Conditions: Generalized Myasthenia Gravis
Keywords: M281 Generalized Myasthenia Gravis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 68
Healthy volunteers: no

Brief summary:
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.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None

Interventions: intervention 1: M281 intervention 2: Placebo
Intervention descriptions: intervention 1: M281 administered as IV infusion intervention 2: Placebo administered as intravenous (IV) infusion

Protocol document:
Prot_000.pdf: 
Confidential 
Page 1 of 56 
Clinical Trial Protocol: MOM-M281-004 
 
Study Title: 
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 
Study Number: 
MOM-M281-004 
Study Phase: 
2 
Product Name: 
M281  
IND Number: 
138975 
EudraCT 
Number: 
2018-002247-28 
Indication: 
Generalized myasthenia gravis 
Investigators: 
Multicenter 
 
 
Sponsor: 
Momenta Pharmaceuticals, Inc.  
301 Binney Street 
Cambridge, MA 02142 USA 
Telephone: (617) 491-9700 
Sponsor Contact: 
Santiago Arroyo, MD 
Chief Medical Officer 
Medical Monitor: 
 
Pharmaceutical Product Development, Inc 
 
 
Date 
Original Protocol: 
13 July 2018  
Amendment 1: 
26 October 2018 
Amendment 2: 
11 December 2018 
Amendment 3: 
04 June 2019 
Amendment 3.2: 
28 August 2019 
 
Confidentiality Statement 
The confidential information in the following document is provided to you as an Investigator, 
potential Investigator, or consultant for review by you, your staff, and applicable Institutional 
Review Board/Independent Ethics Committee or Regulatory Health Authority. The 
information contained herein should not be disclosed to others, without written authorization 
from Momenta Pharmaceuticals, Inc. 
PPD
NCT03772587


M281  
 
Momenta Pharmaceuticals, Inc. 
Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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SYNOPSIS 
Sponsor: 
Momenta Pharmaceuticals, Inc. 
Name of Finished Product: 
M281  
Study Title: 
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  
Study Number: 
MOM-M281-004 
Study Phase: 2 
Primary Objective(s):  
The primary objectives are to evaluate: 
• The safety and tolerability of treatment with M281 in patients with generalized 
myasthenia gravis (gMG) who have an insufficient clinical response to ongoing, stable 
standard of care therapy, and 
• The efficacy of M281 for gMG as measured by the change in Myasthenia Gravis – 
Activities of Daily Living (MG-ADL) score. 
 
Secondary Objective(s): 
The secondary objectives are to evaluate: 
• The efficacy of M281 as measured by changes in the Quantitative Myasthenia Gravis 
(QMG) score and the revised Myasthenia Gravis Quality of Life - 15 Scale 
(MG-QoL15r), 
• The pharmacokinetics (PK) of M281, and 
• The pharmacodynamic (PD) activity of M281 as measured by effects on total serum 
immunoglobulin (Ig)G concentrations.  
 
Exploratory Objective(s): 
The exploratory objectives are to: 
• Evaluate the PD activity of M281 as measured by effects on serum concentrations of 
IgG1, IgG2, IgG3, IgG4, IgA, IgM, and IgE; 
• Evaluate the PD activity of M281 as measured by effects on serum levels of pathogenic 
autoantibodies associated with gMG (anti-acetylcholine receptor [anti-AChR] and anti-
muscle-specific kinase [anti-MuSK]); 
• Characterize pathogenic MG autoantibodies (anti-AChR and anti-MuSK) and their 
potential for disease modification and possible relationship with clinical status; 
• Evaluate the immunogenicity of M281 as assessed by the presence of total and 
neutralizing anti-M281 antibodies in patients with gMG; 


M281  
 
Momenta Pharmaceuticals, Inc. 
Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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• Evaluate the response to treatment with M281 in patients with gMG, as measured by 
exploratory efficacy endpoints, including, but not limited to, use of rescue therapy, time 
to response, duration of response, and number of MG exacerbations; and 
• Evaluate the potential relationship between change in MG-ADL score and change in 
anti-AChR levels in patients treated with M281, for patients positive for anti-AChR 
antibodies only. 
 
Study Design: 
This multicenter, randomized, double-blind, placebo-controlled study is designed to evaluate 
the safety, tolerability, efficacy, PK, PD, and immunogenicity of M281 compared with 
placebo when administered by intravenous (IV) infusion to patients with gMG.  
Following a Screening Period of up to 4 weeks, approximately 60 eligible patients will be 
randomized 1:1:1:1:1 to one of 5 treatment groups (approximately 12 per group).  The 
randomization will be stratified first by autoantibody type (anti-MuSK vs anti-AChR), and 
for patients positive for anti-AChR, the randomization will be further stratified by Baseline 
MG-ADL score (≤10, >10). The treatment groups are as follows: 
• Group 1:  placebo once every 2 weeks (Q2W) 
• Group 2:  5 mg/kg M281 once every 4 weeks (Q4W) 
• Group 3:  30 mg/kg M281 Q4W 
• Group 4:  60 mg/kg M281 as a single dose 
• Group 5:  60 mg/kg M281 Q2W 
 
During the Treatment Period, patients will attend clinic visits beginning at Baseline (Day 1) 
and every other week for 8 weeks to receive study drug (placebo or M281) and undergo 
safety, efficacy, PK, PD, and immunogenicity assessments.   
To maintain the study blind with respect to assigned treatment and treatment regimen, all 
patients will receive an IV infusion (either placebo or M281) every other week; thus, all 
patients will receive a total of 5 infusions.  Pharmacokinetic samples, vital signs, and an 
electrocardiogram (ECG) will be obtained before the start of each infusion.  Patients will be 
observed for safety after the first 3 infusions per the Infusion Manual; if no clinically relevant 
adverse events (AEs) related to the infusion are observed in these first 3 infusions, the post-
infusion observation period is no longer needed.  The last infusion will be administered at the 
Day 57 visit.  During the Follow-up Period (the 8-week period after the last infusion), clinic 
visits will be conducted for all patients at Day 85 and Day 113 for further safety, efficacy, 
PK, PD, and immunogenicity assessments needed to characterize the anticipated prolonged 
effects of M281.  Serum biomarkers may be explored. 
Upon completion of the study at Day 113, patients have the option to enroll in a separate 
open-label extension study where they would receive treatment with M281. 
An independent Drug Safety Monitoring Board (DSMB) will be responsible for oversight of 
patient safety during the study. 


M281  
 
Momenta Pharmaceuticals, Inc. 
Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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Study Population:  
Approximately 60 randomized patients with gMG.  The sample size may be increased by up 
to 30 additional patients based on the results of the interim analysis. 
 
Test Product, Dose, and Mode of Administration:  
M281 for IV infusion at doses of 5 mg/kg (Q4W), 30 mg/kg (Q4W), 60 mg/kg (Q2W), and 
60 mg/kg as a single dose 
Placebo for IV infusion 
 
Duration of Treatment:  
8 weeks 
 
Efficacy Assessments: 
Efficacy will be assessed using the following measures in the following order:  MG-ADL, 
QMG, MG-QoL15r, Myasthenia Gravis Foundation of America (MGFA) Clinical 
Classification, and selected elements of the MGFA Post-intervention Status (MGFA-PIS). 
 
Safety Assessments: 
Safety assessments include collection of AEs and serious AEs (SAEs), vital signs, physical 
examinations, clinical laboratory testing (including chemistry, hematology, coagulation, and 
urinalysis), ECG findings, and the Columbia-Suicide Severity Rating Scale (C-SSRS).  After 
the patient has signed the informed consent, any new clinically relevant finding or worsening 
of a pre-existing condition will be reported as an AE.   
Events of severe infection and hypoalbuminemia (Grade 3 or higher according to the 
Common Terminology Criteria for Adverse Events [CTCAE] v5.0) will be considered AEs 
of special interest (AESIs). 
 
Pharmacokinetic Assessments: 
Blood samples will be drawn for analysis of M281 concentrations. 
 
Assessments of Pharmacodynamics and Biomarkers: 
Blood samples will be drawn for analysis of the following PD parameters: concentrations of 
total serum IgG, and titers of anti-AChR and anti-MuSK autoantibodies. Exploratory PD will 
evaluate changes in serum concentrations of IgG subclasses (IgG1, IgG2, IgG3, IgG4), and 
IgA, IgM, and IgE.  Additional blood samples will be drawn to explore characteristics of 
pathogenic MG antibodies (anti-AChR and anti-MuSK). 
 
Immunogenicity Assessments: 
Total and neutralizing anti-M281 antibodies will be assessed, as applicable. 
 


M281  
 
Momenta Pharmaceuticals, Inc. 
Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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Statistical Methods:  
Adverse events will be coded using a standardized medical dictionary (Medical Dictionary 
for Regulatory Activities [MedDRA]) and tabular summaries of proportions of patients with 
AEs in each treatment group will be presented.  Descriptive statistics and a summary of 
abnormalities using shift tables will be presented for safety laboratory tests, vital signs, 
ECGs, other laboratory parameters, and the C-SSRS.  
The primary efficacy endpoint is change from baseline to Day 57 in the total MG-ADL score 
for each treatment group compared with placebo.  A mixed-effect model repeat measures 
(MMRM) analysis including data at Days 15, 29, 43, and 57 will be used for the primary 
efficacy analysis. 
Serum concentrations of M281, PD parameters, and immunogenicity results will be 
summarized using descriptive statistics.  Selected serum biomarkers will be assayed and their 
potential relationship to clinical status may be explored. 
An interim analysis will be performed when approximately 30 patients have completed the 
Day 57 assessments.  The results will be used to adjust the sample size, if necessary, and to 
guide future development activities.  If the model adjusted standard deviation of MG-ADL 
change from baseline is >4.0, up to 30 additional patients may be recruited. 
 
Date of Protocol Amendment 3.2:  28 August 2019 
 
 


M281  
 
Momenta Pharmaceuticals, Inc. 
Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................9 
1 
INTRODUCTION ...........................................................................................................11 
2 
STUDY OBJECTIVES ....................................................................................................13 
2.1 
Primary Objectives.................................................................................................13 
2.2 
Secondary Objectives.............................................................................................13 
2.3 
Exploratory Objective(s) ........................................................................................14 
3 
INVESTIGATIONAL PLAN ..........................................................................................14 
3.1 
Overall Study Design and Plan ..............................................................................14 
3.2 
Rationale for Study Design and Control Group .....................................................15 
3.3 
Study Duration and Dates ......................................................................................16 
4 
STUDY POPULATION SELECTION ...........................................................................16 
4.1 
Study Population ....................................................................................................16 
4.2 
Inclusion Criteria ...................................................................................................16 
4.3 
Exclusion Criteria ..................................................................................................18 
5 
STUDY TREATMENT(S) ..............................................................................................21 
5.1 
Description of Treatment(s) ...................................................................................21 
5.1.1 
Study Drug ...................................................................................................21 
5.1.2 
Placebo .........................................................................................................21 
5.2 
Treatments Administered .......................................................................................21 
5.3 
Selection and Timing of Dose for Each Patient .....................................................21 
5.4 
Method of Assigning Patients to Treatment Groups..............................................22 
5.5 
Blinding..................................................................................................................22 
5.6 
Concomitant Therapy.............................................................................................23 
5.7 
Restrictions ............................................................................................................23 
5.7.1 
Prior Therapy ...............................................................................................23 
5.7.2 
Fluid and Food Intake ..................................................................................23 
5.7.3 
Patient Activity Restrictions ........................................................................23 
5.8 
Treatment Compliance ...........................................................................................24 
5.9 
Packaging and Labeling .........................................................................................24 
5.10 
Storage and Accountability ....................................................................................24 
6 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................24 
6.1 
Safety Assessments ................................................................................................28 
6.1.1 
Adverse Events ............................................................................................28 
6.1.1.1 
Performing Adverse Events Assessments ..........................................28 
6.1.1.2 
Timing ................................................................................................28 
6.1.1.3 
Severity ..............................................................................................28 


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Clinical Trial Protocol: MOM-M281-004 
 
