Title: The Efficacy, Safety, and PK/PD of Efgartigimod Followed by Telitacicept in Generalized Myasthenia Gravis: Protocol of a Randomized Controlled Trial Objective: This study aims to evaluate the efficacy, safety, and pharmacokinetics/pharmacodynamics (PK/PD) of efgartigimod followed by telitacicept in patients with generalized myasthenia gravis (gMG). Specifically, the trial seeks to determine the optimal treatment strategy for gMG by assessing the effect of sequential biologic therapy on disease management.

Study Design: This is a multi-center, open-label, randomized controlled trial involving 60 acetylcholine receptor antibody-positive gMG patients.

Study Overview: This study is a multi-center, open-label, randomized controlled trial designed to evaluate the efficacy, safety, and pharmacokinetics/pharmacodynamics (PK/PD) of a sequential treatment regimen combining efgartigimod followed by telitacicept in patients with generalized myasthenia gravis (gMG). The trial aims to determine whether the sequential use of these two biologics provides enhanced therapeutic benefits compared to monotherapy and to identify the optimal interval between treatments.

Background: Generalized myasthenia gravis (gMG) is an autoimmune neuromuscular disorder primarily characterized by skeletal muscle weakness and fatigue due to pathogenic autoantibodies, most commonly against acetylcholine receptors (AChR). While conventional treatments for gMG include cholinesterase inhibitors, steroids, and immunosuppressants, biologic therapies have shown great promise in addressing the underlying autoimmune mechanisms.

New biologics, such as efgartigimod (a neonatal Fc receptor inhibitor) and telitacicept (a BLyS/APRIL inhibitor), have demonstrated efficacy in treating gMG, but the optimal sequencing and duration of their use have not been thoroughly explored. Efgartigimod, which accelerates the depletion of pathogenic IgG antibodies, has shown quick symptom relief but with a relatively short duration of effect. Telitacicept, an antibody fusion protein that inhibits BLyS and APRIL to suppress B-cell maturation, has demonstrated potential for longer-term disease control. This trial seeks to evaluate the sequential combination of these two biologics, specifically exploring the best interval between treatments.

Study Design: This study is designed to explore the efficacy, safety, and PK/PD characteristics of efgartigimod followed by telitacicept in patients with AChR-Ab-positive generalized myasthenia gravis (gMG). The trial will enroll 60 patients who are randomized into three groups:

Efgartigimod + Telitacicept (1-week interval) group (E+1w+T) Efgartigimod + Telitacicept (2-week interval) group (E+2w+T) Telitacicept-only group (T only) The trial will be conducted at five clinical centers, with a study period from February 2025 to February 2026.

Treatment Regimens:

Efgartigimod + Telitacicept Sequential Therapy:

Efgartigimod (10 mg/kg) will be administered intravenously once per week for 4 weeks. Following a 1-week or 2-week break after the efgartigimod treatment, telitacicept (240 mg) will be administered subcutaneously once per week for a total of 24-25 weeks.

Telitacicept-only Group:

Patients in the Telitacicept-only group (T only) will receive telitacicept (240 mg) subcutaneously once a week for 30 weeks, without prior treatment with efgartigimod.

Primary and Secondary Endpoints:

Primary Endpoint: The primary endpoint of this study is the change from baseline in the Quantitative Myasthenia Gravis (QMG) score at Week 30. The QMG score is a validated clinical measure used to assess the severity of myasthenia gravis symptoms.

Secondary Endpoints:

Change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score.

The proportion of patients achieving minimal manifestation status (MMS) is defined as having no significant functional impairment despite observable weakness.

Change in steroid and immunosuppressant doses at Weeks 24 and 30. Incidence of MG exacerbations, myasthenic crises, and adverse events. PK/PD characteristics of telitacicept, including blood drug concentration, B-cell counts, and levels of BLyS/APRIL.

Pharmacokinetics and Pharmacodynamics:

Pharmacokinetics (PK) includes testing the blood concentration, clearance（CI）, and distribution volume of telitacicept, and pharmacodynamics (PD) includes testing serum immunoglobulins, B cell counts, and/or Blys+APRIL levels.

IgG levels will be assessed at baseline, after 4 weeks of efgartigimod treatment, and during telitacicept therapy to monitor the drug's pharmacodynamic effects on immune parameters.

Safety Monitoring:

Safety will be assessed by recording the incidence of adverse events (AEs), serious adverse events (SAEs), and any other clinically relevant changes in laboratory values or vital signs.

