Evaluation of Imlifidase for Achieving Negative Virtual Crossmatch in Highly Sensitized Patients Undergoing Living Donor Renal Transplantation

The primary objective of this study is to evaluate the ability of **Imlifidase** treatment to achieve a negative virtual crossmatch in patients with an available live donor kidney. This is clinically relevant as achieving a negative virtual crossmatch is crucial for the success of kidney transplantation in highly sensitized recipients, potentially increasing the pool of compatible donors and improving transplantation outcomes.

Secondary objectives include:

• Proportion of patients requiring a second dose of Imlifidase.
• Monitoring the appearance of pre-existing donor-specific antibodies (DSA) daily until day 14.
• Assessment of de novo DSA appearance over 14 days post-treatment.
• Measurement of HLA/DSA antibody levels at various time points up to one year post-treatment.
• Evaluation of renal function at specified intervals post-transplantation using estimated glomerular filtration rate (eGFR) and serum/plasma creatinine levels.
• Patient survival at 12 months post-transplantation.
• Graft survival at 12 months post-transplantation.
• Proportion of patients with biopsy-confirmed rejection over one year.
• Proportion of patients experiencing infusion-related reactions within 48 hours of Imlifidase infusion.
• Proportion of patients with adverse events within 30 days post-transplantation.
• Proportion of patients with severe or serious infections at 6 and 12 months.
• Overall safety over one year as measured by reported serious adverse events (SAEs).

The clinical trial involves **kidney transplant** candidates who are highly sensitized, with a calculated panel reactive antibody (cPRA) of 50% or greater. The study population includes both male and female participants, aged between 18 and 65 years. Participants are selected based on their low probability of receiving a transplant through a kidney exchange program from a living donor. They must be part of a living donor program with an accepted potential living donor. The trial population is characterized by the presence of donor-specific antibodies and a positive crossmatch with a non-HLA identical donor. Participants must meet specific criteria, including a maximum of two Class II donor-specific antibodies and a Jordan RIS Score of no more than 17 points. Women of childbearing age are required to use contraceptive measures due to the potential risks of Imlifidase during pregnancy. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, and all participants must have given written informed consent and comply with study requirements.

The clinical trial is designed to evaluate the efficacy of **imlifidase** in achieving a negative virtual crossmatch in highly sensitized patients undergoing kidney transplant from a living donor. This is a Phase 2, randomized, double-blind, controlled trial. The trial is expected to commence on November 15, 2024, and conclude by February 15, 2026. Participants will be involved in the study for a maximum treatment period of one day, with follow-up assessments extending up to one year post-transplantation.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will determine eligibility based on criteria such as age, sensitization level, and donor compatibility. Participants must be highly sensitized kidney transplant candidates aged 18 to 65 years, with a low probability of receiving a transplant through a kidney exchange program. The presence of donor-specific antibodies and a positive crossmatch with a non-HLA identical donor are required for inclusion. Women of childbearing age must adhere to contraceptive measures due to the potential risks of **imlifidase** during pregnancy.

Following the screening, participants will receive up to two doses of **imlifidase** to facilitate the conversion of a positive virtual crossmatch to negative within six hours. Secondary endpoints include evaluating T-cell crossmatch conversion within 24 hours, monitoring the rebound of preexisting donor-specific antibodies, and assessing the appearance of de novo DSAs. Renal function and patient survival will be evaluated at several time points, including 24 hours, two weeks, and at 1, 3, 6, and 12 months post-transplantation. Safety assessments will focus on infusion-related reactions, adverse events, and serious infections within specified timeframes.

Participants may be withdrawn from the study if they experience severe adverse reactions, fail to comply with study requirements, or if the investigator deems it necessary for their safety. The end-of-study visit will occur at the 12-month mark, where final assessments of graft survival, patient survival, and overall safety will be conducted. The trial aims to provide valuable insights into the potential of **imlifidase** to improve outcomes for highly sensitized kidney transplant recipients.

The clinical trial involves the administration of **Imlifidase**, a protein-based experimental medication, utilized in the context of living donor renal transplantation for highly sensitized recipients. **Imlifidase** is provided in the pharmaceutical form of a **solution for infusion**. The active substance, **Imlifidase**, is administered intravenously at a dosage of 0.50 mg/kg. The maximum daily dose and the total dose are both set at 0.50 mg/kg. The treatment period is limited to a single day, ensuring a concise administration schedule. The medication is not formulated for pediatric use and is not classified as an orphan drug. The primary objective of the trial is to evaluate the efficacy of **Imlifidase** in achieving a negative virtual crossmatch in patients with an available live donor kidney.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on the administration of **Imlifidase**. Participant compliance is monitored through the controlled administration of the infusion, ensuring adherence to the dosing schedule. The trial does not involve any additional medicinal products or devices, and the administration route is strictly via infusion. The study is designed to assess the specific impact of **Imlifidase** on the targeted patient population, with compliance and dosing closely monitored to maintain the integrity of the trial outcomes.

Efficacy in the clinical trial titled "IMLIFIDASE IN LIVING DONOR RENAL TRANSPLANTATION: HIGHLY SENSITIZED RECIPIENTS (LIVEDES STUDY)" will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients achieving conversion of a positive virtual crossmatch to negative within 6 hours following treatment with **Imlifidase**, with up to two doses administered. Secondary endpoints include the evaluation of flow cytometry T-cell crossmatch conversion within 24 hours of treatment and the requirement for a second dose of **Imlifidase**.

Additional secondary endpoints involve monitoring the rebound of preexisting donor-specific antibodies (DSA) by measuring the difference in mean fluorescence intensity (MFI) of each DSA daily until day 14 post-treatment compared to pre-treatment levels. The appearance of de novo DSAs will also be evaluated daily until day 14, with positivity defined by a bead MFI over 750 and above the bead-specific threshold. HLA/DSA antibody levels will be assessed at various time points from pre-dose to 2 weeks, and at 1, 3, 6 months, and 1 year post-treatment. Renal function will be evaluated at several time points between 24 hours and 2 weeks, and at 1, 3, 6 months, and 1 year post-transplantation, using estimated glomerular filtration rate (eGFR) and serum/plasma creatinine levels as measures.

Patient survival and graft survival will be assessed at 1 year and 12 months post-transplantation, respectively, with analyses including both overall and death-censored evaluations. The incidence of acute allograft rejection within 12 months will be evaluated, stratified by type: cell-mediated rejection or antibody-mediated rejection. Safety assessments will include monitoring for infusion-related reactions within 48 hours of **Imlifidase** infusion, adverse events within 30 days post-transplantation, and severe or serious infections requiring hospitalization within 30 days, at 6 months, and at 12 months. The safety of **Imlifidase** treatment will also be evaluated concerning reported serious adverse events (SAEs).