Safety and Efficacy Study of RA101495 in Subjects With Generalized Myasthenia Gravis

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the safety and efficacy of RA101495 in patients with generalized Myasthenia Gravis (gMG). Subjects will be randomized in a 1:1:1 ratio to receive daily SC doses of 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or matching placebo for 12 weeks.

Official Title
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A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of RA101495 in Subjects With Generalized Myasthenia Gravis

Conditions
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Generalized Myasthenia Gravis

Intervention / Treatment
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* Drug: zilucoplan (RA101495)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of gMG [Myasthenia Gravis Foundation of America (MGFA) Class II-IVa] at Screening Positive serology for acetylcholine receptor (AChR) autoantibodies QMG score ≥ 12 at Screening and Randomization No change in corticosteroid dose for at least 30 days prior to Randomization or anticipated to occur during the 12-week Treatment Period No change in immunosuppressive therapy, including dose, for at least 30 days prior to Randomization or anticipated to occur during the 12-week Treatment Period Exclusion Criteria: Thymectomy within 6 months prior to Randomization or scheduled to occur during the 12 week Treatment Period History of meningococcal disease Current or recent systemic infection within 2 weeks prior to Randomization or infection requiring intravenous (IV) antibiotics within 4 weeks prior to Randomization

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.1 mg/kg zilucoplan (RA101495)<br> | Drug: zilucoplan (RA101495)<br>* Daily subcutaneous (SC) injection<br>|
| Experimental: 0.3 mg/kg zilucoplan (RA101495)<br> | Drug: zilucoplan (RA101495)<br>* Daily subcutaneous (SC) injection<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Daily subcutaneous (SC) injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main Portion: Change From Baseline to Week 12 in Quantitative Myasthenia Gravis (QMG) Score | The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for myasthenia gravis (MG). The scale consists of 13 individual assessments, each scored on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the individual scores with a range of 0-39. Higher scores are representative of more severe impairment. | From Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Activities of Daily Living (MG-ADL) Scale | The MG-ADL is a brief 8-item survey designed to evaluate MG symptom severity. The scale consists of 8 items each scored on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the 8 individual scores with range of 0-24. Higher scores are associated with more severe symptoms of MG. | From Baseline to Week 12 | 
| Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life 15r (MG-QOL15r) Survey | The MG-QOL15r is a 15-item survey that was designed to assess quality of life in participants with MG. The survey consisted of 15 questions and the corresponding responses were each scored on a 0-2 point scale (0=Not much at all, 1=Somewhat, 2=Very Much). The total score is the sum of the 15 individual item scores with a range of 0-30. Higher scores indicate more severe impact of the disease on aspects of the participant's life. | From Baseline to Week 12 | 
| Main Portion: Change From Baseline to Week 12 in the MG Composite Scale Total Score | The MG Composite is a 10-item scale that has been used to measure the clinical status of participants with MG, in order to evaluate treatment response. It consists of 10 items which included ptosis (score range=0 to 3), double vision on lateral gaze left/right/both (score range=0 to 4), eye closure (score range=0 to 2), talking (score range=0 to 6), chewing (score range=0 to 6), swallowing (score range=0 to 6), breathing (score range=0 to 9), neck flexion or extension (score range=0 to 4), shoulder abduction (score range=0 to 5) and hip flexion (score range= 0 to 5). The total score is the sum of the 10 individual scores with a range of 0-50. Higher scores in the MG Composite indicate more severe impairment due to the disease. | From Baseline to Week 12 | 
| Main Portion: Percentage of Participants With >= 3-point Reduction in QMG Total Score at Week 12 | The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for MG. The scale consists of 13 individual assessments, each scored on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the individual scores with a range of 0-39. Higher scores are representative of more severe impairment. | Week 12 | 
| Main Portion: Percentage of Participants Who Required Rescue Therapy Over the 12-week Treatment Period | Percentage of participants who used at least 1 dose of rescue medication were reported. | Up to Week 12 | 
| Main Portion: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A serious adverse event (SAE) is any untoward medical occurrence that at any dose resulted in death, life-threatening, significant or persistent disability/incapacity, congenital anomaly/birth defect, important medical event, initial inpatient hospitalization or prolongation of hospitalization. | From Baseline to Week 12 | 
| Main Portion: Change From Baseline in Sheep Red Blood Cell (sRBC) Lysis Assay at Week 12 (Pre-dose) | A BioTek ELx800 automated microplate reader is used to measure the optical density at 415 nanometer (nm) of human plasma samples to calculate the percent lysis of sheep erythrocytes that has occurred as a result of total complement activity. The measure of complement activity is determined by the degree of hemolysis of the erythrocytes. | Baseline and Week 12 (Pre-dose) | 
| Main Portion: Change From Baseline in C5 Levels at Week 12 (Pre-dose) | Blood samples were collected from participants to assess Complement Component 5C levels. | Baseline and Week 12 (Pre-dose) | 
| Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758 and RA103488 are the metabolites of RA101495. | 1, 3 and 6 hours postdose on Day 1; Pre-dose on Week 1, 2, 4, 8 and 12 | 
| Main Portion: Maximum Plasma Concentration (Cmax) on Day 1 | Cmax is defined as the maximum observed plasma concentration. | Pre-dose, 1, 3 and 6 hours postdose on Day 1 | 
| Main Portion: Time Corresponding to Cmax (Tmax) on Day 1 | Tmax is defined as the time to observe maximum plasma concentration. | Pre-dose, 1, 3 and 6 hours postdose on Day 1 | 
| Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758 and RA103488 are the metabolites of RA101495. | Pre-dose, 1, 3 and 6 hours postdose on Day 1; Pre-dose on Week 1, 2, 4, 8 and 12 |