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6.1.1.4 
Relationship .......................................................................................29 
6.1.1.5 
Expectedness ......................................................................................30 
6.1.1.6 
Adverse Events of Special Interest ....................................................30 
6.1.1.7 
Clinical Laboratory Adverse Events ..................................................30 
6.1.1.8 
Serious Adverse Events .....................................................................30 
6.1.1.9 
Treatment-Emergent Adverse Events ................................................31 
6.1.1.10 
Pregnancy ...........................................................................................31 
6.1.2 
Concomitant Medication Assessments ........................................................32 
6.1.3 
Physical Examination...................................................................................32 
6.1.4 
Vital Signs ....................................................................................................32 
6.1.5 
Clinical Laboratory Tests .............................................................................32 
6.1.6 
Electrocardiograms ......................................................................................34 
6.1.7 
Columbia-Suicide Severity Rating Scale .....................................................34 
6.2 
Efficacy Assessments.............................................................................................34 
6.2.1 
Myasthenia Gravis – Activities of Daily Living ..........................................34 
6.2.2 
Quantitative Myasthenia Gravis ..................................................................35 
6.2.3 
Revised Myasthenia Gravis Quality of Life – 15 ........................................35 
6.2.4 
Myasthenia Gravis Foundation of America Post-Intervention Status .........35 
6.2.5 
Myasthenia Gravis Foundation of America Clinical Classification ............36 
6.3 
Pharmacokinetic Assessments ...............................................................................36 
6.4 
Assessments of Pharmacodynamics and Biomarkers ............................................36 
6.5 
Immunogenicity Assessments ................................................................................36 
6.6 
Removal of Patients from the Trial or Study Drug ................................................37 
6.7 
Stopping Criteria ....................................................................................................37 
6.7.1 
Study Drug Stopping/Interruption Rules for Individual Patients ................37 
6.7.2 
Study Stopping Rules ...................................................................................38 
6.8 
Other Study Procedures .........................................................................................39 
6.9 
Appropriateness of Measurements .........................................................................39 
7 
QUALITY CONTROL AND ASSURANCE .................................................................40 
8 
PLANNED STATISTICAL METHODS ........................................................................40 
8.1 
General Considerations ..........................................................................................40 
8.2 
Determination of Sample Size ...............................................................................40 
8.3 
Analysis Populations ..............................................................................................41 
8.4 
Demographics and Baseline Characteristics ..........................................................41 
8.5 
Primary Endpoints .................................................................................................41 
8.5.1 
Primary Safety Endpoint ..............................................................................41 
8.5.2 
Primary Efficacy Endpoint ..........................................................................41 
8.6 
Secondary Endpoints .............................................................................................42 
8.6.1 
Secondary Efficacy Endpoints .....................................................................42 


M281  
 
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Clinical Trial Protocol: MOM-M281-004 
 
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8.6.2 
Other Secondary Endpoint(s) .......................................................................43 
8.7 
Exploratory Endpoints ...........................................................................................43 
8.8 
Interim Analysis .....................................................................................................44 
9 
ADMINISTRATIVE CONSIDERATIONS ....................................................................44 
9.1 
Investigators and Study Administrative Structure .................................................44 
9.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................44 
9.3 
Ethical Conduct of the Study .................................................................................45 
9.4 
Patient Information and Consent ...........................................................................45 
9.5 
Patient Confidentiality ...........................................................................................45 
9.6 
Study Monitoring ...................................................................................................46 
9.7 
Case Report Forms and Study Records .................................................................46 
9.8 
Data Monitoring Committee ..................................................................................47 
9.9 
Protocol Violations/Deviations ..............................................................................47 
9.10 
Access to Source Documentation ..........................................................................47 
9.11 
Data Generation and Analysis ...............................................................................47 
9.12 
Retention of Data ...................................................................................................47 
9.13 
Publication and Disclosure Policy .........................................................................48 
10 REFERENCE LIST .........................................................................................................49 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Selection and Timing of Infusions for Each Treatment Arm ..............22 
Table 2. 
Schedule of Study Assessments ...........................................................25 
Table 3. 
List of Clinical Laboratory Tests .........................................................33 
 
LIST OF APPENDICES 
Appendix 1 
Sponsor Signatures...............................................................................51 
Appendix 2 
Investigator’s Signature .......................................................................52 
Appendix 3 
Myasthenia Gravis – Activities of Daily Living ..................................53 
Appendix 4 
Quantitative Myasthenia Gravis ..........................................................54 
Appendix 5 
Revised Myasthenia Gravis Quality of Life – 15 ................................55 
Appendix 6 
Myasthenia Gravis Foundation of America Post-Intervention 
Status ....................................................................................................56 
 


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Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AChR 
acetylcholine receptor 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CRA 
clinical research associate 
CS 
clinically significant 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
D5W 
dextrose 5% in water 
DSMB 
Drug Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FcRn 
neonatal Fc receptor 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
gMG 
generalized myasthenia gravis 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
ITT 
intent to treat 
IV 
intravenous 
IVIG 
intravenous immunoglobulin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MG 
myasthenia gravis 


M281  
 
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Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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MG-ADL 
Myasthenia Gravis – Activities of Daily Living 
MGFA 
Myasthenia Gravis Foundation of America 
MGFA-PIS 
Myasthenia Gravis Foundation of America Post-intervention Status 
MG-QoL15r 
Revised Myasthenia Gravis Quality of Life – 15 Scale 
MMRM 
mixed-effects model repeated measures 
MuSK 
muscle-specific kinase 
nADA 
neutralizing anti-drug antibody 
NCS 
not clinically significant 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PP 
per protocol 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
QMG 
Quantitative Myasthenia Gravis 
QTc 
QT interval corrected for heart rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
US FDA 
United States Food and Drug Administration 
 


M281  
 
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Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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1 INTRODUCTION 
Myasthenia gravis (MG) is a rare, heterogeneous, neuromuscular disease characterized by 
fluctuating, fatigable muscle weakness.  Generalized myasthenia gravis (gMG) is 
characterized by the fluctuating and variable combination of weakness in ocular, bulbar, 
limb, neck, and respiratory muscles.  Myasthenia gravis is caused by pathogenic 
autoantibodies directed against proteins in the postsynaptic membrane of the neuromuscular 
junction.  In most patients (approximately 85% of cases), circulating antibodies target the 
acetylcholine receptor (AChR); to a lesser extent (<10% of cases), antibodies to the 
muscle-specific kinase (MuSK), or lipoprotein-related protein 4 are present (Meriggioli and 
Sanders 2012; Zhang et al 2012).  
Preferred symptomatic treatment is with the acetylcholinesterase inhibitor, pyridostigmine.  
However, to meet the treatment goals of restoring or maintaining full or nearly full physical 
function and high quality of life, most patients with MG also require treatment with 
immunosuppressive medication(s) (Gilhus 2016; Gilhus et al 2016; Mantegazza and Antozzi 
2018).  This includes treatment aimed at reducing the production of autoantibodies, such as 
immunosuppression with corticosteroids and second-line agents (azathioprine, 
cyclophosphamide, mycophenolate mofetil/mycophenolic acid, and B cell 
modification/ablation), as well as those aimed at increasing autoantibody removal such as 
plasma exchange, immunoadsorption, or immunomodulatory doses of intravenous 
immunoglobulin (IVIG) (Sanders et al 2016; Gilhus 2016; Gilhus et al 2016).  
While many patients with gMG can be managed with current therapies, 10%-15% of patients 
fail to respond adequately to or cannot tolerate multiple therapies for MG and continue to 
suffer profound muscle weakness and severe disease symptoms that limit function and can be 
life-threatening (Silvestri and Wolfe 2014; Howard et al 2013; Howard et al 2017; Sanders 
et al 2016; Sathasivam 2014; Mantegazza and Antozzi 2018), and up to 80% fail to achieve 
complete and stable remission (Mantegazza 2018).  Despite medical advances in patient care, 
a recent analysis of data from patient registries indicates that gMG is still associated with 
increased mortality compared to the general population, with an estimated mortality rate ratio 
of 1.4 (range 1.24–1.60) (Hansen et al 2016).  Thus, there is a clear unmet medical need for 
new safe and effective treatments for gMG. 
Momenta Pharmaceuticals, Inc. (Momenta) is developing M281 for the treatment of MG, 
with an initial focus on patients with gMG.  M281 is a fully human, aglycosylated 
immunoglobulin (Ig)G1 antibody that targets the neonatal Fc receptor (FcRn) IgG binding 
site with high affinity, thereby interfering with the binding of native IgG.  In cells of the 
reticuloendothelial system, FcRn binding of IgG protects it from degradation and contributes 
to its long half-life.  Interference with FcRn function leads to a decrease in IgG levels.  In 
patients with gMG, M281 is expected to reduce circulating levels of antibodies by blocking 
IgG recycling, including the pathogenic autoantibodies that cause MG, and to ameliorate 
manifestations of the disease. 
The efficacy of blocking FcRn with anti-FcRn antibodies has been demonstrated in an 
experimental animal model of autoimmune MG.  In this study, administration of an anti-rat 


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Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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FcRn monoclonal antibody resulted in a dose-dependent amelioration of disease symptoms 
induced by administration of an anti-AChR monoclonal antibody, and a corresponding 
reduction in serum concentration of pathogenic antibody (Liu et al 2007). 
In humans, intravenous (IV) administration of an anti-FcRn IgG4 monoclonal antibody 
(rozanolixizumab) was shown to decrease IgG levels in healthy volunteers to approximately 
50% of baseline following a single 7-mg/kg dose (Kiessling et al 2017).  Similar results were 
observed in a Phase 1 study of the humanized IgG4 monoclonal antibody, SYNT001, where 
single IV infusions at doses of 1, 3, 10, and 30 mg/kg produced dose-dependent reductions in 
IgG, with a nadir of 47% in the 30 mg/kg dose group (Blumberg et al 2017), and a Phase 1 
study of the antibody Fc-fragment, ARGX-113, where a single IV infusion of 10 mg/kg drug 
reduced IgG by 50% and multiple infusions (up to 4 weekly infusions) reduced IgG by up to 
85% (Argenx 2017).  Preliminary data from an ongoing Phase 2, double-blind, 
placebo-controlled study of ARGX-113 (4 weekly IV infusions of 10 mg/kg ARGX-113 vs 
placebo) in patients with gMG showed promising results, with 75% of patients in the 
ARGX-113 group showing a clinically meaningful and statistically significant improvement 
in symptoms as measured by the Myasthenia Gravis – Activities of Daily Living (MG-ADL) 
scale for a period of at least 6 consecutive weeks (versus 25% of patients on placebo) 
(Argenx 2017).  These clinical studies demonstrate that interference with IgG binding to 
FcRn rapidly decreases IgG to low but predictable steady state levels, and thus should rapidly 
and effectively decrease circulating levels of pathogenic autoantibodies to ameliorate 
pathology and morbidity associated with gMG. 
Potential Risks and Plans for Mitigation 
Reduction of Serum Albumin Levels: 
Asymptomatic decreases in serum albumin concentrations to a mean of 20% to 25% decrease 
from baseline were observed in the Phase 1 clinical study (MOM-M281-001).  This mild 
hypoalbuminemia was self-limited over the duration of dosing of M281 and recovered 
rapidly following dose cessation.  To mitigate any potential risk of hypoalbuminemia in the 
present study, patients need to have a normal serum albumin level to be eligible for entering 
the study.  Serum albumin levels and clinical symptoms related to hypoalbuminemia will be 
monitored throughout the study, and hypoalbuminemia-related adverse event (AE) stopping 
rules are included in Section 6.7.1 of this protocol. 
Reduction of Circulating IgG Levels: 
In the Phase 1 clinical study (MOM-M281-001), subjects administered with M281 showed 
dose-dependent reduction of circulating IgG levels, which is an anticipated 
pharmacodynamic (PD) effect of M281 and contributes to its potential benefit in MG.  It is 
important to note that the normal immune response to produce IgM and IgG in response to a 
foreign antigen proceeds during treatment with FcRn blockers (Nixon et al 2015).  To date, 
M281 has not been associated with an increase in infection-related events in nonclinical or 
clinical studies.  Published clinical studies of other investigational agents that interfere with 
FcRn have not revealed an increase in incidence or severity of infections (Kiessling et al 
2017; Argenx 2017; Blumberg et al 2017; Robak et al 2017).  These observations are 


M281  
 
Momenta Pharmaceuticals, Inc. 
Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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suggestive, but not definitive, that the risk for infections associated with M281 administration 
may prove to be low.  Given the theoretical potential for increased infection risk with 
reduced circulating IgG levels, procedures have been included in this protocol to mitigate the 
theoretical risk, including related criteria for study eligibility and infection-related AE 
stopping rules. 
Elevation of Serum Creatine Kinase (CK): 
Transient and asymptomatic elevations in serum CK levels were observed in 3 subjects in the 
15 mg/kg multiple-ascending-dose cohort in the Phase 1 study.  No CK elevations were 
observed in any of the preclinical studies of M281.  To mitigate any potential risk in the 
present study, patients who have serum CK level ≥2 × upper limit of normal (ULN) are 
excluded from entering the study.  Serum CK levels will be monitored during the study and 
CK-related AE stopping rules are included in Section 6.7.1 of this protocol. 
Altogether, the current evidence from animal and human studies of FcRn blockade suggests 
that inhibition of FcRn-mediated IgG recycling by M281 may prove to be an effective 
treatment for patients with gMG.  A completed study of M281 in healthy volunteers 
(MOM-M281-001) showed that M281 was well tolerated at single doses up to 60 mg/kg (the 
highest single dose tested) and at multiple doses up to 30 mg/kg (the highest repeat dose 
tested).  This first study in patients with gMG will evaluate the therapeutic potential of single 
(60 mg/kg) and repeat doses of M281 (5, 30, and 60 mg/kg) for the treatment of patients with 
gMG, with the goal of determining the optimal dose and regimen for the Phase 3 study. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objectives  
The primary objectives of this study are to evaluate: 
• The safety and tolerability of treatment with M281 in patients with gMG who have an 
insufficient clinical response to ongoing, stable standard of care therapy, and 
• The efficacy of M281 for gMG as measured by the change in MG-ADL score. 
 
