Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of Efgartigimod Alfa SC in Antibody-Mediated Rejection in Kidney Transplant Recipients

The primary objective of this study is to evaluate the **safety** and **tolerability** of efgartigimod PH20 SC in kidney transplant recipients diagnosed with **antibody-mediated rejection** (AMR). This is clinically relevant as ensuring the safety and tolerability of new treatments is crucial for patient care and the successful management of AMR, a significant complication in kidney transplantation.

Secondary objectives include:

• Evaluating the proof of concept (PoC) of efgartigimod PH20 SC in kidney transplant recipients with AMR.
• Assessing the pharmacodynamic (PD) effect of efgartigimod PH20 SC, specifically focusing on total immunoglobulin G (IgG).
• Assessing the pharmacokinetic (PK) profile of efgartigimod PH20 SC.
• Assessing the immunogenicity of efgartigimod PH20 SC.

The clinical trial involves a total of **5 participants** diagnosed with **antibody-mediated rejection** following a kidney transplant. The study population includes both male and female subjects, aged between **18 and 80 years**. Participants were selected based on their medical history of kidney transplantation, having received a transplant from either a living or deceased donor at least six months prior to screening. The trial includes individuals with active or chronic active antibody-mediated rejection, confirmed by the presence of detectable donor-specific antibodies. Participants are required to have been on a stable regimen of immunosuppressive medications, including mycophenolate mofetil and tacrolimus, for a specified duration before enrollment. The study population is considered vulnerable, and the trial aims to evaluate the safety and tolerability of efgartigimod PH20 SC in this specific group. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** Phase 2 study designed to evaluate the safety, tolerability, and efficacy of **Efgartigimod** PH20 SC administered via a prefilled syringe in kidney transplant recipients diagnosed with **antibody-mediated rejection**. The trial is expected to commence recruitment on November 11, 2024, and conclude by September 30, 2027. Participants will be randomly assigned to receive either the investigational product, Efgartigimod, or a placebo, both administered as a subcutaneous injection. The trial will involve multiple study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, transplant history, and current medication regimen.

Following the screening, eligible participants will undergo a baseline visit where initial assessments, including laboratory tests and vital sign measurements, will be conducted. Subsequent visits will occur at regular intervals to monitor the incidence and severity of adverse events, assess laboratory parameters, and measure vital signs and ECG. Secondary endpoints will include evaluations of eGFR, histologic changes in kidney biopsy, urine protein creatinine ratio, and graft and participant survival. The study will also measure changes in total IgG levels and the pharmacokinetics of Efgartigimod over time.

The expected duration of participant involvement is up to 48 weeks, with conditions for early termination including the occurrence of severe adverse events or significant protocol deviations. The end-of-study visit will involve comprehensive assessments to evaluate the overall safety and efficacy outcomes. Participants may be withdrawn from the study if they experience permanent treatment discontinuation due to adverse events or if they no longer meet the study criteria. The trial aims to provide valuable insights into the management of antibody-mediated rejection in kidney transplant recipients.

The clinical trial involves the administration of **Efgartigimod**, a solution for injection in a pre-filled syringe. The active substance in this experimental medication is **efgartigimod alfa**, a protein of human monoclonal origin, specifically an anti-FcRn receptor fragment. The pharmaceutical form is a solution intended for subcutaneous injection. The maximum daily dose is 1000 mg, with a total maximum dose of 36000 mg over a treatment period of 48 weeks. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen. The product is developed by ARGENX BV and is identified by the sponsor product code ARGX-113.

The study also includes a **placebo** treatment, which is a prefilled syringe designed to mimic the administration of Efgartigimod. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo is administered via subcutaneous injection, similar to the experimental medication, to ensure consistency in the administration process. The placebo is crucial for evaluating the safety, tolerability, and efficacy of Efgartigimod in comparison to a non-active treatment.

The efficacy of Efgartigimod PH20 SC in the clinical trial will be assessed through a series of primary and secondary endpoints. Primary endpoints include the incidence and severity of adverse events (AEs), the percentage of participants with permanent treatment discontinuation due to AEs, and laboratory assessments, vital sign measurements, and ECG results. These parameters will provide a comprehensive overview of the treatment's safety profile.

Secondary endpoints will focus on evaluating the treatment's impact on kidney function and overall health outcomes. These include measurements of estimated glomerular filtration rate (eGFR) in terms of absolute values and changes from baseline, histologic changes in kidney biopsy, and the urine protein creatinine ratio. Additionally, graft and participant survival rates will be monitored. The study will also assess the percentage change from baseline in total IgG levels in serum over time, as well as the serum concentration of Efgartigimod and its pharmacokinetic parameter Ctrough. The incidence and prevalence of antidrug antibodies (ADA) against Efgartigimod and antibodies against rHuPH20 in plasma over time will also be evaluated.