Evaluating the Pharmacodynamic Noninferiority of Efgartigimod PH20 SC Administered Subcutaneously as Compared to Efgartigimod Administered Intravenously in Patients With Generalized Myasthenia Gravis

Study Overview
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Brief Summary
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The purpose of this study is to investigate the Pharmacodynamics (PD), Pharmacokinetics (PK), safety, tolerability, immunogenicity, and clinical efficacy of efgartigimod coformulated with recombinant human hyaluronidase PH20 (rHuPH20) as compared to efgartigimod IV infused in patients with generalized myasthenia gravis (gMG). The study duration is approximately 12 weeks. After screening, patients will be randomized to receive either efgartigimod infusions or efgartigimod PH20 subcutaneously (SC)

Detailed Description
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Main objective of the trial: To demonstrate that the pharmacodynamic (PD) effect of injections of 1000 mg efgartigimod PH20 SC (efgartigimod co-formulated with recombinant humanhyaluronidase PH20 for subcutaneous administration), administered once weekly for 4 administrations, is NI (noninferior) to IV infusions of efgartigimod (efgartigimod formulation for intravenous infusion) at a dose of 10 mg/kg administered once weekly for 4 administrations. Secondary objectives: To compare the PD effect of efgartigimod PH20 SC and efgartigimod IV over time; To evaluate the pharmacokinetics (PK) of efgartigimod PH20 SC and efgartigimod IV; To evaluate the safety, tolerability, and immunogenicity of efgartigimod PH20 SC and efgartigimod IV; To evaluate the clinical efficacy of efgartigimod PH20 SC and efgartigimod IV.

Official Title
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A Phase 3, Randomized, Open-Label, Parallel-Group Study to Compare the Pharmacodynamics, Pharmacokinetics, Efficacy, Safety, Tolerability, and Immunogenicity of Multiple Subcutaneous Injections of Efgartigimod PH20 SC With Multiple Intravenous Infusions of Efgartigimod in Patients With Generalized Myasthenia Gravis

Conditions
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Generalized Myasthenia Gravis