2.2 
Secondary Objectives  
The secondary objectives of this study are to evaluate: 
• The efficacy of M281 as measured by changes in the Quantitative Myasthenia Gravis 
(QMG) score and the revised Myasthenia Gravis Quality of Life – 15 Scale 
(MG-QoL15r), 
• The pharmacokinetics (PK) of M281, and 
• The PD activity of M281 as measured by effects on total serum IgG concentrations. 
 


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2.3 
Exploratory Objective(s) 
The exploratory objectives are to: 
• Evaluate the PD activity of M281 as measured by effects on serum concentrations of 
IgG1, IgG2, IgG3, IgG4, IgA, IgM, and IgE; 
• Evaluate the PD activity of M281 as measured by effects on serum levels of pathogenic 
autoantibodies associated with gMG (anti-AChR and anti-MuSK); 
• Characterize pathogenic MG autoantibodies (anti-AChR and anti-MuSK) and their 
potential for disease modification and possible relationship with clinical status; 
• Evaluate the immunogenicity of M281 as assessed by the presence of total and 
neutralizing anti-M281 antibodies in patients with gMG; 
• Evaluate the response to treatment with M281 in patients with gMG, as measured by 
exploratory efficacy endpoints, including, but not limited to, use of rescue therapy, time 
to response, duration of response, and number of MG exacerbations; and 
• Evaluate the potential relationship between change in MG-ADL score and change in anti-
AChR levels in patients treated with M281, for patients positive for anti-AChR 
antibodies only. 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This multicenter, randomized, double-blind, placebo-controlled study is designed to evaluate 
the safety, tolerability, efficacy, PK, PD, and immunogenicity of M281 compared with 
placebo when administered by IV infusion to patients with gMG.  
Following a Screening Period of up to 4 weeks, approximately 60 eligible patients will be 
randomized 1:1:1:1:1 to one of 5 treatment groups (approximately 12 per group).  The 
randomization will be stratified first by autoantibody type (anti-MuSK vs anti-AChR), and 
for patients positive for anti-AChR, the randomization will be further stratified by Baseline 
MG-ADL score (≤10, >10).  The treatment groups are as follows: 
• Group 1:  placebo once every 2 weeks (Q2W) 
• Group 2:  5 mg/kg M281 once every 4 weeks (Q4W) 
• Group 3:  30 mg/kg M281 Q4W 
• Group 4:  60 mg/kg M281 as a single dose 
• Group 5:  60 mg/kg M281 Q2W 
 
During the Treatment Period, patients will attend clinic visits beginning at Baseline (Day 1) 
and every other week for 8 weeks to receive study drug (placebo or M281) and undergo 
safety, efficacy, PK, PD, and immunogenicity assessments.  To maintain the study blind with 
respect to assigned treatment and treatment regimen, all patients will receive an IV infusion 


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Clinical Trial Protocol: MOM-M281-004 
 
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(either placebo or M281) every other week; thus, all patients will receive a total of 
5 infusions.  Pharmacokinetic samples, vital signs, and an electrocardiogram (ECG) will be 
obtained before the start of each infusion.  Patients will be observed for safety after the first 
3 infusions per the Infusion Manual; if no clinically relevant AEs related to the infusion are 
observed in these first 3 infusions, the post-infusion observation period is no longer needed.  
The last infusion will be administered at the Day 57 visit.  During the Follow-up Period (the 
8-week period after the last infusion), clinic visits will be conducted for all patients at Day 85 
and Day 113 for further safety, efficacy, PK, PD, and immunogenicity assessments needed to 
characterize the anticipated prolonged effects of M281.  Serum biomarkers may be explored. 
Upon completion of the study at Day 113, patients have the option to enroll in a separate 
open-label extension study where they would receive treatment with M281. 
An independent Drug Safety Monitoring Board (DSMB) will be responsible for oversight of 
patient safety during the study. 
The Schedule of Study Assessments is provided in Section 6. 
3.2 
Rationale for Study Design and Control Group 
The study will enroll patients with gMG who have an insufficient clinical response (defined 
as a QMG score of ≥12 and MG-ADL score of ≥4) to ongoing, stable standard of care 
therapy.  Considering the intended effects of M281 on IgG levels and the role of pathogenic 
autoantibodies in gMG, these patients are likely to benefit from treatment with M281 and are 
likely to represent the target population. 
A randomized, double-blind, placebo-controlled, parallel group study design was chosen 
because it is the most robust study design.  A placebo comparator arm was chosen for this 
study as it provides the most valid comparison versus active treatment for the analyses of 
safety, efficacy, PK, PD, and immunogenicity.  A placebo arm is warranted because patients 
in this study are not required to stop their current standard of care medications; patients can 
remain on stable doses of their current pharmacologic therapies (eg, glucocorticosteroids, 
acetylcholinesterase inhibitors, immunosuppressants, other remedies/supplements) 
throughout the study.  The parallel group design allows recruitment of patients for all 
treatment arms with the same time frame, thus avoiding the potential problem of imbalance 
when cohorts are recruited sequentially. 
The doses of M281 chosen for administration during this study (5 mg/kg Q4W, 30 mg/kg 
Q4W, 60 mg/kg single dose, 60 mg/kg Q2W) were selected to ensure safety and tolerability 
while attempting to map the efficacious dose and dose regimen range for the treatment of 
patients with gMG.  The doses consider safety, tolerability, and potential efficacy using data 
derived from nonclinical studies in nonhuman and data from the completed Phase 1 study of 
M281 in healthy normal volunteers, MOM-M281-001.  The no observed adverse effect level 
in the 26-week, repeat-dose, Good Laboratory Practice-compliant toxicology study in 
cynomolgus monkeys was the highest dose tested of 300 mg/kg, which is 5-fold higher than 
the maximum proposed dose in this study (60 mg/kg Q2W) on a dose basis and 10-fold 
higher on a dose-per-week basis.  Moreover, all dose levels administered in the Phase 1 study 


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Clinical Trial Protocol: MOM-M281-004 
 
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in humans (up to 60 mg/kg single doses and up to 30 mg/kg once weekly for up to 4 weeks) 
were considered safe and well tolerated.  Analysis of PK data following single doses at 
60 mg/kg indicates that negligible accumulation will occur with Q2W dosing, suggesting that 
the clinically observed maximum serum concentration and area under the concentration-time 
curve are not likely to be exceeded.  No accumulation is anticipated with Q4W dose 
regimens. 
The efficacy of M281 in gMG is expected to be related to total serum IgG lowering.  
Therefore, IgG lowering was examined to select the doses to predict efficacy.  The highest 
dose of 60 mg/kg Q2W was selected to saturate the FcRn target for the full dosing interval 
(thereby minimizing total serum IgG concentration), while the lowest dose of 5 mg/kg Q4W 
was selected to target minimally differentiated IgG lowering from placebo at trough.  
Intermediate doses were selected with the goal of maximizing the potential for differentiation 
with the percentage of total serum IgG lowering.  A single-dose arm at the highest planned 
dose level for this study (60 mg/kg) is included based on observations in the first-in-human 
study and simulations that indicate a profound IgG lowering effect at this dose level. 
The effects of M281 on IgG levels and the potential for symptom improvement are 
anticipated to be rapid; therefore, an 8-week Treatment Period is deemed sufficient for this 
study.  The 8-week Follow-up Period will allow for full characterization of the duration of 
efficacy and PK after the last infusion of M281 and will allow for observation of the return of 
PD parameters.  
3.3 
Study Duration and Dates 
The study includes a Screening Period of up to 4 weeks, an 8-week Treatment Period, and an 
8-week Follow-up Period (beginning after the last infusion) for a total study duration of 
20 weeks. 
4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Approximately 60 patients with gMG will be enrolled in this study among approximately 
60 study centers internationally. 
4.2 
Inclusion Criteria 
Each patient must meet the following criteria to be eligible for this study. 
1. Is a male or female outpatient ≥18 years of age. 
2. Has a documented history of gMG and clinical signs/symptoms of gMG. 
3. Has a documented diagnosis of gMG by a positive serologic test for a gMG-related 
pathogenic autoantibody (anti-AChR or anti-MuSK autoantibodies), confirmed prior to 
randomization, and is on stable therapy for MG. If the patient receives the first dose of 
M281 before the Screening results are available and the results are subsequently negative, 
the patient may be replaced. 


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4. Has a Myasthenia Gravis Foundation of America (MGFA) Clinical Classification 
Class II, III, or IVa at Screening. 
5. Has a QMG score of ≥12 and MG-ADL score of ≥4 at Screening and Baseline. 
6. If taking a glucocorticosteroid, the patient must provide/obtain documentation showing 
the dose and regimen has been stable for at least 4 weeks prior to Screening. 
7. If taking an acetylcholinesterase inhibitor, the patient must provide/obtain documentation 
showing the dose and regimen has been stable for at least 2 weeks prior to randomization 
on Day 1. 
8. If taking statins at Screening, the patient must provide/obtain documentation showing the 
dose and regimen has been stable for at least 2 months prior to Screening. 
9. If currently receiving immunosuppressants, the patient must provide/obtain 
documentation showing that the patient has been on the given immunosuppressant for 
≥6 months and has been on a stable dose for ≥3 months prior to Screening.  Allowed 
concomitant immunosuppressants are azathioprine, mycophenolate mofetil/ 
mycophenolic acid, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide.  
10. Has total serum IgG at or higher than the lower limit of normal at Screening. However, if 
the patient is on immunomodulatory agents, the patient may be included as long as the 
IgG level is not lower than 75% of the lower limit of normal.  
11. Has serum albumin and serum calcium concentrations within the normal range of the 
reference laboratory at Screening. 
12. Has sufficient venous access to allow drug administration by infusion and blood sampling 
as per the protocol. 
13. Is up to date on all age-appropriate vaccinations as per routine local medical guidelines. 
14. [This inclusion criterion was removed under Amendment 3.2; original numbering was 
retained.] 
15. Women of childbearing potential, defined as women physiologically capable of 
becoming pregnant, must have a negative serum pregnancy test at the Screening visit and 
a negative urine pregnancy test at Baseline.  Menopausal women must have an elevated 
serum follicle-stimulating hormone level (FSH) at Screening; if the FSH is not elevated, 
they are considered to be of childbearing potential and must have a negative serum 
pregnancy test at Screening and a negative urine pregnancy test at Baseline to be eligible.  
16. Women of childbearing potential (including menopausal women who do not have 
elevated FSH) must agree to remain totally abstinent (ie, refrain from sexual intercourse 
during the study) or to consistently use a reliable and highly effective method of 
contraception (eg, condom plus diaphragm, condom plus spermicide, diaphragm plus 
spermicide, or intrauterine device or oral/injectable/implanted hormonal contraceptive 
used in combination with an additional barrier method) during the study and for 30 days 
after the last study treatment.   
Note:  Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method 
are not acceptable methods of contraception.  Female condom and male condom should 
not be used together. 
17. Male patients must agree to remain totally abstinent (ie, refrain from sexual intercourse 
during the study) or to consistently use a reliable and highly effective method of 
contraception (eg, condom plus diaphragm, condom plus spermicide, diaphragm plus 
spermicide, or intrauterine device or oral/injectable/implanted hormonal contraceptive 


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Momenta Pharmaceuticals, Inc. 
Clinical Trial Protocol: MOM-M281-004 
 
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used in combination with an additional barrier method) to avoid pregnancy of the 
patient’s partner(s) during the study and for 100 days following the last study treatment, 
unless the patient provides documentation of a vasectomy at least 6 months prior to 
Screening.  Male patients must also abstain from sperm donation during the study and for 
100 days following the last treatment.   
Note:  Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method 
are not acceptable methods of contraception.  Female condom and male condom should 
not be used together. 
18. A patient using herbal, naturopathic, and traditional Chinese remedies and ayurvedic and 
nutritional supplements is eligible if the use of these medications is acceptable to the 
Investigator.  These remedies must be at a stable dose and regimen using the same 
preparation for ≥2 months prior to Screening. 
19. Is able to understand and voluntarily provide written informed consent to participate in 
the study and comply with all study procedures. 
 
4.3 
Exclusion Criteria 
Patients who meet any of the following criteria (at Screening unless otherwise specified) will 
be excluded from the study. 
1. Has MGFA Class I, IVb, or V disease, or presence of MG crisis (MGFA Class V) at 
Screening or Baseline, history of MG crisis within 1 month of the Screening visit, or 
fixed weakness (and/or ‘burnt out’ MG).  If the clinical status of the patient changes such 
that the patient meets Inclusion Criterion #4 (MGFA Clinical Class II, III, or IVa), the 
patient can be re-screened once. 
2. Has received rituximab or eculizumab within 12 months prior to Screening. 
3. Has received plasmapheresis, immunoadsorption therapy, or IVIG within 6 weeks prior 
to randomization on Day 1.  The patient may be re-screened after the exclusionary period 
of 6 weeks has passed. 
4. Has a gastric tube or is ventilator dependent. 
5. Has an unresected thymoma (based on imaging results) or any history of malignant 
thymoma. 
6. Has had a thymectomy within 12 months prior to Screening, or thymectomy is planned 
during the study. 
7. Has a history of any neurologic disorder other than MG that might interfere with the 
accuracy of study assessments, including but not limited to any chronic 
neurodegenerative disease, major congenital neurologic defect or Lambert-Eaton 
myasthenic syndrome, drug-induced MG, or hereditary forms of myasthenic syndrome.  
8. Has an altered level of consciousness, dementia, or abnormal mental status.  
9. Has current suicidal ideation evidenced by a “yes” response to Questions 4 or 5 in the 
Suicidal Ideation section of the Columbia-Suicide Severity Rating Scale (C-SSRS) at 
Screening or Baseline, or a history of active suicidal ideation or suicidal behavior in the 
past year prior to Screening. 