NCI-CTCAE v5.0 will be used to grade the severity of adverse events. Telitacicept will be administered cautiously, with specific attention to potential infections or autoimmune complications, given its mechanism of action on B cells.

Exploratory and Additional Analyses:

An exploratory analysis will evaluate whether the sequencing and timing of efgartigimod and telitacicept impacts the long-term disease control in gMG patients.

The study will also assess how the sequential administration of efgartigimod and telitacicept compares to telitacicept-only therapy in terms of symptom control and reduction in disease-related markers.

Statistical Methods:

The study uses Analysis of Covariance (ANCOVA) to compare changes from baseline in QMG scores between the treatment groups.

The statistical analysis will follow the Intention-to-treat (ITT) principle, with efficacy measured in the Full Analysis Set (FAS) and safety in the Safety Analysis Set (SS).

Sample Size: Each treatment group is expected to enroll 20 patients, accounting for a 15% dropout rate, bringing the total sample size to 60 patients (20:20:20).

Power Analysis: The study is powered at 80% to detect a 4-point improvement in QMG score between the sequential treatment groups and the Telitacicept-only group, with a significance level of α=0.025.

Discussion:

This study is the first to explore sequential biologic therapy using efgartigimod followed by telitacicept in generalized myasthenia gravis.

The study builds on prior research showing the efficacy and safety of both drugs individually, but it is the first to explore their combined use in a sequential regimen.

Given that efgartigimod and telitacicept have different mechanisms of action-efgartigimod rapidly depleting IgG autoantibodies and telitacicept inhibiting B-cell maturation-the combination is expected to offer long-term symptom relief, with the potential to reduce the need for other immunosuppressive therapies.

This trial will help determine the optimal timing for sequential administration, providing important insights for future treatment strategies in gMG patients.

Study Limitations:

As this is a pilot exploratory trial, the results should be interpreted cautiously due to the relatively small sample size.

Follow-up will be limited to 30 weeks, which may not capture the full long-term effects and safety profile of the combination therapy.

Conclusion:

The efgartigimod followed by telitacicept sequential therapy has the potential to significantly improve the treatment of gMG, offering a new approach to managing patients who have previously experienced inadequate symptom control with conventional therapies. The results from this study could provide crucial evidence for the development of a robust sequential biologic treatment strategy for gMG.

Inclusion Criteria:

• The patient voluntarily signs the informed consent form.
• Age ≥18 and ≤80 years, regardless of gender.
• Meets the diagnostic criteria for Myasthenia Gravis (MG) as per the 2020 China MG Diagnosis and Treatment Guidelines, with serological evidence of positive AChR-Ab.
• MG Clinical Classification according to the Myasthenia Gravis Foundation of America (MGFA) Staging System: Grade II-IV.
• Patients with fluctuating MG symptoms before enrollment, as indicated by MG-ADL score ≥6 or Quantitative Myasthenia Gravis score (QMG) ≥8, maintained for more than 24 hours.

Exclusion Criteria:

• Coexisting active autoimmune diseases, such as Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Sjögren's Syndrome, etc.
• Patients with active infections, such as Herpes Zoster, HIV, active Tuberculosis, active Hepatitis.
• Patients with thymoma who have undergone surgery within the past 6 months.
• Patients with malignancies other than thymoma.
• Patients with severe liver or renal dysfunction, defined as: Liver function: ALT or AST > 3 ×ULN (upper limit of normal). Renal function: Glomerular filtration rate (GFR) < 30 mL/min/1.73m².
• IgG ≤ 400 mg/dL.
• Patients who have used biologic agents before enrollment and are within 5 half-lives of the drug, such as those who have used Telitacicept within the past 2 months, Efgartigimod within the past 1 month, or Rituximab within the past 6 months.
• Patients who have received intravenous immunoglobulin (IVIg) or undergone plasmapheresis within the past 2 months before enrollment.
• Patients who have received any live vaccines within 3 months before the study or plan to receive any vaccines during the study.
• Pregnant or breastfeeding women, or those planning to conceive during the trial.
• Patients with allergies to human-derived biologics.
• Patients who have participated in any clinical trial within the 28 days before enrollment or are within 5 half-lives of the investigational drug used in a prior clinical trial.
• Other patients deemed unsuitable for enrollment by the investigator (e.g., severe mental disorders).