A Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of M281 Administered to Adults With Generalized Myasthenia Gravis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and efficacy of M281 administered to participants with generalized myasthenia gravis (gMG) who have an insufficient clinical response to ongoing standard of care therapy.

Official Title
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A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of M281 Administered to Adults With Generalized Myasthenia Gravis

Conditions
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Generalized Myasthenia Gravis

Intervention / Treatment
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* Drug: M281
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Participants must be ≥18 years of age with a documented history of Generalized Myasthenia Gravis (gMG) and clinical signs/symptoms of gMG, not pregnant or breastfeeding, and no history of any neurologic disorder other than MG that might interfere with the accuracy of study assessments. Additional, more specific criteria are defined in the protocol.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group 1<br> | Other: Placebo<br>* Placebo administered as intravenous (IV) infusion<br>|
| Experimental: Group 2<br> | Drug: M281<br>* M281 administered as IV infusion<br>|
| Experimental: Group 3<br> | Drug: M281<br>* M281 administered as IV infusion<br>|
| Experimental: Group 4<br> | Drug: M281<br>* M281 administered as IV infusion<br>|
| Experimental: Group 5<br> | Drug: M281<br>* M281 administered as IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) as a Measure of Safety and Tolerability | An adverse event (AE) is any untoward medical event that occurs in a participant administered an investigational product and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAE are defined as any AE occurring during or after the initiation of the first infusion of study drug. | Up to Day 113 | 
| Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) | An AE is any untoward medical event that occurs in a participant administered an investigational product and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are defined as any AE occurring during or after the initiation of the first infusion of study drug. An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: death, life-threatening AE, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. | Up to Day 113 | 
| Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESI) | An AE is any untoward medical event that occurs in a participant administered an investigational product and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are defined as any AE occurring during or after the initiation of the first infusion of study drug. For this study, any common terminology criteria for adverse events (CTCAE) Grade 3 or higher event of severe infection or hypoalbuminemia was considered as AESI. | Up to Day 113 | 
| Change From Baseline to Day 57 in the Myasthenia Gravis - Activities of Daily Living (MG-ADL) Total Score | The MG-ADL was used to assess the participant's MG symptom severity. It assesses eight functions (talking, chewing, swallowing, breathing, impairment of ability to brush teeth or comb hair, impairment of ability to arise from a chair, double vision, and eyelid droop) which were rated on a 4-point scale: 0 (no impairment) to 3 (severe impairment). The total score is the sum of the eight function scores and ranges from 0 to 24. Higher scores indicated greater symptom severity/difficulty in performing daily living activities. | Baseline to Day 57 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total MG-ADL Score as a Function of Total Serum Immunoglobulin G (IgG) at Day 57 | Estimate of additional change from baseline in MG-ADL total score for every 10 percent (%) additional reduction in IgG based on a linear regression of change from baseline in MG-ADL total score on percent reduction in IgG at Day 57. The MG-ADL was used to assess the participant's MG symptom severity. It assesses eight functions (talking, chewing, swallowing, breathing, impairment of ability to brush teeth or comb hair, impairment of ability to arise from a chair, double vision, and eyelid droop) which were rated on a 4-point scale: 0 (no impairment) to 3 (severe impairment). The total score is the sum of the eight function scores and ranges from 0 to 24. Higher scores indicated greater symptom severity/difficulty in performing daily living activities. | Baseline and Day 57 | 