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10. Is currently breastfeeding, pregnant, intends to become pregnant during the study, or is 
planning egg donation during the study or within 30 days after the last dose of study 
drug. 
11. Has a serious or clinically significant infection (eg, pneumonia, biliary tract infection, 
diverticulitis, Clostridium difficile infection) requiring parenteral anti-infectives and/or 
hospitalization, within 8 weeks prior to Screening.  The patient may be re-screened after 
the 8-week exclusionary period has passed.  Any patient with an infection requiring oral 
anti-infectives, (eg, sinusitis, bronchitis, uncomplicated urinary tract infection), within the 
4 weeks prior to Screening will be excluded, but may be subsequently re-screened after 
the 4-week exclusionary period has passed.  
Note:  An uncomplicated, presumably viral, upper respiratory tract infection (eg, ‘the 
common cold’) is not an exclusion. 
12. Has a chronic infection (eg, bronchiectasis, chronic osteomyelitis, chronic pyelonephritis) 
or requires chronic treatment with anti-infectives (eg, antibiotics, antivirals). 
13. Has received a live vaccine within 3 months prior to Screening, or has a known need to 
receive a live vaccine during the study or within at least 3 months after the last dose of 
study drug in this study.  The patient can be re-screened after the 3-month exclusionary 
period has ended. 
14. Has any confirmed or suspected clinical immunodeficiency syndrome not related to 
treatment of his/her gMG, including human immunodeficiency virus (HIV) infection, or 
has a family history of congenital or hereditary immunodeficiency unless confirmed 
absent in the patient. 
15. Has a positive or equivocal QuantiFERON®-TB Gold test, and/or a known close 
exposure to family or individuals known to have tuberculosis (TB).  
Note:  A patient with an equivocal QuantiFERON®-TB Gold test result will be allowed 
one retest; if the retest is negative, the patient is eligible.  If the retest is positive, the 
patient is excluded from this study.  If the retest remains equivocal and the patient has no 
known risk factors or exposures to TB, the patient can be included in the study after 
consultation with Medical Monitor. 
16. Has a history of or positive test results for HIV-1 and HIV-2 antibodies, hepatitis B virus 
(HBV core antibody), or hepatitis C virus (HCV).  Patients who have been treated for 
HCV and demonstrate a negative serum HCV ribonucleic acid level at 12 weeks or 
longer after the completion of HCV therapy may be included in the study after 
consultation with the Medical Monitor. Patients with spontaneous resolution of HCV (as 
confirmed by specialist) may be included in the study if demonstrating a negative serum 
HCV ribonucleic acid level after consultation with the Medical Monitor.    
17. Has current alcohol/substance abuse/dependence, a history of alcohol/substance 
abuse/dependence within the 12 months prior to Screening, or in the Investigator’s 
opinion, shows evidence of ongoing alcohol/substance abuse/dependence. 
18. Is currently participating in another interventional clinical trial, or has received any 
investigational drug (eg, abatacept, belimumab) within five half-lives of the given 
investigational drug.  
19. Has donated or had significant loss of whole blood (480 mL or more) within 30 days, or 
plasma within 14 days prior to Screening.  The patient can be re-screened after the 
relevant exclusionary period has passed. 


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Clinical Trial Protocol: MOM-M281-004 
 
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20. Had any major surgery within 3 months prior to Screening, or has plans for or has been 
scheduled for any elective surgery or any major dental procedure during the study. 
21. Has a history of a major organ transplant (eg, heart, lung, kidney, liver), or hematopoietic 
stem cell/marrow transplant. 
22. Received treatment for malignancy within the 5 years prior to Screening, with the 
exceptions of properly treated basal or squamous cell carcinoma of the skin or properly 
treated carcinoma in situ of the cervix. 
23. Has a hypersensitivity to M281 or any constituent of the study drug solution. 
24. Has had a prior severe drug reaction that included shock or severe hypersensitivity. 
25. Has liver impairment with Child-Pugh Class B or C.  
26. Has a history of severe and/or uncontrolled hepatic, gastrointestinal, renal, pulmonary, 
cardiovascular, psychiatric, or musculoskeletal disorder, hypertension, or any other 
medical or autoimmune disorder that, in the opinion of the Investigator, might interfere 
with patient's full participation in the study, or might jeopardize the safety of the patient 
or the validity of the study results. 
27. Has any other medical condition(s) likely to require treatment with oral or parenteral 
glucocorticosteroids (eg, severe asthma), or has required oral or parenteral 
glucocorticosteroids in the past 3 months (inhalational, intra-articular, topical or ocular 
glucocorticosteroids are not exclusionary), or taking any immunosuppressive agents not 
being used to treat MG. 
28. Is receiving a systemic biologic antibody for any concurrent disease. 
29. Has a QT interval corrected for heart rate (QTc) of >450 msec for males or >470 msec 
for females; or QTc >480 msec in patients with Bundle Branch Block, by the Fridericia 
formula. 
30. Has any of the following abnormal laboratory values at Screening: aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase 
≥2× ULN; or bilirubin ≥1.5× ULN (isolated bilirubin greater than 1.5× ULN is 
acceptable if bilirubin is fractionated and direct bilirubin is <35%, or if there is a prior 
diagnosis of Gilbert disease without any condition that causes elevation of bilirubin).  
Note:  AST, ALT, alkaline phosphatase, or bilirubin levels that lead to exclusion can be 
re-tested once within the Screening Period and within 2 weeks of the first test.  If the 
repeat test is still outside of the normal range, the patient can be re-screened once 
provided rescreening is approved by the Medical Monitor.  
31. Has elevated CK ≥2× ULN at Screening. However, if the patient has CK ≥2× ULN and 
<5× ULN at Screening, and in the opinion of the investigator the patient has no 
CK-related disease and the CK level is believed to be the results of non-pathologic 
factors, the CK may be repeated and if stable/improved, the patient can be enrolled. 
Note:  Patients who are ineligible because of elevated CK values can be re-tested as 
appropriate within the 4-week Screening Period.  If the repeat test(s) is still outside of the 
normal range, the patient can be re-screened once. 
32. Has had a splenectomy. 
 


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5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
Study Drug 
M281 is a sterile solution intended for IV infusion following dilution with dextrose 5% in 
water (D5W). It will be supplied in an open-label fashion to the study centers in 20-mL glass 
vials nominally containing 30 mg/mL (600 mg) of M281 protein in solution.  The glass vial 
has a 20 mm chlorobutyl stopper and an aluminum overseal. 
M281 is formulated to a target concentration of 30 mg/mL in 25 mM sodium phosphate, 
25 mM sodium chloride, 8.7% weight/weight trehalose, 0.01% weight/volume 
polysorbate 80, pH 6.5. 
5.1.2 
Placebo 
Placebo for IV infusion may be sourced by the study center or supplied by the Sponsor based 
on local regulations and availability. 
5.2 
Treatments Administered 
M281 will be diluted with D5W and administered by IV infusion at doses of 5 mg/kg Q4W, 
30 mg/kg Q4W, 60 mg/kg Q2W, or 60 mg/kg as a single dose based on the patient’s body 
weight at Baseline.  There will be no dosage adjustment for weight gained or lost during the 
study.  Placebo will be administered in the same manner.  
Patients will be observed for safety after the first 3 infusions per the Infusion Manual; if no 
clinically relevant AEs related to the infusion are observed in these first 3 infusions, the post-
infusion observation period is no longer needed. 
Details for preparation of the infusion will be provided in the Drug Handling Manual. 
Infusion is to be administered as specified in the Infusion Manual. 
5.3 
Selection and Timing of Dose for Each Patient 
To maintain the study blind with respect to assigned treatment and treatment regimen, all 
patients will receive an IV infusion (either placebo or M281) every other week; thus, all 
patients will receive a total of 5 infusions over the 8-week treatment period as shown in 
Table 1.  Patients in the placebo group will receive an infusion Q2W beginning on Day 1.  
Patients in the M281 5 mg/kg Q4W, and 30 mg/kg Q4W dose groups will receive a placebo 
infusion at the Day 15 and Day 43 visits to maintain blinding of the study.  Patients in the 
M281 60 mg/kg single-dose arm will receive placebo infusions on Days 15, 29, 43, and 57.  
Only patients in the M281 60 mg/kg Q2W group will not receive any placebo infusions. 
Infusions will be administered on the designated infusion days at the study facility after 
completion of all assessments specified for the given infusion day as shown on the Schedule 


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Clinical Trial Protocol: MOM-M281-004 
 
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of Study Assessments (Table 2 in Section 6).  The infusions will be administered without 
regard to meal times.  The infusion time is noted in the Infusion Manual.  Guidelines for 
management of infusion reactions are provided in the study manual.  The date of infusion, 
start and end times, the volume administered, and the time of the first infusion rate change (if 
applicable) for all doses are to be recorded. 
Table 1. 
Selection and Timing of Infusions for Each Treatment Arm 
Treatment Arm 
Infusion Timepoints 
Day 1 
Visit 
Day 15 
Visit 
Day 29 
Visit 
Day 43 
Visit 
Day 57 
Visit 
Placebo Q2W 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
M281 5 mg/kg Q4W 
M281 
Placebo 
M281 
Placebo 
M281 
M281 30 mg/kg Q4W 
M281 
Placebo 
M281 
Placebo 
M281 
M281 60 mg/kg single dose 
M281 
Placebo 
Placebo 
Placebo 
Placebo 
M281 60 mg/kg Q2W 
M281 
M281 
M281 
M281 
M281 
Abbreviations:  Q2W = every 2 weeks; Q4W = every 4 weeks. 
 
5.4 
Method of Assigning Patients to Treatment Groups 
Eligible patients will be randomized on Day 1 to a treatment assignment according to a 
randomization schedule generated by the Sponsor or designee.  The study personnel will use 
a web-based interactive response system to obtain the randomization number for each 
eligible patient. 
5.5 
Blinding 
The study is double-blinded.  The patient, investigator, and Sponsor will be blinded to study 
treatment for the duration of the study.  An unblinded site pharmacist will be responsible for 
preparing the study drug for infusion while the remainder of site personnel will remain 
blinded.  
Laboratory measurements related to expected PD activity and immunogenicity of M281 (ie, 
total serum IgG and IgG subtypes [IgG1, IgG2, IgG3, and IgG4], anti-AChR and anti-MuSK 
autoantibodies, albumin, and anti-M281 antibodies) will be blinded to the patient, 
investigator, and Sponsor and not provided during study conduct with the exception of total 
serum IgG at the Day 113 Visit if the patient does not enter the MOM-M281-005 open-label 
extension study.   
If an emergency occurs that necessitates knowledge of a patient’s treatment assignment, the 
Investigator can obtain the information via the web-based interactive response system. 
An unblinded interim analysis will be conducted as described in Section 8.8. 


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5.6 
Concomitant Therapy 
Patients must continue their baseline stable therapeutic regimen (standard of care) for gMG 
throughout the duration of the study and must maintain the same dose and regimen 
throughout the study, unless toxicity or safety issues mandate a change.  All 
medications/therapies administered to patients at any time during the study (from the time the 
patient signs the informed consent), or changes to the dose/regimen of any 
medication/therapy, are to be recorded in the electronic case report form (eCRF).   
Use of herbal, naturopathic, and traditional Chinese remedies, and ayurvedic and nutritional 
supplements may also continue during the study, if the patient is on a stable dose and 
regimen at study entry and the use of these medications is acceptable to the Investigator.  The 
patient must maintain the same dose and regimen using the same preparation throughout the 
study. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
Patients who received rituximab or eculizumab within 12 months prior to Screening are not 
eligible for the study.  Patients who underwent plasmapheresis, received immunoadsorption 
therapy, or received IVIG within 6 weeks prior to Randomization are not eligible for the 
study (see Section 4.3, Exclusion Criteria). 
Patients must continue their baseline stable therapeutic regimen (standard of care) throughout 
the duration of the study (see Section 4.2, Inclusion Criteria) with the exception that 
acetylcholinesterase inhibitors must be withheld for approximately 10 hours or longer at each 
study visit before the assessments of MG symptoms/status (efficacy assessments) are 
conducted.  If possible, all efficacy assessments should be done at approximately the same 
time of day as performed at Screening, prior to study drug administration, and in the order 
defined in the Schedule of Study Assessments (Table 2 of Section 6).  Patients may take their 
dose of acetylcholinesterase inhibitor once the efficacy assessments are completed. 
5.7.2 
Fluid and Food Intake  
Patients are not required to be fasting at any time during the study and the study does not 
include any requirements with respect to food intake.  Patients may only have room 
temperature food/fluids within 1 hour before the efficacy assessments are conducted and until 
efficacy assessments are completed. 
5.7.3 
Patient Activity Restrictions 
Patients may continue their usual activities, including exercise, during the study, but patients 
should not begin any new exercise program during the study, or have excessive exertion on 
the day of or day before a study visit. 


