Safety and Efficacy Study of Zilucoplan in Subjects With Immune-Mediated Necrotizing Myopathy

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 zilucoplan in patients with Immune-Mediated Necrotizing Myopathy (IMNM). Subjects will be randomized in a 1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan or matching placebo for 8 weeks.

Official Title
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A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of Zilucoplan in Subjects With Immune-Mediated Necrotizing Myopathy

Conditions
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Immune Mediated Necrotizing Myopathy

Intervention / Treatment
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* Drug: zilucoplan
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of IMNM (Immune-Mediated Necrotizing Myopathy) Positive serology for anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) or anti-signal recognition particle (SRP) autoantibodies Clinical evidence of weakness (≤ grade 4 out of 5) on manual muscle testing in at least one proximal limb muscle group Creatine kinase (CK) of >1000 U/L at Screening No change in corticosteroid dose for at least 30 days prior to Baseline or anticipated to occur during the first 8-weeks on study No changes in immunosuppressive therapy, including dose, for at least 30 days prior to Baseline or anticipated to occur during the first 8-weeks on study Exclusion Criteria: History of meningococcal disease Current or recent systemic infection within 2 weeks prior to Screening or infection requiring intravenous (IV) antibiotics within 4 weeks prior to Screening Recent initiation of intravenous immunoglobulin (IVIG) (i.e., first cycle administered less than 90 days prior to Baseline) Rituximab use within 90 days prior to Baseline or anticipated to occur during study Statin use within 30 days prior to Baseline or anticipated to occur during study Plasma exchange within 4 weeks prior to Baseline or expected to occur during the 8-week Treatment Period

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: 0.3 mg/kg zilucoplan<br>Daily subcutaneous (SC) injection | Drug: zilucoplan<br>* Daily subcutaneous (SC) inection<br>|
| Placebo Comparator: Placebo<br>Daily subcutaneous (SC) injection | Other: Placebo<br>* Daily subcutaneous (SC) inection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline to Week 8 in Serum Creatine Kinase (CK) Levels | All laboratory samples were obtained prior to administration of study drug at applicable visits. CK levels were measured by a central laboratory. | Baseline (Day 1) and end of Main Portion (Week 8) | 
| Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE) | A TEAE was defined as: An adverse event (AE) that occurred after study treatment start that was not present at the time of treatment start. An AE that increased in severity after treatment start if the event was present at the time of treatment start. | Baseline (Day 1) to end of Main Portion (Week 8) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Achieve at Least Minimal Response Based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Response Criteria Scale | The ACR/EULAR scale utilized a conjoint analysis-based continuous model using absolute percent change from Baseline in core set measures (physician, patient, and Myositis Disease Activity Assessment Tool (MDAAT); muscle strength; Health Assessment Questionnaire (HAQ); and muscle enzyme levels). A total improvement score (range 0-100) was determined by summing scores for each core set measure and comparing improvement in each respective core set measure. The threshold for minimal improvement was ≥20 in the total improvement score with higher scores indicating a better outcome. | Baseline (Day 1) and end of Main Portion (Week 8) | 
| Change From Baseline to Week 8 in Triple Timed Up and Go Test (3TUG) Time | The 3TUG test involved the ambulatory participant getting up from a seated position in a chair, walking at their normal pace for 3 meters, turning around, walking back to the chair, and sitting down. This sequence was repeated 3 times without rest, and the 3TUG test time is the average of the 3 lap times. A negative change from baseline indicated a better outcome. | Baseline (Day 1) and end of Main Portion (Week 8) | 
| Change From Baseline to Week 8 in Proximal Manual Muscle Testing (MMT) Score | The proximal MMT assessed muscle strength using manual muscle testing in 7 muscle groups (left and right sides assessed separately). The total MMT score for this study, inclusive of both sides, could range from 0-140, where 0 means no strength in any muscles and 140 means full strength in all the muscles examined. A negative change from Baseline indicated a worse outcome. | Baseline (Day 1) and end of Main Portion (Week 8) | 
| Change From Baseline to Week 8 in Physician Global Activity Visual Analogue Scale (VAS) Score | The Physician Global Activity VAS Score measured the treating physician's global evaluation of the participant's overall disease activity using a 10 cm VAS labelled with no activity at the left end and maximum activity at the right end. The Physician Global Activity VAS Score ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome. | Baseline (Day 1) and end of Main Portion (Week 8) | 
| Change From Baseline to Week 8 in Patient Global Activity VAS Score | The Patient Global Activity VAS Score measured the treating participant's global evaluation of their overall disease activity using a 10 cm VAS labelled with no activity at the left end and maximum activity at the right end. The Patient Global Activity VAS score ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome. | Baseline (Day 1) and end of Main Portion (Week 8) | 
| Change From Baseline to Week 8 in HAQ Score | The HAQ had 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and activities with 2 to 3 questions for each section. Scoring within each section ranged from 0 (without any difficulty) to 3 (unable to do). The total HAQ score was then calculated by summing the scores and dividing by the number of categories answered. The total HAQ score for this study could range from 0-3, where 0 means no functional impairment and 3 means complete functional impairment. A negative change from Baseline indicated a better outcome. | Baseline (Day 1) and end of Main Portion (Week 8) | 
| Change From Baseline to Week 8 in MDAAT Extramuscular Disease Activity VAS Score | The MDAAT extramuscular disease activity VAS score measured the degree of disease activity of extramuscular organ systems and muscle. The scoring was performed by the physician and ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome. | Baseline (Day 1) and end of Main Portion (Week 8) | 
| Change From Baseline to Week 8 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score | The FACIT-Fatigue Scale is a 13-item tool which measured an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue was measured on a 4-point Likert scale. The total FACIT-Fatigue Scale score for this study could range from 0-52, where 0 means the participants were very much fatigued during their usual daily activities and 52 means the participants were not at all fatigued during their usual daily activities. A negative change from Baseline indicated a worse outcome. | Baseline (Day 1) and end of Main Portion (Week 8) |