Pharmacokinetics, Pharmacodynamics, and Safety Evaluation of Efgartigimod Alfa in Pediatric Patients with Generalized Myasthenia Gravis

The primary objective of this study is to confirm an age-adjusted optimum dose of **efgartigimod** administered intravenously and to provide model-predicted evidence for a treatment response in children aged 2 to less than 18 years with **Generalized Myasthenia Gravis**. This is clinically relevant as it aims to establish a safe and effective dosing regimen tailored to pediatric patients, potentially improving therapeutic outcomes and minimizing adverse effects.

Secondary objectives include:

• Evaluating the safety and tolerability of efgartigimod IV.
• Assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of efgartigimod IV.
• Determining the immunogenicity of efgartigimod IV.
• Evaluating the activity and impact on quality of life of efgartigimod IV.
• Assessing the effect of efgartigimod treatment on antibody response to vaccines.

The clinical trial involves a total of **7 participants** diagnosed with **Generalized Myasthenia Gravis** (gMG). The study population includes both male and female subjects, specifically children and adolescents aged between 2 to less than 18 years. Participants were selected based on their ability to understand the trial requirements and provide informed consent, either personally or through a legally authorized representative. The trial targets individuals who have an unsatisfactory response to immunosuppressants, steroids, or acetylcholinesterase inhibitors and are on stable concomitant gMG therapy. Participants must meet the clinical criteria defined by the Myasthenia Gravis Foundation of America (MGFA) class II, III, and IVa, and have a positive serologic test for anti-AChR antibodies. The trial population is considered vulnerable due to the age range and health condition. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **pharmacokinetics**, **pharmacodynamics**, safety, and activity of **efgartigimod alfa** in pediatric patients diagnosed with **generalized myasthenia gravis**. This is a Phase 2/3, open-label, uncontrolled trial. The study aims to confirm an age-adjusted optimum dose of efgartigimod administered via intravenous infusion and to provide model-predicted evidence for a treatment response. The trial is expected to last until March 31, 2025, with participant recruitment having commenced on October 26, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis, and previous treatment responses. Eligible participants are those aged 2 to less than 18 years, with a confirmed diagnosis of generalized myasthenia gravis, and who meet specific clinical criteria. Following the screening, participants will receive the investigational product, Vyvgart 20 mg/mL concentrate for solution for infusion, over a maximum treatment period of 26 weeks. The study will include regular follow-up visits to monitor the primary endpoints, which involve measuring efgartigimod concentrations and pharmacodynamic parameters such as total IgG levels and anti-acetylcholine receptor antibodies.

Secondary endpoints will assess the incidence and severity of adverse events, changes in laboratory test results, and various clinical scores related to the disease and quality of life. Participants' involvement is expected to last for the duration of the treatment period, with conditions for early termination including withdrawal of consent, non-compliance with the protocol, or adverse events that necessitate discontinuation. The trial will conclude with an end-of-study visit to evaluate the overall outcomes and collect final data.

The clinical trial involves the administration of **efgartigimod alfa**, an experimental medication, to evaluate its pharmacokinetics, pharmacodynamics, safety, and activity in children aged 2 to less than 18 years with generalized myasthenia gravis. The investigational product, marketed under the name Vyvgart, is provided as a 20 mg/mL concentrate for solution for infusion. The pharmaceutical form is a sterile concentrate intended for intravenous infusion. The maximum daily dose of efgartigimod alfa is 1200 mg, with a total maximum dose of 10800 mg over the treatment period. The maximum treatment period is 26 weeks. The administration route is exclusively via intravenous infusion, and the product is classified as a biological medicinal product. The active substance, efgartigimod alfa, is a protein of non-human origin, specifically designed for this therapeutic application.

In this open-label, uncontrolled trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The primary objective is to confirm an age-adjusted optimum dose of efgartigimod administered intravenously and to provide model-predicted evidence for a treatment response. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The trial is conducted under the authorization of the European Union, with the marketing authorization number EU/1/22/1674/001, and is designated as an orphan drug under the number EMA/OD/245/17.

Efficacy in this clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoints include the measurement of **efgartigimod** concentrations for compartmental, model-driven analysis to determine age and size dependency of clearance and volume of distribution, as well as pharmacodynamic (PD) parameters such as total IgG levels and anti-acetylcholine receptor antibodies (AChR-Ab) for PK/PD modeling analysis. Secondary endpoints will evaluate the incidence and severity of adverse events (AEs), serious adverse events (SAEs), and AEs of special interest (AESIs), along with changes in laboratory test results, physical examination results, vital sign measurements, and electrocardiogram (ECG) results. Additionally, efgartigimod serum concentrations, levels of total IgG and AChR-Ab, and the incidence and prevalence of antidrug antibodies (ADAs) against efgartigimod will be assessed.

Further secondary endpoints include the Myasthenia Gravis Activities of Daily Living (MG-ADL) total score, the Quantitative Myasthenia Gravis (QMG) total score, the EQ-5D-Y total score, and the Quality of Life in Neurological Disorders (Neuro-QoL) Pediatric Fatigue Score, all measured as absolute values and changes from baseline. The change in protective antibody titers to vaccines received before or during the trial will also be evaluated. These efficacy parameters will be collected and analyzed at various timepoints throughout the trial to provide comprehensive data on the treatment response in children with generalized myasthenia gravis.