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Clinical Trial Protocol: MOM-M281-004 
 
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5.8 
Treatment Compliance 
Scheduled IV infusions of study drug will occur at the study center under observation by 
study staff, thus ensuring treatment compliance. 
5.9 
Packaging and Labeling 
M281 will be supplied open-label in a carton labeled with the local language.  Placebo will 
also be open-label and should be labeled as required per local regulations. 
5.10 Storage and Accountability 
Vials of M281 must be stored at 2°C to 8°C in a secure, controlled-access location.  Placebo 
must be stored in a secure, controlled-access location.  Storage temperatures for placebo will 
be detailed in the Drug Handling Manual.  M281 and placebo must only be used for patients 
who have consented to participate in this trial. 
At the end of the study, a final reconciliation must be made between the amount of study 
drug supplied, dispensed, and subsequently destroyed or returned to the Sponsor.  A written 
explanation must be provided for any discrepancies. 
6 
STUDY ASSESSMENTS AND PROCEDURES 
The Schedule of Study Assessments is presented in Table 2. 


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Table 2. 
Schedule of Study Assessments 
 
Screening Perioda 
-Day -28 to Day -1 
Treatment Period 
Follow-Up Period  
(No Study Treatment) 
Study Day  
Baseline 
(Day 1)b 
Day 15b 
Day 29b 
Day 43b 
Day 57b 
Day 85 
Day 113 
Visit Window (± Days) 
-- 
-- 
± 1  
± 3  
± 3  
± 3  
± 7  
± 7  
Informed Consent 
X 
 
 
 
 
 
 
 
Site Visit 
X 
X 
X 
X 
X 
X 
X 
X 
Med History and Demographics 
X 
 
 
 
 
 
 
 
Vital Signsc  
X 
X 
X 
X 
X 
X 
X 
X 
Weight  
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Physical Examinationd 
Xd 
Xd 
X  
X  
X  
X  
X  
Xd  
12-Lead ECGe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe  
X 
X  
C-SSRS 
X 
X 
 
X 
 
X 
X 
 
Efficacy Assessmentsf 
 
MG-ADL 
X 
X 
X 
X 
X 
X 
X 
X 
QMG 
X 
X 
X 
X 
X 
X 
X 
X 
MG-QoL15r 
 
X 
X 
X 
X 
X 
X 
X 
MGFA Clinical Classification 
X 
X 
 
 
 
X 
 
X 
MGFA-PIS – selected elements 
 
 
 
 
 
X 
 
X 
Pregnancy test (women of 
childbearing potential, and 
menopausal females if FSH is not 
elevated)g 
X  
X 
  
  
 
  
 
 
Blood sample for FSH 
(menopausal females only)g 
X 
 
 
 
 
 
 
 
QuantiFERON-Gold TB Testh 
X 
 
 
 
 
 
 
 
Blood sample for HIV-1 & 2, 
Hepatitis B (HBV core antibody), 
Hepatitis C 
X 
 
 
 
 
 
 
 


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Table 2. 
Schedule of Study Assessments 
 
Screening Perioda 
-Day -28 to Day -1 
Treatment Period 
Follow-Up Period  
(No Study Treatment) 
Study Day  
Baseline 
(Day 1)b 
Day 15b 
Day 29b 
Day 43b 
Day 57b 
Day 85 
Day 113 
Visit Window (± Days) 
-- 
-- 
± 1  
± 3  
± 3  
± 3  
± 7  
± 7  
Blood sample for anti-AChR and 
anti-MuSK autoantibody levelsi  
Xi 
X 
X 
X 
X 
X 
X 
X 
Blood sample for exploratory 
biomarkers 
-- 
X 
 
X 
 
X 
X 
X 
Safety Laboratory Testingj 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for total and 
neutralizing anti- M281 
antibodies   
 
X 
X 
X 
X 
X 
X 
X 
Blood sample for levels of total 
IgG and IgG subclasses 
X 
X 
X 
X 
X 
X 
X 
Xk 
Blood sample for IgA, IgM, and 
IgE levels 
 
X 
 
X 
 
X 
 
X 
Confirm Patient Eligibility and 
Randomizel 
 
X 
 
 
 
 
 
 
Serum PKm 
 
Xm 
Xm 
Xm 
Xm 
Xm 
X 
 
Study Drug Infusionb 
 
X 
X 
X 
X 
X 
 
 
AEs / Prior and Concomitant 
Medications/Rescue Therapyn  
Monitored throughout the study 
Abbreviations:  AE = adverse event; anti-AChR= anti-acetylcholine receptor autoantibody; anti-MuSK = anti-muscle-specific kinase autoantibody; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HBV= hepatitis B virus; HCV = hepatitis C 
virus; HIV= human immunodeficiency virus; Ig = immunoglobulin; MG = myasthenia gravis; MG-ADL= Myasthenia Gravis – Activities of Daily Living; 
MGFA-PIS = Myasthenia Gravis Foundation of America Post-intervention status; MG-QoL15r= revised Myasthenia Gravis Quality of Life – 15 Scale; 
PD = pharmacodynamic; PK = pharmacokinetics; QMG = Quantitative Myasthenia Gravis scale; TB= tuberculosis. 
a 
Patients who fail to meet all the entry criteria may be retested as noted in Section 4 and study manual, and/or rescreened after a period of at least 4 weeks. 
Details for rescreening procedures will be provided in the study manual.  
b 
Infusion to be administered as specified in the Infusion Manual. Patients will be observed for safety after the first 3 infusions per the Infusion Manual; if no 
clinically relevant AEs related to the infusion are observed in these first 3 infusions, the post-infusion observation period is no longer needed.  


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c 
Vital signs (temperature, recumbent systolic blood pressure and diastolic blood pressure, and pulse rate) will be measured immediately prior to the start of 
each infusion.  For the first infusion, vital signs will also be measured after completion of the infusion as specified in the Infusion Manual. 
d 
Full physical examinations to be performed at Screening, Baseline, and Day 113, and a focused physical examination at all other visits.  Focused physical 
examinations should determine if there has been any change in neurologic function, upper respiratory tract (ears, nose, throat, and sinuses), eyes and lungs, 
abdomen, or skin. 
e 
12-lead ECGs will be conducted at every scheduled visit. On infusion days, the ECG will be taken immediately prior to the beginning of the infusion. For 
the first infusion, a single 12-lead ECG will also be conducted within 10 minutes after the infusion has been completed.  
f 
The patient’s acetylcholinesterase inhibitor dose must be withheld for approximately 10 hours or longer prior to performing the MG assessments (including 
those conducted during the Screening Period to determine patient eligibility).  All MG assessments must be done starting at approximately the same time of 
day as performed at Screening, and prior to study drug administration on infusion days.  The applicable MG assessments must be performed in the order 
shown in this Schedule of Study Assessments.  Patients may take their dose of acetylcholinesterase inhibitor once the MG assessments are completed.  
g 
Women of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to infusion of 
study drug.  Menopausal women must have an elevated follicle-stimulating hormone level (FSH) at Screening; if the FSH is not elevated, menopausal 
women must have a negative serum pregnancy test to be eligible, and a negative urine pregnancy test on Day 1 prior to infusion of study drug.  
h 
Patients with a positive QuantiFERON®-TB Gold test result are excluded from this study.  Patients with an equivocal QuantiFERON®-TB Gold test result at 
Screening will be allowed one retest; if the retest is negative, the patient is eligible.  If the retest is positive or equivocal, the patient is excluded from this 
study. 
i 
If the patient receives the first dose of M281 before the Screening results are available and the results are subsequently negative, the patient may be replaced. 
j 
Includes chemistry, hematology, coagulation function (including prothrombin time), and urinalysis. 
k 
For patients who do not enroll in the open-label extension study, if the total serum IgG is not at least 600 mg/dL at this visit, the investigator must continue 
to regularly follow the patient until total serum IgG is 600 mg/dL or higher. 
l 
Confirmation of patient eligibility on Day 1 is based on the Baseline QMG and MG-ADL scores, Baseline C-SSRS, review of medications/therapies, and 
negative urine pregnancy test (performed at the study center) for women of childbearing potential before first administration of study drug.  Menopausal 
women must have an elevated FSH or negative serum pregnancy test at Screening and negative urine pregnancy test on Day 1 before first administration of 
study drug to be eligible.  
m 
On infusion days, blood samples for measurement of M281 serum concentrations will be taken immediately prior to the beginning of the infusion. After the 
first infusion and after the infusion on Day 57, blood samples for measurement of M281 serum concentrations will also be taken post-infusion (as specified 
in the Infusion Manual).  
n 
All medications/therapies to be collected from the time of informed consent throughout the patient’s participation in the study.  Reporting of AEs will start 
following the patient signing the informed consent form.  Administration of rescue therapy for worsening of MG-related symptoms should also be recorded.  
 


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6.1 
Safety Assessments 
Safety assessments include collection of AEs and serious AEs (SAEs), vital signs, physical 
examinations, clinical laboratory testing (including chemistry, hematology, coagulation, and 
urinalysis), ECG findings, and the C-SSRS.  After the patient has signed the informed 
consent, any new clinically relevant finding or worsening of a pre-existing condition will be 
reported as an AE.   
Severe infections and hypoalbuminemia will be considered AEs of special interest (AESIs). 
6.1.1 
Adverse Events 
An AE can be any unfavorable and unintended sign (eg, an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, without any judgment 
about causality.  An AE can therefore be any unfavorable and unintended sign, symptom, 
disease, concurrent illness, or clinically significant abnormal laboratory finding that emerges 
or worsens (ie, aggravated in severity or frequency from the baseline condition) during the 
study.  Clinically significant abnormal results of laboratory tests or diagnostic procedures are 
to be reported as AEs. 
6.1.1.1 
Performing Adverse Events Assessments 
At each contact with the patient, the Investigator or designee will capture AEs by specific 
questioning and, as appropriate, by examination.  Patients will be asked non-leading 
questions to capture medically related changes to their well-being.  Participants will also be 
asked if they have been hospitalized, had any accidents, sought care from a health 
professional, used any new medications/therapies, or changed concomitant medication 
regimens (both prescription and over-the-counter) due to an AE.  
6.1.1.2 
Timing 
Reporting of AEs (including SAEs) will start following the patient signing the informed 
consent form (ICF).  Reporting of AEs will end at the final visit (Day 113). 
6.1.1.3 
Severity 
The Investigator will grade the severity/intensity of each AE using the National Cancer 
Institute, Common Terminology Criteria for Adverse Events v5.0 (CTCAE) classifications 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quic
k_Reference_8.5x11.pdf). 


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The CTCAE provides specific criteria for grading adverse events as well as laboratory tests; 
in general, the grades are as follows: 
Grade 1, Mild:  asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated  
Grade 2, Moderate:  minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living  
Grade 3, Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living  
Grade 4, Life-threatening consequences; urgent intervention indicated  
Grade 5, Death related to AE 
6.1.1.4 
Relationship 
The Investigator must assess all AEs for relationship to study drug by examining and 
evaluating the patient based on temporal relationship and his/her clinical judgment.  The 
degree of certainty about causality will be graded using the categories below: 
Definitely Related – There is clear evidence to suggest a causal relationship to study drug; 
other possible contributing factors can be ruled out.  The clinical event, including an 
abnormal laboratory test result, occurs in a plausible time relationship to study drug 
administration and cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the study drug (dechallenge) should be clinically plausible.  
The event must be pharmacologically or phenomenologically definitive, with use of a 
satisfactory rechallenge procedure if necessary. 
Probably Related – There is evidence to suggest a causal relationship to study drug, and the 
influence of other factors is unlikely.  The clinical event, including an abnormal laboratory 
test result, occurs within a reasonable time after administration of the study intervention, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a 
clinically reasonable response on withdrawal (dechallenge).  Rechallenge information is not 
required to fulfill this definition. 
Possibly Related – There is some evidence to suggest a causal relationship to study drug 
(eg, the event occurred within a reasonable time after administration of the study drug).  
However, other factors may have contributed to the event (eg, the patient’s clinical condition, 
other concomitant events).  Although an AE may rate only as “possibly related” soon after 
discovery, it can be flagged as requiring more information and later be upgraded to “probably 
related” or “definitely related”, as appropriate. 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal relationship 


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improbable (eg, the event did not occur within a reasonable time after administration of the 
study drug) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (eg, the patient’s clinical condition, other concomitant treatments). 
Not Related – The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology.  There must be an 
alternative, definitive etiology documented by the clinician. 
6.1.1.5 
Expectedness 
The Sponsor will be responsible for determining whether an AE is expected or unexpected.  
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the Reference Safety Information in the Investigator’s Brochure for M281. 
6.1.1.6 
Adverse Events of Special Interest 
For this study, any CTCAE Grade 3 or higher event of severe infection or hypoalbuminemia 
will be considered an AESI.  These cases will be handled similarly to an SAE for reporting 
purposes and reviewed by the DSMB as they occur. 
6.1.1.7 
Clinical Laboratory Adverse Events 
Investigators will indicate on the laboratory report whether abnormal values are clinically 
significant (CS) or not clinically significant (NCS).  All CS abnormal laboratory results will 
be considered as AEs and are to be reported in the eCRF. 
6.1.1.8 
Serious Adverse Events 
DEFINITION 
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. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
REPORTING SERIOUS ADVERSE EVENTS 
The Investigator will report to the Sponsor any SAE or AESI within 24 hours of becoming 
aware of the event, whether or not the event is considered related to study drug.  The report 


