Phase 2 Study of Empasiprubart in Deceased Donor Renal Allograft Recipients at Risk for Delayed Graft Function

The primary objective of this study is to evaluate the **efficacy** of ARGX-117 compared to placebo in improving allograft function in deceased donor kidney transplants at risk for delayed graft function (DGF). This is clinically relevant as DGF is a significant complication in renal transplantation, impacting graft survival and patient outcomes.

Secondary objectives include:

• Evaluating the efficacy of ARGX-117 compared to placebo in reducing the risk of DGF, promoting early recovery, and improving overall allograft function in deceased donor kidney transplants.
• Assessing the safety and tolerability of ARGX-117 compared to placebo.
• Evaluating the pharmacokinetics (PK) of ARGX-117.
• Assessing the pharmacodynamics (PD) of ARGX-117.
• Evaluating the immunogenicity of ARGX-117.

The clinical trial involves a total of **21 participants** who are being evaluated for the efficacy of ARGX-117 in improving allograft function in deceased donor kidney transplants at risk for **delayed graft function**. The study population includes both male and female subjects, aged between 18 and 70 years, who are diagnosed with end-stage renal disease (ESRD) and have been stable on chronic dialysis for at least three months. Participants are recipients of de novo or second-time, single kidney transplants from deceased donors, either DCD (donation after cardiac/circulatory death) or DBD (donation after brain death), and are ABO compatible with the donor allograft, except for type A2 donor to type B recipient kidneys. They have a negative cross match and have received pretransplant vaccinations for Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae, or are willing to receive these vaccinations approximately 3 to 4 months posttransplant. The trial includes a vulnerable population, and participants are required to agree to use contraceptive measures consistent with local regulations. The selection criteria ensure that the participants are at least the local legal age of consent for clinical studies.

The clinical trial is a **Phase 2**, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety, efficacy, and tolerability of **ARGX-117** in improving allograft function in recipients of a deceased donor renal allograft at risk for **delayed graft function**. The trial will involve participants who are at least 18 years old and less than 70 years old, diagnosed with end-stage renal disease (ESRD), and have been stable on chronic dialysis for at least three months. Participants will receive either ARGX-117 or a placebo via **intravenous infusion**. The trial is expected to start recruitment on October 17, 2023, and conclude by April 6, 2026.

The trial will consist of several key visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as ABO compatibility with the donor allograft and a negative cross-match. Participants must have received pretransplant vaccinations or be willing to receive them posttransplant. Following the screening, participants will be randomized to receive either the investigational product or placebo. The primary endpoint is the estimated glomerular filtration rate (eGFR) at 24 weeks posttransplant, with secondary endpoints including the proportion of participants with delayed graft function, duration of dialysis treatment, and safety outcomes.

Study visits will include regular follow-up assessments to monitor the efficacy and safety of the treatment, with specific evaluations at 72 hours posttransplant, study day 8, and at 52 weeks posttransplant. The end-of-study visit will occur at the conclusion of the 52-week period. Participants are expected to be involved in the study for approximately 52 weeks, with conditions for early termination including adverse events or withdrawal of consent. The trial will ensure rigorous monitoring of safety outcomes, including adverse events and vital sign measurements, to maintain participant safety throughout the study duration.

The clinical trial involves the administration of **ARGX-117**, an investigational medicinal product formulated as a **concentrate for solution for infusion**. The active substance in ARGX-117 is **empasiprubart**, a humanized monoclonal antibody targeting complement component 2. The pharmaceutical form is designed for **intravenous infusion**, and the dosing regimen is specified in **milligrams per kilogram (mg/kg)**. The maximum treatment period for ARGX-117 is set at 8 weeks. The administration schedule and specific dosage are determined based on the participant's body weight, and compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

The study also includes a **placebo** comparator, which is a solution designed to mimic the appearance and administration route of ARGX-117. The placebo is referred to as "Placebo to ARGX-117 IV concentrate solution for infusion" and serves as a control to evaluate the efficacy and safety of the experimental treatment. The placebo is administered via the same **intravenous infusion** route, ensuring blinding of both participants and investigators to the treatment allocation. The placebo does not contain any active pharmaceutical ingredients, and its administration schedule mirrors that of the experimental treatment to maintain consistency across study arms.

The efficacy of ARGX-117 in improving allograft function in recipients of deceased donor renal allografts at risk for delayed graft function (DGF) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the estimated glomerular filtration rate (**eGFR**) at 24 weeks posttransplant. Secondary endpoints include the proportion of participants with DGF and functional DGF (fDGF), the duration of dialysis treatment for DGF within the first 30 days posttransplant, and the composite renal response (CRR) at 72 hours posttransplant and on study day 8. Additional secondary endpoints involve the iBox score at 52 weeks posttransplant, dialysis-free participant survival through 52 weeks, and eGFR at 52 weeks posttransplant.

Safety outcomes will also be evaluated, including the incidence of adverse events (AE) and adverse events of special interest (AESI), vital sign measurements, and clinical laboratory tests. The incidence of primary non-function (PNF), serum concentrations, and pharmacokinetic (PK) parameters for ARGX-117 will be measured. Changes from baseline in free C2, total C2, and CH50 activity, as well as the incidence and prevalence of anti-drug antibodies (ADA) against ARGX-117, will be assessed. The proportion of participants with an ongoing dialysis requirement at study day 31 and (death-censored) allograft survival through 52 weeks posttransplant will also be analyzed.