A MULTICENTER OPEN-LABEL, UNCONTROLLED STUDY TO EVALUATE THE PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY, TOLERABILITY, AND ACTIVITY OF ZILUCOPLAN IN PEDIATRIC STUDY PARTICIPANTS FROM 2 TO LESS THAN 18 YEARS OF AGE WITH ACETYLCHOLINE RECEPTOR ANTIBODY POSITIVE GENERALIZED MYASTHENIA GRAVIS

The primary objective of this study is to assess the **pharmacokinetics** (PK) and **pharmacodynamics** (PD) of zilucoplan (ZLP) when administered by subcutaneous injection once daily in pediatric participants aged 2 to less than 18 years with **generalized Myasthenia Gravis** (gMG). Understanding the PK and PD profiles of ZLP in this population is clinically relevant as it provides critical insights into the drug's absorption, distribution, metabolism, and excretion, as well as its biological effects, which are essential for optimizing therapeutic strategies in pediatric patients with gMG.

Secondary objectives include:

• Assessing the safety and tolerability of zilucoplan administered by subcutaneous injection once daily in the specified pediatric population.
• Evaluating the immunogenicity of zilucoplan in these participants.
• Determining the activity of zilucoplan in the treatment of gMG in the pediatric cohort.

The clinical trial involves a total of **6 participants** diagnosed with **Generalized Myasthenia Gravis** (gMG). The study population consists of pediatric subjects aged **2 to <18 years**, encompassing both male and female participants. The trial population was selected based on specific inclusion criteria, including a confirmed diagnosis of gMG and meeting the Myasthenia Gravis Foundation of America (MGFA) Clinical Classification II to IV. Participants are required to have documented vaccination against meningococcal infections or receive appropriate prophylactic antibiotic treatment if not fully vaccinated. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, given the pediatric age range of the participants.

The clinical trial is designed as a **multicenter open-label, uncontrolled study** to evaluate the pharmacokinetics, pharmacodynamics, safety, tolerability, and activity of **zilucoplan sodium** in pediatric participants aged 2 to less than 18 years with **generalized myasthenia gravis**. The trial will involve the administration of zilucoplan via subcutaneous injection once daily. The study aims to assess the plasma concentrations of zilucoplan and changes in complement component 5 levels and sheep red blood cell lysis at Week 4. Secondary endpoints include the occurrence of treatment-emergent adverse events, serious adverse events, and infections, as well as changes in MG-activities of daily living scores and Pediatric Quality of Life Inventory scores.

The trial is expected to commence recruitment on December 6, 2023, and conclude by December 4, 2026. Participants will be involved in the study for a maximum treatment period of 31 days. The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age, diagnosis of generalized myasthenia gravis, and vaccination status. Follow-up visits will occur throughout the treatment period to monitor safety and efficacy, with the primary assessment at Week 4. The end-of-study visit will finalize data collection and assess the overall outcomes of the treatment.

Participants may be withdrawn from the study if they experience treatment-emergent adverse events leading to the permanent withdrawal of the investigational medicinal product or if they do not adhere to the study protocol. The trial is categorized as a phase II to III study, reflecting its exploratory nature in a pediatric population. The study will not involve any low-intervention procedures, and all participants will receive the investigational product without a control group. The trial's design and methodology are structured to ensure comprehensive data collection on the pharmacological effects of zilucoplan in the specified patient population.

The clinical trial involves the administration of **Zilucoplan sodium**, a chemical substance, as the primary experimental medication. Zilucoplan sodium is provided in two pharmaceutical forms: a **solution for injection in a pre-filled syringe** and a **solution for injection**. The medication is administered via **subcutaneous use**. The dosing regimen involves a daily administration, with the dosage expressed in **mg/Kg milligram(s)/kilogram**. The maximum treatment period for Zilucoplan sodium is 31 days. The pre-filled syringe is equipped with a safety needle guard, specifically the BD Ultrasafe Plus, which does not have a CE mark. The standard syringe used is the B. Braun Omnifix®, which is CE marked. The trial aims to assess the pharmacokinetics and pharmacodynamics of Zilucoplan sodium in pediatric participants aged 2 to less than 18 years with acetylcholine receptor antibody positive generalized myasthenia gravis.

In addition to the experimental treatment, the study includes a non-experimental treatment involving **normal human immunoglobulins**. This treatment is categorized under the ATC code **J06BA**. The pharmaceutical form of this treatment is denoted as **PHF00230MIG**, and the route of administration is currently unspecified. The maximum treatment period for this non-experimental treatment is 1 day. The role of this treatment in the trial is auxiliary, and it is not a pediatric formulation. The study does not specify a maximum daily or total dose for this treatment.

The efficacy of the investigational medicinal product, **zilucoplan sodium**, in the treatment of acetylcholine receptor antibody positive generalized myasthenia gravis will be assessed through a series of primary and secondary endpoints. Primary efficacy endpoints include the measurement of plasma concentrations of **zilucoplan** at Week 4 (Day 29), as well as changes from baseline in sheep red blood cell (sRBC) lysis and complement component 5 (C5) levels at the same time point. These parameters will be collected and analyzed to evaluate the pharmacokinetic and pharmacodynamic profiles of the drug.

Secondary efficacy endpoints will focus on the occurrence of treatment-emergent adverse events (TEAEs), serious adverse events (TESAEs), and TEAEs leading to permanent withdrawal of the investigational product. Additionally, the study will monitor the occurrence of treatment-emergent infections and the presence of antidrug antibodies (ADA) and anti-polyethylene glycol (PEG) antibodies at Week 4. Changes in clinical scores, such as the MG-activities of daily living (MG-ADL) score, Quantitative MG (QMG) score, and Pediatric Quality of Life Inventory (PedsQoL) Version 4 domain scores, will be evaluated from baseline to Week 4. The Myasthenia Gravis Foundation of America Post-Interventional Status (MGFA PIS) will also be assessed at Week 4 to determine the overall impact of the treatment on disease status.