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must include an assessment of whether there is a reasonable possibility that the study drug 
caused the event. 
Send SAE and AESI reports to: 
MMS Holdings 
6880 Commerce Blvd 
Canton, MI 48187 
USA 
E-mail: 
MomentaPharmaDrugSafety@mmsholdings.com 
 
The Sponsor will be responsible for notifying the regulatory authorities per local 
requirements of any unexpected fatal or life-threatening suspected adverse reaction as soon 
as possible, but in no case later than 7 calendar days after the Sponsor’s initial receipt of the 
information.  In addition, the Sponsor must notify the regulatory authorities and all 
participating investigators of any safety reports of potential serious risks, from clinical trials 
or any other source, as soon as possible, but in no case later than 15 calendar days after the 
Sponsor determines that the information qualifies for reporting. 
It is the responsibility of the Sponsor to determine the reportability of SAEs.  
All SAEs will be followed until satisfactory resolution or until the Investigator deems the 
event to be chronic or the patient is stable.  Other supporting documentation of the event may 
be requested by the DSMB or Sponsor and should be provided as soon as possible. 
6.1.1.9 
Treatment-Emergent Adverse Events 
A treatment-emergent AE (TEAE) is defined as any AE occurring during or after the 
initiation of the first infusion of study drug. 
6.1.1.10 
Pregnancy 
Any pregnancy (including the pregnancy of the partner of a male study patient) occurring 
from the time the patient signed in the ICF until 30 days (for female patients) or 100 days 
(for the female partner of a male patient) after the last dose of study treatment must be 
reported to the Sponsor using a clinical trial pregnancy form.  To ensure patient safety, each 
pregnancy must be reported to the Sponsor, via MMS Holdings, the safety group that will be 
processing the information (see Section 6.1.1.8), within 24 hours of the Investigator learning 
of its occurrence.  The pregnancy should be followed up to determine outcome (including 
premature termination) and status of mother and child.  The patient and/or patient’s partner 
will be requested to provide written informed consent to enable collection of information 
pertaining to the outcome of the pregnancy. 
While pregnancy itself is not an AE/SAE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be reported as an AE or SAE as 
appropriate and must be communicated by the Investigator to MMS Holdings within 
24 hours of receipt of notification of an event.  An abortion, whether accidental, therapeutic, 


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or spontaneous, should always be reported as an SAE.  Similarly, any congenital anomaly 
birth defect in a child born to a patient exposed to the study treatment should be recorded and 
reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the Investigator’s attention 
after the patient has completed the study and considered by the Investigator as possibly 
related to the study drug must be promptly reported to MMS Holdings. 
6.1.2 
Concomitant Medication Assessments 
From the time the patient signs the informed consent, all medications/therapies, and 
procedures administered to patients at any time during the study, including MG rescue 
medication/therapy, are to be recorded in the eCRF.  Medications to be reported in the eCRF 
are concomitant prescription medications, over-the-counter medications and supplements. 
Other therapies and procedures (eg, immunizations) are also to be recorded. 
6.1.3 
Physical Examination 
Height will be measured at Screening only.  Weight will be measured at Screening and at all 
other visits.  A full physical examination will be performed at Screening, Baseline, and 
Day 113; at all other visits, a focused physical examination will be performed to determine if 
there has been any change in neurologic function, upper respiratory tract (ears, nose, throat, 
and sinuses), eyes and lungs, abdomen, or skin. 
6.1.4 
Vital Signs 
Vital signs measurements will include recumbent blood pressure and pulse rate, and body 
temperature.  The patient will be resting in the recumbent position for 3 to 5 minutes before 
all vital signs are recorded, according to the practices of the investigative site.  
The Investigator will determine if any of the vital sign measurements are clinically 
significant or not clinically significant.  Clinical significance is defined as any variation in 
assessment results that has medical relevance and may result in an alteration in medical care 
(eg, active observation, diagnostic measures, or therapeutic measures).  If a clinically 
significant change from screening values is noted, the clinically significant value and reason 
for clinical significance will be documented on the AE page of the patient’s eCRF.  The 
Investigator will continue to monitor the patient with additional assessments until the values 
have reached reference range and/or the values at Screening, or until the Investigator 
determines that follow-up is no longer medically necessary. 
6.1.5 
Clinical Laboratory Tests 
Patients will be in a seated or supine position during blood collection.  Patients are not 
required to be fasting.  Instructions for blood sample collection, processing, storage, and 
shipping are described in the Laboratory Manual.   
Clinical laboratory tests will include the parameters listed in Table 3.  


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Table 3. 
List of Clinical Laboratory Tests 
Hematology: 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin  
Mean corpuscular hemoglobin concentration  
Mean corpuscular volume 
Platelet count 
Red blood cell count  
White blood cell count with differential  
 
Urinalysis:  
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Microscopic examination of sediment  
Nitrite  
Occult blood 
pH 
Protein 
Myoglobin (if serum creatine kinase is 
elevated) 
Specific gravity 
Urobilinogen 
 
Hepatitis B virus (HBV core antibody), 
hepatitis C virus, HIV-1 and HIV-2 (at Screening 
only to assess eligibility) 
 
Serum/urine human chorionic gonadotropin (for 
females of childbearing potential and 
menopausal females if follicle-stimulating 
hormone is not elevated) 
 
Serum follicle-stimulating hormone (only for 
menopausal females at Screening to assess 
eligibility) 
Serum Chemistry: 
Albumina 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase  
Blood urea nitrogen 
Calcium 
Carbon dioxide 
Chloride 
Creatinine 
Creatine kinase; MB and MM subtypes if 
creatine kinase is elevated 
Troponin if creatine kinase is elevated 
Gamma-glutamyl transferase  
Glucose 
Lactate dehydrogenase  
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
 
Coagulation:  
Prothrombin time 
Activated partial thromboplastin time 
QuantiFERON-Gold tuberculosis test (at 
Screening only to assess eligibility) 
a 
Knowledge of a patient’s albumin level could potentially be unblinding; therefore, albumin results obtained 
after initiation of study drug will not be reported to the patient, Investigator, or Sponsor during study 
conduct.  
 
Clinically significant changes from baseline in laboratory results must be considered an AE 
and recorded in the eCRF.  Clinical significance is defined as any variation in a laboratory 
result that has medical relevance and that results in a change in medical care.  The 


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Investigator will continue to monitor the patient until the finding is resolved, or in the 
judgment of the Investigator follow-up is no longer medically necessary. 
6.1.6 
Electrocardiograms 
A single 12-lead ECG will be obtained after the patient has been in the supine position for at 
least 5 minutes.  A central ECG service will measure and interpret the ECG recordings.  
Electrocardiogram reports will include comments on whether the tracings are normal or 
abnormal, rhythm, presence of arrhythmia or conduction defects, morphology, any evidence 
of myocardial infarction, or ST segment, T Wave, and U Wave abnormalities.  In addition, 
the following intervals will be measured and reported: RR, PR, QRS, QT, and QTc. 
The Investigator will determine if the ECG results are CS or NCS.  Clinical significance is 
defined as any variation in assessment results that has medical relevance and may result in an 
alteration in medical care (eg, active observation, diagnostic measures, or therapeutic 
measures).  If an ECG finding is identified as CS, the patient should be assessed by the 
Investigator for symptoms (for example, palpitations, near syncope, syncope).  Any CS 
finding should be documented as an AE on the AE eCRF, and the Investigator must to 
continue to monitor the patient until the finding is resolved, or in the judgment of the 
Investigator, follow-up is no longer medically necessary. 
6.1.7 
Columbia-Suicide Severity Rating Scale 
The C-SSRS is administered by trained study personnel (ie, C-SSRS certified).  The C-SSRS 
Baseline/Screening version will be used for the Screening Visit, and the C-SSRS Since Last 
Visit version will be used for subsequent visits as specified in Table 2.  When the C-SSRS is 
administered on an infusion day, the C-SSRS must be administered before the infusion.  
Any patient who answers “yes” to Questions 4 or 5 in the Suicidal Ideation section of the 
C-SSRS at Screening or Baseline should not be enrolled and should be referred to a mental 
health specialist by the Investigator.  During the course of the study after initiation of study 
treatment, any patient who answers “yes” to Questions 4 or 5 in the Suicidal Ideation section 
or answers “yes” to any question in the Suicidal Behavior section of the C-SSRS will be 
referred by Investigators to a mental health specialist.  After initiation of study treatment, 
affirmative answers to Questions 4 or 5 for suicidal ideation or to any question for suicidal 
behavior will be reported in the eCRF as an AE. 
6.2 
Efficacy Assessments 
6.2.1 
Myasthenia Gravis – Activities of Daily Living 
The MG-ADL is administered by a trained qualified healthcare professional (eg, physician, 
physician assistant, nurse practitioner, nurse) and provides a rapid assessment of the patient’s 
MG symptom severity (Appendix 3).  The MG-ADL should be administered by the same 
healthcare professional for a given patient throughout the study, if possible, and the 
assessment should be performed at approximately the same time of day throughout the study.  
Eight functions (talking, chewing, swallowing, breathing, impairment of ability to brush teeth 


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or comb hair, impairment of ability to arise from a chair, double vision, eyelid droop) are 
rated on a 4-point scale.  The total score can range from 0 to 24.  A higher score indicates 
greater symptom severity. 
6.2.2 
Quantitative Myasthenia Gravis  
The QMG test is a standardized quantitative strength assessment comprising 13 components 
(Appendix 4) and is administered by a trained qualified healthcare professional (eg, 
physician, physician assistant, nurse practitioner, nurse).  The QMG should be administered 
by the same healthcare professional for a given patient throughout the study, if possible, and 
the assessment should be performed at approximately the same time of day throughout the 
study.  The quantitative results of each strength component are mapped to the following 
4-point scale: 
• 0 = None 
• 1 = Mild 
• 2 = Moderate 
• 3 = Severe 
 
The total score can range from 0 to 39.  A higher score indicates greater weakness. 
6.2.3 
Revised Myasthenia Gravis Quality of Life – 15 
The MG-QoL15r (Appendix 5) is a 15-item, health-related quality of life measure designed 
to assess limitations related to living with MG (Burns et al 2016).  Responses to each item 
are rated by the patient, using a reflection period of “over the past few weeks” on the 
following 3-point scale: 
• 0 = Not at all 
• 1 = Somewhat 
• 2 = Very much 
 
The total score can range from 0 to 30. A higher score indicates more limitation. 
6.2.4 
Myasthenia Gravis Foundation of America Post-Intervention Status 
The Myasthenia Gravis Foundation of America Post-intervention Status (MGFA-PIS) is a 
measure of the patient’s MG status after treatment/intervention (Appendix 6).  For the 
purpose of this study, only two elements of the MGFA-PIS will be assessed. 
1. The Investigator will indicate whether or not the patient meets the following definition of 
Minimal Manifestations: 
- 
The patient has no symptoms of functional limitations from MG, but has some 
weakness on examination of some muscles (Yes/No).  


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2. The patient’s change in status will be derived as follows: 
- 
Improved = A decrease of ≥3 in the QMG score from baseline. 
- 
Unchanged = No change in the QMG score over baseline. 
- 
Worse = Any increase in the QMG score over baseline. 
- 
Died of MG = The patient died of MG or of complications of MG therapy. 
 
6.2.5 
Myasthenia Gravis Foundation of America Clinical Classification 
This clinical classification system was established by the MGFA for clinician/physician 
assessment of a patient’s MG severity (Jaretzki et al 2000).  The system comprises 5 classes 
of disease severity ranging from Class I (ocular muscle weakness only) to Class V (the 
patient is intubated).  Classes II through IV are each further divided into 2 subclasses based 
on which muscle groups are primarily affected.  The MGFA Clinical Classification should be 
assessed by the same clinician/physician for a given patient throughout the study, if possible. 
6.3 
Pharmacokinetic Assessments 
Patients will undergo blood sampling as specified in Table 2 to determine serum M281 
concentration(s).  Instructions for blood collection, processing, storage and shipping are 
described in the Laboratory Manual. 
6.4 
Assessments of Pharmacodynamics and Biomarkers 
Blood samples for PD analysis of total serum IgG, anti-AChR autoantibodies, and 
anti-MuSK autoantibodies will be collected.  Blood samples will also be collected for 
assessment of exploratory PD biomarkers in serum (concentrations of IgG1, IgG2, IgG3, 
IgG4, IgA, IgM, and IgE).  Additional blood samples will be collected to explore 
characteristics of pathogenic MG antibodies (anti-AChR and anti-MuSK).  At Screening and 
Baseline, samples will be tested for both anti-AChR and anti-MuSK; thereafter, samples will 
only be tested for the antibody that was positive at Screening/Baseline.  Blood samples will 
be collected at the time points specified in Table 2. 
Aside from IgA, IgM, and IgE, the PD parameters could potentially be unblinding; therefore, 
results of PD parameters obtained after initiation of study drug will not be reported to the 
patient, Investigator, or Sponsor during study conduct with the exception of total serum IgG 
at the Day 113 Visit if the patient does not enter the MOM-M281-005 open-label extension 
study.  
Instructions for blood sample collection, processing, storage, and shipping are described in 
the Laboratory Manual. 
6.5 
Immunogenicity Assessments 
Blood samples will be drawn to determine the presence/absence and titers of total and 
neutralizing anti-M281 antibodies, if applicable.  Knowledge of anti-drug antibody (ADA) 
levels could potentially be unblinding; therefore, these results after initiation of study drug 
will not be reported to the patient, Investigator, or Sponsor during study conduct. 


