corticosteroids (CS) compared to the standard of care (SOC) regimen.
• Evaluating the rate of graft functional impairment at 12 months in tegoprubart-treated participants compared to those treated with tacrolimus.
• Assessing the rate of biopsy-proven acute rejection (BPAR) at 12 months post-transplant in tegoprubart-treated participants compared to tacrolimus-treated participants.
• Evaluating the incidence of new onset diabetes mellitus after transplant (NODAT) at 12 months in tegoprubart-treated participants compared to tacrolimus-treated participants.
• Assessing overall patient and graft survival at 12 months post-transplant in tegoprubart-treated participants compared to tacrolimus-treated participants.

The clinical trial involves a total of **91 participants** who are being studied for the **prophylaxis of renal allograft rejection**. The study population includes both male and female subjects aged 18 years and older, who are recipients of their first kidney transplant from either a living or deceased donor. Participants were selected based on their ability to understand the study's key components and provide informed consent, as well as their willingness to comply with study requirements, including medication restrictions. The trial includes individuals who are surgically sterile or postmenopausal, and those of childbearing potential must adhere to strict contraceptive measures. Both male and female participants are required to use highly effective contraception methods during the study and for a specified period after the last administration of the study drug. The trial population is considered vulnerable, reflecting the specific health status and medical needs of kidney transplant recipients. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a Phase 2, multicenter, randomized, open-label study designed to evaluate the safety and efficacy of **tegoprubart** in patients undergoing kidney transplantation. The trial aims to assess graft function at 12 months post-transplant in participants treated with tegoprubart compared to those treated with **tacrolimus**. The study will involve approximately 120 de novo kidney transplant recipients who will receive induction with **rabbit anti-thymocyte globulin (rATG)**, maintenance with corticosteroids, and **mycophenolate**. Participants will be randomized in a 1:1 ratio to receive either tegoprubart 20 mg/kg intravenously every 21 days after an initial loading period or twice daily oral tacrolimus.

The trial is expected to commence recruitment on November 27, 2023, and conclude by January 30, 2026. The study visits are structured to include an initial screening visit to determine eligibility based on specific inclusion criteria, such as being a recipient of a first kidney transplant and being willing to comply with study requirements. Participants will undergo regular follow-up visits to monitor graft function and overall health, with the primary endpoint being the mean estimated glomerular filtration rate (eGFR) at 12 months. Secondary endpoints include the rate of graft functional impairment, new-onset diabetes after transplantation (NODAT), and patient and graft survival rates at 12 months.

Participant involvement is anticipated to last for the duration of the trial, with the maximum treatment period for tegoprubart being 365 days. Conditions that may lead to early termination from the study include non-compliance with study protocols, adverse reactions to the study drug, or withdrawal of consent. The trial is not categorized as low intervention and is conducted under controlled conditions to ensure the reliability and validity of the results.

The clinical trial involves the administration of several experimental and non-experimental treatments to evaluate their safety and efficacy in patients undergoing kidney transplantation. The primary experimental medication is **Tegoprubart**, administered as a 190 mg or 475 mg vial for intravenous use. Tegoprubart is a humanized IgG1k monoclonal antibody against CD40L, used to prevent organ transplant rejection. The maximum daily dose is 20 mg/kg, with a total dose not exceeding 66 grams over a treatment period of up to 365 days. Compliance with the dosing schedule is monitored through regular assessments.

**Mycophenolate Mofetil** is used as an auxiliary treatment in various forms, including CellCept 1 g/5 ml powder for oral suspension, 250 mg capsules, and 500 mg film-coated tablets. The maximum daily dose for these formulations is 1000 mg, administered orally, with a treatment period of up to 12 months. Mycophenolate Mofetil is an immunosuppressant that helps prevent organ transplant rejection by inhibiting lymphocyte proliferation.

**Mycophenolic Acid** is provided in the form of Myfortic 360 mg and 180 mg gastro-resistant tablets. These tablets are administered orally with a maximum daily dose of 720 mg. The treatment duration is up to 12 months. Mycophenolic Acid serves as an immunosuppressant to prevent organ transplant rejection by inhibiting inosine monophosphate dehydrogenase, crucial for lymphocyte proliferation.

**Tacrolimus** is administered as Prograf 0.5 mg, 1 mg, and 5 mg hard capsules, as well as a 5 mg/ml concentrate for solution for infusion. The maximum daily dose is 0.1 mg/kg, with a total dose not exceeding 36.5 mg/kg over a 12-month period. Tacrolimus is a calcineurin inhibitor that suppresses the immune response to prevent organ transplant rejection.

**Prednisolone** is provided as 5 mg tablets, with a maximum daily dose of 5 mg and a total dose of 770 mg over a 12-month period. Prednisolone is a glucocorticoid used to treat inflammatory conditions and prevent organ transplant rejection by modulating the immune response.

**Antithymocyte Immunoglobulin** is administered as Thymoglobuline 25 mg powder for solution for infusion. The maximum daily dose is 1.5 mg/kg, with a total dose not exceeding 6 mg/kg over a 10-day period. This immunosuppressant is used to prevent organ transplant rejection by depleting T-lymphocytes.

Participant compliance with the dosing schedules is monitored through regular clinical assessments and documentation. The trial aims to assess the graft function at 12 months post-transplant in Tegoprubart-treated participants compared to those treated with Tacrolimus. The study is conducted in accordance with regulatory guidelines to ensure the safety and efficacy of the treatments administered.

Efficacy in this clinical trial will be assessed primarily by evaluating the mean estimated glomerular filtration rate (**eGFR**) at 12 months post-transplant. This parameter serves as the primary endpoint to determine the effectiveness of **tegoprubart** in comparison to **tacrolimus** in maintaining graft function in patients undergoing kidney transplantation. Secondary endpoints include the rate of graft functional impairment, defined as an eGFR of less than 60 mL/min/1.73m² or a decrease in eGFR of 10 mL/min/1.73m² or more from Month 1 to Month 12. Additional secondary endpoints are the rate of new-onset diabetes after transplantation (NODAT), patient and graft survival rates, and the rate of biopsy-proven acute rejection (BPAR) at 12 months.

The efficacy parameters will be measured and collected at specified timepoints, with the primary endpoint being assessed at the 12-month mark. The analysis will involve comparing the outcomes between the two treatment groups, those receiving tegoprubart and those receiving tacrolimus, to determine the relative efficacy of the interventions. The study is designed as a Phase 2, multicenter, randomized, open-label trial, with approximately 120 de novo kidney transplant recipients participating. Participants will be randomized in a 1:1 ratio to receive either tegoprubart intravenously every 21 days following an initial loading period or twice daily oral tacrolimus, alongside standard immunosuppressive therapy including rATG induction, corticosteroid maintenance, and mycophenolate.