| Change From Baseline in Total MG-ADL Score as a Response to Percent Change in Total Serum IgG, for Participants Positive for Anti-acetylcholine Receptor (Anti-AChR) Antibodies, at Day 57 | Estimate of additional change from baseline in MG-ADL total score for every 10% additional reduction in IgG based on a linear regression of change from baseline in MG-ADL total score on percent reduction in IgG at Day 57 in anti-AChR positive participants. The MG-ADL was used to assess participant's MG symptom severity. It assesses eight functions (talking, chewing, swallowing, breathing, impairment of ability to brush teeth or comb hair, impairment of ability to arise from a chair, double vision, and eyelid droop) which were rated on a 4-point scale: 0 (no impairment) to 3 (severe impairment). Total score is sum of eight function scores and ranges from 0 to 24. Higher scores indicated greater symptom severity/difficulty in performing daily living activities. | Baseline and Day 57 | 
| Change From Baseline in Total Quantitative Myasthenia Gravis (QMG) Score as a Function of Total Serum IgG at Day 57 | Estimate of additional change from baseline in QMG total score for every 10% additional reduction in IgG based on a linear regression of change from baseline in QMG total score on percent reduction in IgG at Day 57. The QMG test was used to assess the participant's strength. The quantitative results of each of the 13 strength components were mapped to a 4-point scale where 0 equals to (=) none, 1= mild, 2= moderate and 3= severe. The total score is the sum of the 13 scale scores and ranges from 0 to 39. Higher scores indicated more severe impairment. | Baseline and Day 57 | 
| Change From Baseline in Total QMG Score as a Response to Percent Change in Total Serum IgG, for Participants Positive for Anti-acetylcholine Receptor (Anti-AChR) Antibodies, at Day 57 | Estimate of additional change from baseline in QMG total score for every 10% additional reduction in IgG based on a linear regression of change from baseline in QMG total score on percent reduction in IgG at Day 57 in anti-AChR positive participants. The QMG test was used to assess the participant's strength. The quantitative results of each of the 13 strength components were mapped to a 4-point scale where 0 equals to (=) none, 1= mild, 2= moderate and 3= severe. The total score is the sum of the 13 scale scores and ranges from 0 to 39. Higher scores indicated more severe impairment. | Baseline and Day 57 | 
| Number of Participants With a 2-, 3-, 4-, 5-, 6-, 7-, or Greater Than or Equal to (>=) 8-point Improvement in Total MG-ADL Score at Day 57 | The MG-ADL was used to assess the participant's MG symptom severity. It assesses eight functions (talking, chewing, swallowing, breathing, impairment of ability to brush teeth or comb hair, impairment of ability to arise from a chair, double vision, and eyelid droop) which were rated on a 4-point scale: 0 (no impairment) to 3 (severe impairment). The total score is the sum of the eight function scores and ranges from 0 to 24. Higher scores indicated greater symptom severity/difficulty in performing daily living activities. | Day 57 | 
| Change From Baseline in Total QMG Score at Day 57 | The QMG test was used to assess the participant's strength. The quantitative results of each of the 13 strength components were mapped to a 4-point scale where 0 equals to (=) none, 1= mild, 2= moderate and 3= severe. The total score is the sum of the 13 scale scores and ranges from 0 to 39. Higher scores indicated more severe impairment. | Baseline and Day 57 | 
| Number of Participants With a 3-, 4-, 5-, 6-, 7-, or >= 8-point Improvement in Total QMG Score at Day 57 | The QMG test was used to assess the participant's strength. The quantitative results of each of the 13 strength components were mapped to a 4-point scale where 0 equals to (=) none, 1= mild, 2= moderate and 3= severe. The total score is the sum of the 13 scale scores and ranges from 0 to 39. Higher scores indicated more severe impairment. | Day 57 | 
| Change From Baseline in Total Revised Myasthenia Gravis Quality of Life - 15 (MG-QoL-15r) Scale Score at Day 57 | The MG-QoL15r was used to assess the participant's limitations related to living with MG. Each of the 15 questions were rated by the participant on a 3-point scale (0= Not at all, 1= somewhat, 2=very much) based on a recall period of over the past few weeks. The total score is the sum of the 15 question scores and ranges from 0 to 30. Higher scores indicated more limitation. | Baseline and Day 57 | 
