Efficacy and Safety Evaluation of Efgartigimod Alfa in Acetylcholine Receptor Binding Antibody Seronegative Generalized Myasthenia Gravis

The primary objective of this study is to determine the **efficacy** of efgartigimod IV compared to placebo in participants with Acetylcholine Receptor Binding Antibody Seronegative Generalized Myasthenia Gravis (AChR-Ab seronegative gMG) in part A. This is clinically relevant as it aims to establish the therapeutic potential of efgartigimod IV in managing symptoms of this specific subtype of generalized myasthenia gravis, which lacks effective treatment options.

Secondary objectives include:

• To determine the efficacy of efgartigimod IV compared to placebo, and the long-term efficacy of efgartigimod IV in participants with AChR-Ab seronegative gMG.
• To assess the safety and tolerability of efgartigimod IV compared to placebo and the long-term safety and tolerability of efgartigimod IV in participants with AChR-Ab seronegative gMG.
• To assess the pharmacodynamic (PD) effect of efgartigimod IV in participants with AChR-Ab seronegative gMG.

The clinical trial involves a total of **105 participants** diagnosed with **Acetylcholine Receptor Binding Antibody Seronegative Generalized Myasthenia Gravis**. The study population includes both male and female subjects, aged 18 years and older, who are capable of providing informed consent and complying with protocol requirements. Participants are required to have a stable dose of myasthenia gravis therapy, which may include acetylcholinesterase inhibitors, steroids, or nonsteroidal immunosuppressive therapies, either in combination or alone. The trial does not include a vulnerable population. Participants must not have experienced weakness in infancy and should have developed fatigable weakness after the age of 16, with a diagnosis of acquired generalized myasthenia gravis. The selection criteria ensure that participants have a history of abnormal neuromuscular transmission or are anti-muscle-specific kinase antibodies seropositive, with a demonstrated improvement in myasthenia gravis signs following specific treatments. The trial population was selected based on these criteria to evaluate the efficacy of efgartigimod IV compared to placebo.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, Phase 3 study to evaluate the efficacy and safety of **efgartigimod alfa** in adult participants with **Acetylcholine Receptor Binding Antibody Seronegative Generalized Myasthenia Gravis**. The trial will involve a parallel-group design, with participants randomly assigned to receive either the investigational medicinal product, efgartigimod IV, or a placebo. The primary objective is to assess the change in the MG-ADL total score from baseline to day 29. Secondary endpoints include the change in QMG total score and the proportion of participants who are both MG-ADL and QMG responders.

The trial is expected to commence recruitment on October 1, 2024, and is estimated to conclude by July 23, 2027. Participants will be involved in the study for a maximum treatment period of 112 days. The study will include several key visits: an initial screening visit to confirm eligibility based on inclusion criteria such as age, ability to provide informed consent, and stable MG therapy. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events. The end-of-study visit will occur after the completion of the treatment period to assess the final outcomes and gather data for analysis.

Participants are expected to adhere to the study protocol, including the use of contraceptive measures for women of childbearing potential and compliance with scheduled visits. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or the occurrence of significant adverse events. The trial will ensure that all procedures are conducted in accordance with ethical standards and regulatory requirements, maintaining the integrity and scientific validity of the study.

The clinical trial involves the administration of **efgartigimod alfa**, marketed under the name Vyvgart, which is a **concentrate for solution for infusion**. This experimental medication is formulated as a solution for infusion and is administered via **intravenous infusion**. The active substance, efgartigimod alfa, is a protein-based therapeutic agent classified under the ATC code L04AA58. The maximum daily dose of efgartigimod alfa is 1200 mg, with a total maximum dose of 129,600 mg over the course of the treatment period, which spans up to 112 days. The pharmaceutical product is manufactured by Argenx BV and is not a pediatric formulation. The trial aims to evaluate the efficacy and safety of efgartigimod alfa in adult participants with acetylcholine receptor binding antibody seronegative generalized myasthenia gravis.

The study also includes a **placebo** group, which receives a placebo version of the efgartigimod IV concentrate for solution. The placebo is designed to match the experimental treatment in appearance and administration method but does not contain the active substance. The placebo is administered in the same manner as the experimental drug, via intravenous infusion, to maintain the double-blind nature of the trial. The inclusion of a placebo group allows for a controlled comparison to assess the true efficacy of efgartigimod alfa in the target population. Compliance with the dosing schedule and administration is monitored throughout the study to ensure adherence to the protocol.

The efficacy of efgartigimod IV in the treatment of **generalized myasthenia gravis** (gMG) will be assessed in a randomized, double-blinded, placebo-controlled, Phase 3 clinical trial. The primary endpoint for evaluating efficacy is the change in the Myasthenia Gravis Activities of Daily Living (MG-ADL) total score from baseline to day 29 in part A of the study. Secondary endpoints include the change in the Quantitative Myasthenia Gravis (QMG) total score from baseline to day 29 and the proportion of participants who are responders in both MG-ADL and QMG scores in part A.

These efficacy parameters will be measured using validated scales, specifically the MG-ADL and QMG, which are standard tools for assessing symptom severity and functional ability in patients with gMG. Data collection will occur at specified timepoints, with the primary assessment occurring on day 29. The analysis will focus on comparing the changes in scores between the efgartigimod IV group and the placebo group to determine the treatment's effectiveness. The trial is designed to ensure rigorous evaluation of the therapeutic impact of efgartigimod IV on patients with acetylcholine receptor binding antibody seronegative gMG.