Evaluation of Long-term Safety and Efficacy of Pegcetacoplan in Patients with C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis

The primary objective of this study is to establish the long-term **safety** and efficacy of pegcetacoplan in participants with C3 glomerulopathy (C3G) or immune complex membranoproliferative glomerulonephritis (IC-MPGN). This is clinically relevant as it aims to provide insights into the sustained therapeutic benefits and potential risks associated with prolonged use of pegcetacoplan in these conditions, which are characterized by chronic kidney inflammation and can lead to significant renal impairment.

Secondary objectives include characterizing the long-term effects of treatment with pegcetacoplan in participants with C3G or IC-MPGN, focusing on pharmacokinetics (PK), pharmacodynamics (PD), and the immunogenic response. These exploratory objectives are crucial for understanding the drug's behavior in the body over time, its biological effects, and the potential for immune system reactions, which can inform future therapeutic strategies and patient management.

The clinical trial involves a total of **64 participants** diagnosed with **C3 glomerulopathy (C3G)** or **immune complex membranoproliferative glomerulonephritis (IC-MPGN)**. The study population includes both male and female subjects, encompassing a diverse age range, although specific age categories are not detailed. Participants were selected based on their completion of a prior study, APL2-C3G-310, and their demonstrated clinical benefit from the investigational drug, pegcetacoplan. The trial includes individuals who are part of a vulnerable population, indicating additional ethical considerations in the study design. Participants are required to maintain a stable treatment regimen for their condition and have received specific vaccinations as per study requirements. Lifestyle factors such as diet and physical activity are not specified, but participants must be willing and able to self-administer the medication or have a caregiver to assist. The trial includes both genders, with specific contraceptive measures required for participants of childbearing potential. The study aims to assess the long-term safety and efficacy of pegcetacoplan in this patient population.

The clinical trial is designed to evaluate the long-term safety and efficacy of **pegcetacoplan** in participants with C3 glomerulopathy (C3G) or immune complex membranoproliferative glomerulonephritis (IC-MPGN). This is an open-label, nonrandomized, multicenter extension study. The trial is expected to run until July 29, 2027, with recruitment having started on May 29, 2023. Participants are required to have completed participation in a previous study (APL2-C3G-310) and must have experienced clinical benefit from pegcetacoplan as assessed by the investigator. The study involves a series of visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria, which include stable treatment regimens and specific vaccination requirements. Follow-up visits will be conducted to monitor the primary endpoint, which is the log-transformed ratio of urine protein-to-creatinine ratio over time compared to the pretreatment baseline. Secondary endpoints include the stability or improvement of estimated glomerular filtration rate (eGFR) values, proteinuria levels, and changes in the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue) Scale score, among others. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 120 weeks. Conditions that may lead to early termination from the study include non-compliance with the study protocol or withdrawal of consent. Participants are expected to self-administer pegcetacoplan or have a caregiver administer it, and they must adhere to protocol-defined methods of contraception throughout the study and for a specified period after the last dose. The trial is categorized as a phase III therapeutic confirmatory trial, aligning with EMA guidance on disclosure rules.

The clinical trial involves the administration of **Pneumovax 23**, a pneumococcal polysaccharide vaccine. This vaccine is provided in a solution for injection form, available in pre-filled syringes. The active substances include a range of pneumococcal polysaccharide serotypes, specifically serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F. The vaccine is administered either intramuscularly or subcutaneously, with a maximum daily dose of 0.5 ml. The treatment period is limited to a single day.

**ASPAVELI**, containing the active substance **pegcetacoplan**, is another experimental medication used in this trial. It is formulated as a solution for infusion, with a maximum daily dose of 1080 mg/ml and a total dose of 259200 mg/ml over the treatment period. The administration route is subcutaneous, facilitated by the FreedomEdge® Syringe Infusion System, an ambulatory syringe infusion system. The treatment duration extends up to 120 days. This product is classified as an orphan drug and involves a combination product that includes a device.

**Bexsero** is a meningococcal group B vaccine provided as a suspension for injection in pre-filled syringes. The active substances include recombinant Neisseria meningitidis group B NHBA fusion protein, NadA protein, fHbp fusion protein, and outer membrane vesicles from Neisseria meningitidis group B strain NZ98/254, all adsorbed on aluminium hydroxide. The vaccine is administered intramuscularly, with a maximum daily dose of 0.5 ml and a total dose of 1 ml over a one-day treatment period.

**Nimenrix** is a meningococcal conjugate vaccine targeting groups A, C, W-135, and Y. It is provided as a powder and solvent for solution for injection in vials. The active substances are polysaccharides from Neisseria meningitidis groups A, C, W-135, and Y, each conjugated to tetanus toxoid carrier protein. The vaccine is administered intramuscularly, with a maximum daily dose of 0.5 ml and a total dose of 0.5 ml over a one-day treatment period.

Throughout the trial, participant compliance with dosing schedules is monitored to ensure adherence to the specified administration routes and dosages. The trial aims to evaluate the long-term safety and efficacy of pegcetacoplan in participants with C3 glomerulopathy or immune-complex membranoproliferative glomerulonephritis.

The efficacy of pegcetacoplan in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the log-transformed ratio of urine protein-to-creatinine ratio (uPCR) over time compared to the pretreatment baseline. This measurement will provide insights into the drug's impact on proteinuria, a key indicator of kidney function in participants with C3 Glomerulopathy (C3G) or Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN).

Secondary endpoints include the proportion of participants with stable or improved estimated glomerular filtration rate (eGFR) values from pretreatment values over time, and the proportion of participants achieving proteinuria of less than 1 g/day over time. Additionally, changes from pretreatment in the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue) Scale score and eGFR values over time will be evaluated. For participants with pretreatment serum albumin or serum C3 levels below the lower limit of normal (LLN), the proportion achieving normalization of these levels over time will be assessed. Furthermore, the trial will monitor the proportion of participants progressing to a clinical composite outcome, which includes doubling of serum creatinine, progression to chronic kidney disease stage 5 or end-stage renal disease (ESRD), renal transplantation, or death over time.