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Clinical Trial Protocol: MOM-M281-004 
 
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6.6 
Removal of Patients from the Trial or Study Drug 
The investigator may withdraw a patient for any of the following reasons: 
• A protocol violation occurs, 
• A serious or intolerable adverse event occurs, 
• A clinically significant change in a laboratory parameter occurs,  
• The sponsor or investigator terminates the study, or 
• The patient requests to be discontinued from the study. 
• If the patient receives the first dose of M281 before the Screening results for 
autoantibodies (anti-AChR, anti-MuSK) are available and the results are subsequently 
negative, the patient may be withdrawn and replaced. 
 
6.7 
Stopping Criteria 
Unless patient safety precludes doing so, the Medical Monitor should be consulted prior to 
stopping or modifying the dosing schedule of study drug.  The DSMB will be informed about 
any such discussions, with the reason they were initiated, and any laboratory data that was a 
part of the discussions.  Unblinding of study drug in the event of an emergency is the sole 
responsibility, and will occur at the discretion, of the Investigator; however, if possible, the 
Medical Monitor should be consulted before unblinding. 
Discontinuation of study drug administration does not necessarily mean discontinuation from 
the study.  Patients who discontinue treatment with study drug should be asked to continue in 
the study to be followed for safety and to complete all remaining study procedures as 
indicated by this protocol.  Any new clinical finding is to be reported as an AE.  
6.7.1 
Study Drug Stopping/Interruption Rules for Individual Patients 
Study drug administration must be stopped, and the Medical Monitor notified, if any of the 
following events occur: 
• A patient becomes pregnant. 
• A patient develops a CTCAE Grade 4 infection.  
• A patient develops a CTCAE Grade 3 infection that is unresponsive or worsens while on 
anti-infective therapy.  
• Any circumstance or finding that, in the clinical judgment of the Investigator, would 
represent undue risk to the patient. 
 


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Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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Study drug administration may be interrupted after consultation with the Medical Monitor for 
the following events: 
• If a patient develops a CTCAE Grade 3 infection, the Investigator may elect to withhold 
study drug until the clinical scenario clarifies whether the infection is improving or 
getting worse. 
• If a patient develops 3+ pedal edema, ascites, or pleural or pericardial effusions, the 
Investigator will monitor the patient’s condition.  The decision to continue treatment or 
withhold additional doses of study drug will be made by the Investigator, in consultation 
with the Medical Monitor. 
• If a patient develops elevated CK levels, CK fractionation (CKMB, CKMM) and 
troponin will be automatically tested by the laboratory.  If the CKMB or troponin level is 
elevated, the patient will be asked to go immediately to the emergency room for further 
evaluation.  
 
For any patient with elevated CK levels, additional assessments will be as follows: 
- 
CK elevations <5× ULN - further assessment can be made at the discretion of the 
Investigator. 
- 
CK elevations ≥5× ULN - the Investigator will call the patient to inquire about 
excessive exercise, trauma, and any muscle or cardiac-related symptoms.  CK will be 
repeated and if there is a decrease, no action will be taken.  However, if the CK is of 
similar or higher level, the patient will be asked to return to the clinic, where further 
investigation will be done (in-depth clinical assessment, ECG, myoglobin in urine, 
repeat CK with fractionation and troponin level, ALT, and AST).  The decision to 
continue treatment or withhold additional doses of study drug for the patient will be 
made by the Investigator, in consultation with the Medical Monitor. 
 
6.7.2 
Study Stopping Rules 
• In the event of the death of a study patient, treatment will be held in all patients pending 
evaluation by the Sponsor and DSMB recommendation, and until approval is received by 
the applicable regulatory authority(ies) to resume. 
• If a CTCAE Grade 4 event considered potentially related to treatment occurs, treatment 
will not be initiated in new patients, pending evaluation by the Sponsor and DSMB 
recommendation, and until approval is received by the applicable regulatory 
authority(ies) to resume. 
• If a CTCAE Grade 3 or higher infection occurs in three separate patients, treatment will 
be temporarily held in all patients, pending evaluation by the Sponsor and DSMB 
recommendation, and until approval is received by the applicable regulatory 
authority(ies) to resume. 
 
NOTE: Deaths that are definitely not related to study treatment (eg, accidents or other 
external causes) will not trigger study-stopping rules. 


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Clinical Trial Protocol: MOM-M281-004 
 
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6.8 
Other Study Procedures 
Clinical Deterioration and Use of Rescue Therapy  
Study sites are required to evaluate a patient's report of clinical deterioration within 48 hours 
of the patient notifying the Investigator of the onset or worsening of symptoms of gMG. 
Clinical deterioration is defined as any of the following:  
• An MG crisis, defined as MG-related weakness sufficiently severe to necessitate 
intubation, or requires noninvasive ventilation to avoid intubation, or would be severe 
enough to delay extubation following surgery (Sanders et al 2016), with the respiratory 
failure being due to weakness of respiratory muscles.  Severe bulbar (oropharyngeal) 
muscle weakness may accompany the respiratory muscle weakness, or may be the 
predominant feature in some patients.  
• Significant symptomatic worsening on any MG-ADL item of three or more points, 
excluding double vision or eyelid droop (ie, talking, chewing, swallowing, breathing, 
upper and lower extremity weakness). 
• Any patient whom the Investigator believes will jeopardize his/her health if MG rescue 
therapy is not given (eg, emergent situations). 
 
Depending on the severity of worsening of MG-related symptoms, rescue therapy 
(eg, glucocorticosteroids, IVIG, plasmapheresis) will be permitted, as per the clinical 
judgement of the Investigator.  Patients who receive rescue therapy will be discontinued from 
study treatment infusions and PK sampling, but will continue all other assessments 
designated at the Day 85 and Day 113 follow-up visits.  Thus, for patients who receive rescue 
therapy during the Treatment Period, the Day 85 Visit translates to 4 weeks after their last 
dose of study drug, regardless of the study day of their last dose of study drug.  Likewise, the 
Day 113 Visit translates to 8 weeks after their last dose of study drug, regardless of the study 
day of their last dose in the study. 
6.9 
Appropriateness of Measurements 
The measures for assessing efficacy in this study have been shown to be reliable and valid 
scales for measuring clinical status of patients with MG.  The PK and routine safety 
assessments included in this study are standard for Phase 2 clinical studies in patients.  The 
PD biomarkers being studied are relevant for patients with MG based on scientific literature 
and clinical practice. 
Although preclinical studies and the first-in-human study with M281 did not indicate any 
central nervous system effects, the C-SSRS will be used in this study as an additional safety 
assessment based on the recommendation by the United States Food and Drug 
Administration (US FDA) for all clinical trials involving the development of drugs or 
biologics for neurologic indications to assess suicide risk.  The US FDA has provided 
guidance to prospectively assess suicidal ideation and behavior in clinical trials to ensure that 
patients in clinical trials who are experiencing suicidal ideation and behavior are properly 


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Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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recognized and adequately treated and to ensure the collection of more timely and more 
complete data on suicidal ideation and behavior than have been collected in the past 
(US FDA, 2012). 
7 
QUALITY CONTROL AND ASSURANCE 
To assure quality and consistent study data, procedures will only be carried out by the 
Principal Investigator or trained staff under the direction of the Principal Investigator. Study 
related procedures will be carried out in accordance with written materials (eg, study manual, 
Drug Handling Manual, eCRF completion guidelines, etc). 
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, the Sponsor or a Sponsor’s designee may conduct a quality assurance audit of 
the study center(s). 
8 
PLANNED STATISTICAL METHODS 
8.1 
General Considerations 
Descriptive summary statistics will be provided for demographic, disposition, and exposure 
data.  The number and percentage of patients who discontinued from the study, along with 
reasons for discontinuations, will be tabulated and described in listings. 
Continuous data will be summarized using descriptive statistics (number of patients, mean, 
standard deviation, median, minimum, and maximum) and, where appropriate, coefficient of 
variation (CV%) and graphic representation.  Categorical data will be summarized by sample 
size and proportions.  Graphs of actual values and changes over time may also be created as 
appropriate. 
8.2 
Determination of Sample Size 
Approximately 60 patients will be randomized 1:1:1:1:1 to one of the 5 treatment arms of the 
study.  Allowing for 15% attrition, it is expected that approximately 50 patients (10 per arm) 
will be evaluable for the primary efficacy endpoint. 
The study is designed to have at least 80% power and experiment-wise one-sided type I error 
of 5% to detect a difference from placebo in MG-ADL at Day 57 with 12 patients 
(10 evaluable) per arm in the placebo, M281 5 mg/kg Q4W, M281 30 mg/kg Q4W, and 
M281 60 mg/kg Q2W arms, using a dose-responsive test with the doses sorted in ascending 
order.  The M281 60-mg/kg single-dose arm was not included in the powering as its 
relationship to other doses is not defined.  The change from baseline in MD-ADL in the 
placebo and 60 mg/kg Q2W arms were assumed to be -2 and -6.0 points, respectively, and 
the common standard deviation was assumed to be 3 points.  Additionally, the ratio of 
within- to between-patient variance was assumed to be 0.2.  Power was estimated via 
simulations performed in R 3.4.4 (R Core Team, 2018). 


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Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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The sample size may be increased by up to 30 additional patients based on the results of the 
interim analysis (Section 8.8).  
8.3 
Analysis Populations  
The Intent-to-Treat (ITT) Population will include all randomized patients. 
The Safety Population will include all patients who received any amount of M281 or 
placebo.  
The PK Population will include all randomized patients in the Safety Population with at least 
one evaluable serum concentration of M281. 
The Per Protocol (PP) Population is a subset of the ITT Population and will include patients 
who complete the study with no major protocol deviations impacting safety, efficacy, or PD 
assessments.  Assignment to the PP Population will be determined prior to unblinding the 
study. 
8.4 
Demographics and Baseline Characteristics 
Descriptive summary statistics will be provided for demographic data and other baseline 
characteristics for the Safety population overall and by treatment group.   
8.5 
Primary Endpoints 
8.5.1 
Primary Safety Endpoint 
M281 safety and tolerability will be evaluated in terms of the incidence of AEs (including 
SAEs and AESIs) compared with placebo. 
Analysis of all safety data will be performed on the Safety Population and will be presented 
by the treatment received.  Adverse events will be coded using a standardized medical 
dictionary (Medical Dictionary for Regulatory Activities [MedDRA]).  Analysis of AEs in 
terms of incidence by severity and by relatedness will also be provided.  Prior and 
concomitant medications will be coded by the World Health Organization Drug Dictionary 
Enhanced and will be summarized.  Medical history will be listed by patient and coded using 
MedDRA and will be summarized.  Descriptive statistics and a summary of abnormalities 
using shift tables will be presented for safety laboratory tests, vital signs, ECGs, other 
laboratory parameters, and the C-SSRS.  For vital signs and ECGs, descriptive statistics at 
each visit and change from Baseline at each visit will be provided. Physical examinations 
will be summarized as shift tables.  Listings will also be provided for each type of safety 
data. 
8.5.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline to Day 57 in the total MG-ADL score 
for each treatment group compared with placebo. 


