Efficacy and Safety of Imlifidase in Desensitizing Highly Sensitized End-Stage CKD Patients for Kidney Transplantation with Positive Crossmatch

The primary objective of this study is to determine the 1-year **graft failure-free survival** in highly sensitised kidney transplant patients who are pre-treated with **imlifidase** to convert a positive crossmatch against a deceased donor to negative. This is clinically relevant as it addresses the challenge of transplanting kidneys in patients with high levels of antibodies, potentially increasing the pool of available organs and improving transplant outcomes.

Secondary objectives include evaluating various clinical parameters in the imlifidase cohort, such as:

• Renal function up to 1 year post-transplantation
• Patient survival 1 year post-transplantation
• Graft survival 1 year post-transplantation
• Crossmatch conversion within 24 hours of treatment
• HLA/DSA antibody levels up to 1 year post-transplantation
• Pharmacokinetic and pharmacodynamic profiles of imlifidase
• Immunogenicity profile concerning anti-drug antibodies
• Delayed graft function
• Proportion of patients with biopsy- and serology-confirmed antibody-mediated rejections (AMRs) and cell-mediated rejections (CMRs) up to 1 year post-transplantation
• Safety of imlifidase treatment regarding serious adverse events, infusion-related reactions, and severe infections
• Health-related quality of life, specifically patients' life participation

Additionally, similar evaluations are conducted in concurrent and historical reference cohorts to provide comparative data.

The clinical trial involves a total of **6 participants** who are **end-stage chronic kidney disease (CKD) patients** highly sensitized and on the kidney transplant list awaiting a transplant. The study population includes both male and female patients aged between **18 and 75 years**. Participants were selected based on their status as highly sensitized individuals with a high unmet medical need, unlikely to be transplanted under the current kidney allocation system. The trial includes patients who are active on the renal transplant waiting list and have a known donor-specific antibody (DSA) against an available deceased donor. The participants are required to have a positive crossmatch test and must have signed informed consent before any trial-related procedures. The study population is characterized by their vulnerability due to their medical condition and the critical need for a kidney transplant. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The inclusion criteria ensure that participants are those with the highest need for intervention, reflecting the trial's focus on improving outcomes for this specific patient group.

The clinical trial is designed to evaluate the efficacy and safety of **imlifidase** in highly sensitised patients with end-stage chronic kidney disease (CKD) who are on the kidney transplant list. This study is a controlled, open-label, post-authorisation trial that includes non-comparative registry and concurrent reference cohorts. The primary objective is to determine the 1-year graft failure-free survival in patients pre-treated with imlifidase to convert a positive crossmatch against a deceased donor to negative. The trial is expected to conclude by August 31, 2025, with recruitment having commenced on May 23, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and willingness to comply with the protocol. Following the screening, eligible participants will receive the investigational product, Idefirix, administered via intravenous infusion. Subsequent follow-up visits will be scheduled at several time points, including 24 hours, 2 weeks, and at 1, 3, 6 months, and 1 year post-transplantation, to assess renal function, patient and graft survival, and safety outcomes. The end-of-study visit will occur at the 1-year mark post-transplantation.

The expected duration of participant involvement is approximately 1 year, aligning with the primary endpoint of 1-year graft failure-free survival. Conditions that may lead to early termination from the study include withdrawal of consent, non-compliance with the study protocol, or any adverse events that, in the opinion of the investigator, warrant discontinuation for the safety of the participant. The study will also monitor secondary endpoints such as renal function, patient survival, and safety parameters, including the incidence of serious adverse events and infections.

The clinical trial involves the administration of **Idefirix**, which is a powder for concentrate for solution for infusion. The active substance in Idefirix is **imlifidase**, a protein of non-human origin. The pharmaceutical form of the medication is a solution for infusion, and it is administered via **intravenous infusion**. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 0.25 mg/kg. The total dose administered over the treatment period also does not exceed 0.25 mg/kg. The maximum treatment period is limited to one day. Idefirix is not formulated for pediatric use and is classified as an orphan drug, indicating its use in rare conditions. The product is manufactured by Hansa Biopharma AB and has been authorized for use in the European Union.

In this study, Idefirix is used to desensitize kidney transplant patients who have a positive crossmatch against a deceased donor. The primary objective is to assess the 1-year graft failure-free survival in these highly sensitized patients. There are no non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, specified in the trial protocol. Participant compliance with the dosing schedule is monitored to ensure adherence to the treatment regimen. The trial is conducted under controlled, open-label conditions, allowing for the observation of efficacy and safety outcomes in the target patient population.

Efficacy in this clinical trial will be assessed primarily through the evaluation of the 1-year **graft failure-free survival** in patients who have undergone kidney transplantation following treatment with imlifidase. Secondary endpoints will include a comprehensive assessment of renal function at various time points, specifically between 24 hours and 2 weeks, and at 1, 3, and 6 months, as well as 1 year post-transplantation. This will be measured using estimated glomerular filtration rate (eGFR) and serum/plasma creatinine levels. Additionally, patient survival and graft survival at 1 year post-transplantation will be evaluated.

Further efficacy assessments will involve the proportion of patients achieving conversion of a positive crossmatch test to negative within 24 hours after imlifidase treatment, and monitoring of HLA/DSA antibody levels at specified intervals from pre-dose imlifidase to 2 weeks, and at 1, 3, and 6 months, and 1 year post-treatment. Pharmacokinetic (PK) and pharmacodynamic (PD) profiles of imlifidase will be analyzed up to 14 and 9 days post-treatment, respectively. The presence of anti-drug antibodies (ADAs) will be monitored up to 1 year post-treatment.

Additional parameters include the frequency of delayed graft function (DGF), the proportion of patients with biopsy- and serology-confirmed antibody-mediated rejections (AMRs) and biopsy-confirmed cellular-mediated rejections (CMRs) over 1 year. Safety will be assessed by the incidence of serious adverse events (SAEs) and infusion-related reactions within 48 hours of imlifidase infusion, as well as severe or serious infections within 30 days post-transplantation. Patient-reported outcomes will be measured using the PROMIS Social Health domain "Ability to participate in social roles & activities, PROMIS-SF-8a" from baseline to 1 year post-transplantation.