| Change From Baseline in Total Serum IgG at Day 57 | Change from baseline in total serum IgG was reported. Blood samples were collected for analysis of total serum IgG. | Baseline and Day 57 | 
| Change From Baseline in Total MG-ADL Score at Day 85 and Day 113 | The MG-ADL was used to assess the participant's MG symptom severity. It assesses eight functions (talking, chewing, swallowing, breathing, impairment of ability to brush teeth or comb hair, impairment of ability to arise from a chair, double vision, and eyelid droop) which were rated on a 4-point scale: 0 (no impairment) to 3 (severe impairment). The total score is the sum of the eight function scores and ranges from 0 to 24. Higher scores indicated greater symptom severity/difficulty in performing daily living activities. | Baseline, Day 85 and Day 113 | 
| Change From Baseline in Total QMG Score at Day 85 and Day 113 | The QMG test was used to assess the participant's strength. The quantitative results of each of the 13 strength components were mapped to a 4-point scale where 0 equals to (=) none, 1= mild, 2= moderate and 3= severe. The total score is the sum of the 13 scale scores and ranges from 0 to 39. Higher scores indicated more severe impairment. | Baseline, Day 85 and Day 113 | 
| Change From Baseline in Total MG-QoL15r Score at Day 85 and Day 113 | The MG-QoL15r was used to assess the participant's limitations related to living with MG. Each of the 15 questions were rated by the participant on a 3-point scale (0= Not at all, 1= somewhat, 2=very much) based on a recall period of over the past few weeks. The total score is the sum of the 15 question scores and ranges from 0 to 30. Higher scores indicated more limitation. | Baseline, Day 85 and Day 113 | 
| Number of Participants With Shift From Baseline in Myasthenia Gravis Foundation of America (MGFA) Classification at Day 57 | The MGFA was used to assess the participant's MG severity. MGFA classification identifies the subgroup participants with MG who share distinct clinical features or severity of disease: Class I (ocular MG), classes II, III and IV generalized MG with mild, moderate and severe disease, respectively; Class V MG crisis. Separate subclasses under classes II, III and IV are designed: a if the predominant weakness is affecting limb/axial weakness or both; subclass b if the predominant weakness is affecting oropharyngeal or respiratory muscles or both. In the MGFA classification, lower roman numerals mean less severity. Changes in MGFA classification (regardless of subclass) are categorized as Improved (example, III to II), Same (example, II to II), or Worsened (example, II to III). | Baseline and Day 57 | 
| Number of Participants With Shift From Baseline in MGFA Classification to Day 113 | The MGFA was used to assess the participant's MG severity. MGFA classification identifies the subgroup participants with MG who share distinct clinical features or severity of disease: Class I (ocular MG), classes II, III and IV generalized MG with mild, moderate and severe disease, respectively; Class V MG crisis. Separate subclasses under classes II, III and IV are designed: a if the predominant weakness is affecting limb/axial weakness or both; subclass b if the predominant weakness is affecting oropharyngeal or respiratory muscles or both. In the MGFA classification, lower roman numerals mean less severity. Changes in MGFA classification (regardless of subclass) are categorized as Improved (example, III to II), Same (example, II to II), or Worsened (example, II to III). | Baseline to Day 113 | 
| Change From Baseline in Total Serum IgG at Day 85 and Day 113 | Change from baseline in total serum IgG at Day 85 and Day 113 was analyzed. Blood samples were collected for analysis of total serum IgG. | Baseline, Day 85 and Day 113 | 
| Serum Concentrations of Nipocalimab | Serum concentrations of nipocalimab were reported. Concentrations below the lowest quantifiable concentration (< LLOQ) that is <0.15 microgram/milliliter (mcg/mL) was treated as zero in calculating the summary statistics. | Baseline (Pre Infusion and Post Infusion), Day 15 (Pre Infusion), Day 29 (Pre Infusion), Day 43 (Pre Infusion), Day 57 (Pre Infusion and Post Infusion) and Day 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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M281, Generalized Myasthenia Gravis