Intervention / Treatment
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* Biological: efgartigimod PH20 SC
* Biological: efgartigimod IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Bullet list of each inclusion criterium: Must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. At least 18 years of age at the time of signing the informed consent form. Diagnosed with generalized Myasthenia Gravis (gMG) with confirmed documentation and supported by at least 1 of the following: History of abnormal neuromuscular transmission demonstrated by single fiber electromyography or repetitive nerve stimulation History of positive edrophonium chloride test Demonstrated improvement in Myasthenia Gravis (MG) signs upon treatment with oral acetylcholinesterase (AChE) inhibitors as assessed by the treating physician Meeting the clinical criteria as defined by the Myasthenia Gravis Foundation of America (MGFA) class II, III, IVa, or IVb Exclusion Criteria: Bullet list of each exclusion criterium: Are pregnant or lactating, or intend to become pregnant during the study or within 90 days after the last dose of Investigational Medicinal Product. Has any of the following medical conditions: Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection at screening Any other known autoimmune disease that, in the opinion of the investigator, would interfere with an accurate assessment of clinical symptoms of myasthenia gravis or put the participant at undue risk. History of malignancy unless deemed cured by adequate treatment with no evidence of reoccurrence for ≥3 years before the first administration of the IMP. Participants with the following cancers can be included at any time: adequately treated basal cell or squamous cell skin cancer carcinoma in situ of the cervix carcinoma in situ of the breast incidental histological findings of prostate cancer (TNM Classification of Malignant Tumors stage T1a or T1b). Clinical evidence of other significant serious diseases, or the participant has had a recent major surgery, or who have any other condition that, in the opinion of the investigator, could confound the results of the study or put the participant at undue risk.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: efgartigimod PH20 SC<br>Patients receiving efgartigimod PH20 subcutaneous (SC) treatment | Biological: efgartigimod PH20 SC<br>* Subcutaneous injection with efgartigimod PH20 SC<br>|
| Experimental: efgartigimod<br>Patients receiving efgartigimod intravenous (IV) treatment | Biological: efgartigimod IV<br>* Intravenous infusion of efgartigimod<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Total IgG Levels at Day 29 (mITT Analysis Set) | ANCOVA Analysis of Percent Change From Baseline in Total IgG Level at Day 29 (ie, 7 days after the fourth IV or SC administration). | From week 0 to week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Total IgG Levels Over Time (mITT Analysis Set) | Total IgG level percent change from baseline over time for the overall population. | From baseline to week 10 | 
| Percent Change From Baseline in AChR-Ab Levels Over Time in AChR- Ab Positive Patients (mITT Analysis Set) | Percent reduction from baseline in AChR-Ab levels over time in AChR-Ab positive patients measured in mITT Analysis Set. Descriptive statistics have been used for this secondary end point. | From baseline to week 10 | 
| Percent Change From Baseline in IgG Subtype Levels Over Time (mITT Analysis Set) | Median (IQR) Percent Change From Baseline for the IgG Subtypes (IgG1, IgG2, IgG3, and IgG4) in the Overall Population. The highest number of patients among all weeks for the analysis is chosen for each arm. Descriptive statistics have been used for this secondary end point. | Baseline to week 10 | 
| AUEC of the Percent Change From Baseline in Total IgG Level (mITT Analysis Set) | AUEC of the percent reduction from baseline total IgG per dosing interval (days 1-8, days 8-15, days 15-22, and days 22-29), days 1-29, days 1-57 and over the entire study (days 1-71). The highest number of patients among all weeks for the analysis is chosen for each arm. Descriptive statistics have been used for this secondary end point. | From baseline to week 10 | 
| Еfgartigimod IV and PH20 SC Serum Pharmacokinetic Parameter Ctrough | Evaluation of observed predose concentration (Ctrough) (after all doses for the IV and SC treatment arms). The analysis will present data from Week 1 to Week 4. Descriptive statistics have been used for this secondary end point. | From Week 1 to Week 4. | 
| Efgartigimod IV Serum Pharmacokinetic Parameter Cmax | Evaluation of maximum observed concentration (Cmax) (after all doses for the IV treatment arm). The analysis will present data from Baseline to Week 3. Descriptive statistics have been used for this secondary end point. | From Baseline to Week 3 | 
| Incidence of ADA Against Efgartigimod (Safety Analysis Set) | Incidence of antidrug antibodies (ADA) against Efgartigimod in the overall population. ADA analysis is performed with a validated ELISA in a 3-tiered approach (ADA screening analysis, confirmatory analysis and a titration assay). Descriptive statistics have been used for this secondary end point. | From baseline to week 10 | 
| Incidence of Antibodies Against rHuPH20 in the SC Treatment Arm (Safety Analysis Set) | Incidence of antibodies against rHuPH20 in the Efgartigimod PH20 SC Arm. antibody analysis is performed with a validated ELISA in a 3-tiered approach (screening analysis, confirmatory analysis and a titration assay) Descriptive statistics have been used for this secondary end point. | From baseline to week 10 | 
| Incidence and Severity of AEs and SAEs (Safety Analysis Set) | Evaluation of incidence and severity of treatment-emergent adverse events (TEAEs) and incidence of serious AEs (SAEs). Descriptive statistics have been used for this secondary end point. | From baseline to week 10 | 
| MG-ADL Responders (ITT Analysis Set) | Evaluation of number and percentage of Myasthenia Gravis Activities of Daily Living (MG-ADL) responders in the overall population. The MG-ADL is an 8-item patient-reported scale that assesses MG symptoms and their effects on daily activities. It evaluates a participant's capacity to perform different activities in their daily life, including talking, chewing, swallowing, breathing, brushing their teeth, combing their hair, or getting up from a chair. The MG-ADL also assesses double vision and eyelid droop. It is a discrete quantitative variable in which the 8 items are rated by the participant on a scale of 0 to 3. The total score can range from 0 to 24, with higher total scores indicating more impairment. A participant was considered a MG-ADL responder if he/she showed a reduction of at least 2 points from baseline on the MG-ADL score for at least 4 consecutive weeks. Descriptive statistics have been used for this secondary end point. | From baseline to week 10 | 
| QMG Responders (ITT Analysis Set) | Evaluation of number and percentage of Quantitative Myasthenia Gravis (QMG) responders in the overall population (ITT Analysis Set). Descriptive statistics have been used for this secondary end point. One subject in the EFG IV arm had no post-baseline QMG assessment and thus was excluded from the denominator. | From Baseline to Week 10 | 
| Change From Baseline in MG-ADL Total Score Over Time (ITT Analysis Set) | Evaluation of MG-ADL Total Score Change from baseline over time for the overall population (ITT Analysis Set). Descriptive statistics have been used for this secondary end point. The MG-ADL is an 8-item patient-reported scale that assesses MG symptoms and their effects on daily activities. It evaluates a participant's capacity to perform different activities in their daily life, including talking, chewing, swallowing, breathing, brushing their teeth, combing their hair, or getting up from a chair. The MG-ADL also assesses double vision and eyelid droop. It is a discrete quantitative variable in which the 8 items are rated by the participant on a scale of 0 to 3. The total score can range from 0 to 24, with higher total scores indicating more impairment. A participant was considered a MG-ADL responder if he/she showed a reduction of at least 2 points from baseline on the MG-ADL score for at least 4 consecutive weeks. | From baseline to week 10 | 
| Change From Baseline in QMG Score Over Time (ITT Analysis Set) | Evaluation of QMG Total Score change from baseline over time for the overall population (ITT Analysis Set). The QMG (Quantitative Myasthenia Gravis) quantifies disease severity based on impairments of body function and structures as defined by the International Classification of Functioning, Disability and Health. The QMG consists of 13 items that assess ocular, bulbar, and limb function. Six of the 13 items are timed endurance tests measured in seconds. Each item has a possible score from 0 to 3. The total possible score is 39, where higher total scores indicate more severe impairments. It is based on qualitative testing of specific muscle groups to assess limb function. Descriptive statistics have been used for this secondary end point. A participant was considered a QMG responder if he/she showed a reduction of at least 3 points from baseline on the QMG score for at least 4 consecutive weeks. | From baseline to week 10 |