Evaluation of Pegcetacoplan for Safety and Efficacy in Post-Transplant Recurrence of Complement 3 Glomerulopathy or Immune Complex Membranoproliferative Glomerulonephritis

The primary objective of this study is to evaluate the **efficacy** of pegcetacoplan in improving the underlying pathophysiology of **complement 3 glomerulopathy (C3G)** and **immune complex membranoproliferative glomerulonephritis (IC-MPGN)** after 12 weeks of treatment. This is clinically relevant as it aims to address the disease mechanisms in patients experiencing post-transplant recurrence, potentially improving renal function and patient outcomes.

Secondary objectives include:

• To evaluate the effect of pegcetacoplan on key clinical manifestations of the disease after 52 weeks of treatment.
• To evaluate the safety of pegcetacoplan for up to 52 weeks in patients with recurrent C3G/IC-MPGN in a renal allograft.

The clinical trial involves a total of **5 participants** diagnosed with **complement 3 glomerulopathy (C3G)** or **immune complex membranoproliferative glomerulonephritis (IC-MPGN)**. The study population includes both male and female subjects, aged 18 years and older, who are considered part of a vulnerable population. Participants were selected based on their ability to provide informed consent and comply with study requirements, as well as having clinical and pathologic evidence of recurrent C3G or IC-MPGN. The trial does not specify particular lifestyle considerations such as diet or physical activity. Key inclusion criteria include a stable or worsening disease state, an estimated glomerular filtration rate (eGFR) of at least 15 mL/min/1.73 m², and a stable regimen for recurrent C3G/IC-MPGN prior to screening. Participants must also have received vaccinations against specific pathogens or agree to receive them if applicable records are unavailable. The trial includes both men and women, with women of childbearing potential required to use contraception and undergo pregnancy testing. Men are also required to use contraception and refrain from donating semen during the study period.

The clinical trial is designed as an open-label, **randomized**, controlled, Phase 2 study to evaluate the safety and efficacy of **pegcetacoplan** in the treatment of post-transplant recurrence of **complement 3 glomerulopathy (C3G)** or **immune complex membranoproliferative glomerulonephritis (IC-MPGN)**. The primary objective is to assess the efficacy of pegcetacoplan in improving the underlying pathophysiology of C3G/IC-MPGN after 12 weeks of treatment. The trial is expected to conclude by May 2026, with recruitment having commenced in December 2020. Participants will be involved in the study for a maximum treatment period of 76 weeks.

Study visits are structured to include an initial screening visit, where eligibility is confirmed based on criteria such as age, disease stability, and vaccination status. Participants must be at least 18 years old, have clinical and pathologic evidence of recurrent C3G or IC-MPGN, and meet other specific health criteria. Following the screening, participants will undergo regular follow-up visits to monitor treatment efficacy and safety, with assessments including renal biopsies and evaluations of estimated glomerular filtration rate (eGFR) and serum creatinine concentration. The primary endpoint is the proportion of subjects with a reduction in C3c staining on renal biopsy after 12 weeks of treatment. Secondary endpoints include long-term changes in C3c staining, eGFR, and serum creatinine, as well as safety assessments through the incidence of treatment-emergent adverse events.

The study involves the administration of pegcetacoplan via subcutaneous injection using the FreedomEdge® Syringe Infusion System. Participants are required to self-administer the medication or have a caregiver perform the administration. The expected length of participant involvement is up to 76 weeks, with conditions for early termination including significant adverse events or non-compliance with study procedures. The trial is not classified as low intervention, and it is crucial for participants to adhere to the protocol-defined methods of contraception throughout the study duration and for a specified period after the last dose of pegcetacoplan.

The clinical trial involves the administration of **ASPAVELI**, a solution for infusion containing the active substance **pegcetacoplan**. Pegcetacoplan is a protein-based therapeutic agent, specifically classified under the ATC code L04AJ03. The pharmaceutical form of ASPAVELI is a solution for infusion, and it is administered via **subcutaneous injection**. The maximum daily dose is 1080 mg, with a total maximum dose of 82080 mg over the treatment period. The treatment duration is set for a maximum of 76 weeks. The administration of pegcetacoplan is facilitated by the FreedomEdge® Syringe Infusion System, an ambulatory syringe infusion system that ensures precise delivery of the medication. This system is CE-marked, indicating compliance with European health, safety, and environmental protection standards.

In this study, pegcetacoplan is the experimental medication, and no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial aims to evaluate the efficacy of pegcetacoplan in improving the underlying pathophysiology of complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) after 12 weeks of treatment. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol. The study is conducted under the authorization of the European Union, with the marketing authorization number EU/1/21/1595/001, and is designated as an orphan drug under the designation number EU/3/19/2201.

The efficacy of **pegcetacoplan** in the treatment of post-transplant recurrence of complement 3 glomerulopathy (C3G) or immune complex membranoproliferative glomerulonephritis (IC-MPGN) will be assessed through a series of predefined endpoints. The primary efficacy endpoint is the proportion of subjects demonstrating a reduction in C3c staining on renal biopsy after 12 weeks of treatment. Secondary endpoints include the proportion of subjects with a reduction in C3c staining on renal biopsy after 52 weeks, stabilization or improvement in estimated glomerular filtration rate (eGFR) over time, and stabilization or improvement of serum creatinine concentration over time. Additionally, changes from baseline biopsy in C3c staining, as well as changes and percentage changes from baseline in eGFR and serum creatinine concentration, will be evaluated over time.

These efficacy parameters will be measured and collected at specified timepoints throughout the study, with renal biopsies and laboratory tests serving as the primary tools for assessment. The study will also monitor safety through the number and incidence of treatment-emergent adverse events (TEAEs), and changes from baseline in vital signs, clinical laboratory test results, and ECG results. The trial is designed to provide comprehensive data on the efficacy and safety of pegcetacoplan over a treatment period of up to 76 weeks.