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Clinical Trial Protocol: MOM-M281-004 
 
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The primary efficacy endpoint will be evaluated via dose-response analyses, as well as 
mixed-effects model repeated measures (MMRM) analyses, using data at Days 15, 29, 43, 
and 57.  Dose-response analyses will include one-sided tests of linear trend and rank-based 
association.  Models of MG-ADL Day 57 change score versus dose will be explored.  
MMRM analyses will include variables for baseline MG-ADL score, treatment-by-study 
week interaction, and autoantibody type, with variance-covariance structure assumed as 
compound symmetry.  Covariates such as corticosteroids dose, use of immunosuppressants, 
and duration of use may be explored since MG diagnosis may be added to the model along 
with different variance-covariance structures. Further details on the statistical analyses for the 
primary efficacy endpoint will be in the statistical analysis plan (SAP). 
8.6 
Secondary Endpoints 
8.6.1 
Secondary Efficacy Endpoints 
• A model-based analysis of total MG-ADL score change from Baseline and difference 
from placebo in relationship to total serum IgG percent of Baseline and treatment 
frequency.  All five study arms will be included in a simultaneous analysis of total 
MG-ADL score as a function of total serum IgG (Baseline to Day 57). 
• A model-based analysis of total MG-ADL score change from Baseline and difference 
from placebo during the study as a response to percent change in total serum IgG 
(Baseline to Day 57), for patients positive for anti-AChR antibodies only 
• Responder analysis:  number of patients with a 2-, 3-, 4-, 5-, 6-, 7-, or ≥8-point 
improvement in total MG-ADL score from Baseline to Day 57 
• Change in total QMG score from Baseline to Day 57 
• Change in total MG-QoL15r score from Baseline to Day 57 
• Shift in MGFA classification from Baseline to Day 57 for each treatment group 
• Change in total serum IgG from Baseline to Day 57 for each treatment group 
• Change in total MG-ADL, QMG, and MG-QoL15r scores over time after the last dose 
• Responder analysis: number of patients with a 2-, 3-, 4-, 5-, 6-, 7-, or ≥8-point 
improvement in total QMG score over time after the last dose 
• Shift in MGFA classification over time after the last dose 
• Change in total serum IgG over time after the last dose 
 
The model-based analysis of total MG-ADL score change from Baseline, change from 
placebo will assess a set of monotonic models to define the effect of IgG lowering on 
MG-ADL changes from baseline.  The models will be averaged (weighting by Akaike 
information criterion), and the effects will be summarized by median IgG lowering for each 
of the treatment groups.  A second analysis will perform the same model-based assessment 
including only patients positive for anti-AChR antibodies.  Full details for the model-based 
analyses will be provided in the SAP. 


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Clinical Trial Protocol: MOM-M281-004 
 
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The statistical methods for other secondary efficacy endpoints will be similar to that for the 
primary endpoint.  Details on the statistical methods for the secondary endpoints will be in 
the SAP. 
8.6.2 
Other Secondary Endpoint(s) 
Serum concentrations of M281 will be summarized by treatment groups and nominal time 
point using descriptive statistics (number of patients, number of samples above the limit of 
quantification, arithmetic mean, standard deviation, coefficients of variation, geometric 
mean, geometric coefficient of variation, median, minimum, and maximum).  No PK 
parameters will be calculated. 
8.7 
Exploratory Endpoints 
• Change in serum concentration of IgG1, IgG2, IgG3, IgG4, IgA, IgM, and IgE over time 
• Change in gMG-related serum autoantibody titers over time 
• Potency and other characteristics of pathogenic MG antibodies may be assayed and 
possible relationship with clinical status may be explored 
• The incidence of ADA and neutralizing ADA (nADA) seroconversion over time 
• Need for increase (rescue) in glucocorticosteroid use before Day 57 and before Day 113 
• Need for rescue therapy before Day 57 and before Day 113 
• Number of patients with clinical deterioration before Day 57 and before Day 113  
• Number of episodes of myasthenic exacerbation (hospitalizations, ICU admissions, and 
length of stay)  
• Number of patients with a durable response, defined as ≥4 consecutive weeks with 
improvement ≥2 on MG-ADL 
• Duration of response, defined as the first week that the patient has an improvement ≥2 on 
MG-ADL and the response was sustained to the next study visit 
• Number of patients with change in MGFA classification status at Day 57 and over time 
• A model-based analysis of MG-ADL score change from Baseline, change from placebo 
in relationship to anti-AChR titer, for patients positive for anti-AChR antibodies only  
• A simultaneous model of all score-based measurements (QMG, MG-ADL) over time by 
IgG change from Baseline 
• Proportion of patients with minimal manifestations, and change in status at Day 57 and 
Day 113 per the MGFA-PIS 
• Time to response defined as time from first infusion to the first time with improvement 
≥2 on MG-ADL 
• Time to maximum improvement in MG-ADL 
• Time from maximum improvement in MG-ADL to rebound 
 
Details on the statistical methods for the exploratory endpoints will be in the SAP. 


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Clinical Trial Protocol: MOM-M281-004 
 
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8.8 
Interim Analysis 
An interim analysis will be performed when approximately 30 patients have completed the 
Day 57 assessments.  The results will be used to adjust the sample size, if necessary, and to 
guide future development activities.  If the model-adjusted standard deviation of MG-ADL 
change from baseline is >4.0, up to 30 additional patients may be recruited.  
The interim analysis will be conducted by an independent unblinded team.  The study team 
(including the investigator, site personnel, Sponsor, and Sponsor’s designee) will remain 
blinded.  A detailed unblinding plan will be included in the SAP. 
9 
ADMINISTRATIVE CONSIDERATIONS 
9.1 
Investigators and Study Administrative Structure 
A Coordinating Investigator for the study will be identified by the Sponsor or designee.  
Contact information for the Medical Monitor is as follows:   
 
 
Pharmaceutical Product 
Development, Inc. 
Phone (US): 
 
 
Fax (US): 
 
Phone (EU): 
 
 
9.2 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC).  The Investigator must submit written approval from the IRB/IEC to the 
Sponsor before he or she can enroll any patient into the study.  In addition, the IRB/IEC must 
approve all advertising used to recruit patients for the study. 
The Investigator is responsible for informing the IRB/IEC of any amendment to the protocol 
in accordance with local requirements.  Protocol amendments will be prepared and approved 
by the Sponsor or Sponsor’s designee and sent to the appropriate IRB/IEC for review and 
approval.  Documentation of IRB/IEC approval must be forwarded to the Sponsor or 
designee before the procedures associated with the amendment commence. 
The Investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the study drug.  The 
Sponsor will provide this information to the Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/IEC according to local regulations and guidelines. 
PPD
PPD
PPD
PPD


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Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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9.3 
Ethical Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor, its authorized 
representative and Investigators abide by GCP as described in International Council for 
Harmonisation (ICH) guideline E6(R2), and in 21 Code of Federal Regulations (CFR) 
parts 11, 50, 54, 56, and 312.  Compliance with these regulations also constitutes compliance 
with the ethical principles described in the most recent revision of the Declaration of Helsinki 
(October 2013) that is recognized by the US FDA, the European Medicines Agency, and 
other regulatory agencies. 
Investigators from countries who are not permitted to sign the US FDA Form 1572 must sign 
a statement of compliance with internationally recognized rules (ICH E6) governing conduct 
of clinical trials, that satisfies the US FDA regulation in 21 CFR 312 regarding foreign 
clinical studies not conducted under an IND. 
9.4 
Patient Information and Consent 
A template ICF will be provided by the Sponsor or designee.  The ICF must be reviewed and 
approved by the IRB/IEC and must contain all elements required by national or local 
regulations or requirements, US FDA regulations, state and federal laws, and institutional 
policies.  If, during the approval process, the IRB/IEC makes any substantive changes to the 
ICF, then this altered ICF must be provided to the Sponsor or designee for review before it is 
implemented. 
All patients will be provided with the approved written ICF for this study, which will provide 
sufficient information for the patient to make an informed decision about participation in this 
study and to facilitate comprehension of the information.  Each patient will be provided 
adequate opportunity to ask questions and to consider whether to participate.  The 
Investigator is responsible for obtaining the potential participant’s voluntary agreement to 
participate, and to continue providing information as the clinical trial progresses or as the 
patient or situation requires.  
Voluntary informed consent must be obtained from each eligible patient (and/or legally 
authorized representative) before any protocol-defined procedures are performed.  The 
patient’s signature on the ICF indicates his/her willingness to participate in this study.  Other 
study personnel (eg, Principal Investigator, Study Nurse) will sign the ICF in accordance 
with local procedures. 
9.5 
Patient Confidentiality 
The Investigator must assure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times.  In the eCRFs and other 
documents (eg, laboratory reports) submitted to the Sponsor, patients will not be identified 
by name, but by a randomly assigned, patient identification number. 


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Clinical Trial Protocol: MOM-M281-004 
 
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Personal medical information may be reviewed for the purpose of verifying data recorded in 
the eCRF by the study monitor, Sponsor or designee, IRB/IEC, and regulatory authorities. 
Personal medical information will always be treated as confidential and in compliance with 
applicable local laws and regulations. 
9.6 
Study Monitoring 
Clinical research associates (CRAs) representing the Sponsor will routinely visit the study 
site throughout the study.  The Investigator will also ensure that the monitor, or other 
compliance or quality assurance reviewer, is given access to all study-related documents and 
study related facilities (eg, pharmacy, diagnostic laboratory, medical records, etc), and has 
adequate space to conduct the monitoring visit.  In addition to the monitoring visits, frequent 
communications (email, letter, telephone, and/or fax) by the CRA will ensure that the 
investigation is conducted according to protocol design and regulatory requirements.  The 
Investigator, or appropriate designee, will allocate adequate time for monitoring activities 
and follow-up correspondences.  
The CRA will review ICFs, eCRFs, and laboratory and other diagnostic reports, comparing 
them with source documents to verify adherence to the protocol, and to ensure complete, 
accurate, consistent, and timely collection of data.  The CRA will record and report any 
protocol deviations not previously sent to the Sponsor.  The CRA will also confirm that AEs 
and SAEs have been properly documented on eCRFs and confirm that any SAEs have been 
forwarded to the Sponsor and those SAEs that met criteria for reporting have been forwarded 
to the IRB/IEC.  The Investigator will be asked to provide any missing information or to 
clarify any discrepancies found by the CRA/monitor.  It is expected that the Investigator will 
be present for a concluding review at the end of each monitoring visit. 
9.7 
Case Report Forms and Study Records 
Wherever possible, all data will be entered directly into the eCRFs.  In some cases, source 
documents will be used.  A Data Management Plan will be written by the Sponsor or 
designee, which will be finalized prior to performing any data validation.  The Data 
Management Plan will identify any data to be recorded directly in the eCRF (ie, no prior 
written or electronic record of data), and which data should be considered source data.  
Source documents are all original documents, data, and records that pertain to a study patient 
and can be either electronic or physical in origin.  Examples of source documents are:  
hospital records, clinical and office charts, laboratory notes, memoranda, patient diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, X-rays, patient 
files and records kept at the pharmacy, at the laboratories and at technical departments 
involved in the study.  When source document data are shared with originating files (eg, 
hospital records or other clinic charts), photocopies of specific components of these data can 
be included as source document provided that these copies are signed and dated by 
appropriate research site personnel. 


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Source data must be legible and written concurrently with the patient visit, and no data may 
be obliterated.  If the source document contains a patient’s address and phone number, it 
must be obliterated before it is included as a study document and the patient’s name will be 
obliterated except for the first letters of the first, middle (if present), and last names.  The 
completed eCRF must be reviewed and approved by an authorized Investigator before it can 
be considered final. 
9.8 
Data Monitoring Committee 
An independent DSMB will be responsible for safety oversight of the patients in the study.  
The DSMB will meet on a regular basis and review all available data (AEs, SAEs, AESIs, 
and laboratory results); ad hoc meetings may be scheduled as needed.  The specific 
responsibilities of the DSMB will be outlined in a DSMB charter. 
9.9 
Protocol Violations/Deviations 
Except for a change intended to eliminate an immediate hazard to a participant, the protocol 
shall be conducted as described without any changes or deviations.  Any change must be 
reported immediately to the Sponsor and to the IRB/IEC, as required by their regulations. 
9.10 Access to Source Documentation 
The Investigator will permit study related monitoring, audits, and inspections by the 
IRB/IEC, the Sponsor, government regulatory bodies, and compliance and quality assurance 
groups of all study related documents (eg, source documents, regulatory documents, data 
collection instruments, study data, etc).  All authorized personnel, including health authority 
inspector(s), Sponsor and designees, CRAs, Medical Monitor(s), and auditor(s) will be given 
direct access to source data and documentation (eg, medical records, laboratory results, etc) 
for source data verification, provided that patient confidentiality is maintained in accordance 
with local requirements. 
9.11 Data Generation and Analysis 
Data management and control processes specific to the study will be described in the data 
management plan.  Details on the study’s analysis methods will be provided in the SAP, 
which will be developed prior to study completion and database lock. 
9.12 Retention of Data 
The Principal Investigator shall retain all study-related documentation, including source data, 
source documents, eCRFs, laboratory and diagnostic results, protocol and amendments, study 
drug accountability records, regulatory documentation and correspondence, ICFs, patient 
identification lists, and correspondence.  These records should be retained in the format they 
were originally obtained (eg, electronic or paper) unless a quality controlled and authorized 
complete electronic version is created for long-term storage at the end of the study.  The 
Sponsor will provide an electronic copy of the final eCRF for each study patient within 
3 months of study closeout. 


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The Investigator must retain an organized file with all study-related documentation that is 
suitable for inspection by the Sponsor and representatives of Regulatory Authorities. 
The Investigator must retain essential documents until notified by the Sponsor, and at least 
for 15 years after study completion.  
Documents should be stored in such a way that they can be accessed and data can be 
retrieved at a later date.  Consideration should be given to security and environmental risks. 
Documentation retention will generally comply with Section 8 of the ICH consolidated 
guideline on GCP, Essential Documents for the Conduct of a Clinical Trial. 
No study document will be destroyed without prior written agreement between the Sponsor 
and the Investigator or the Research Site should the Investigator leave the institution.  Should 
the Investigator wish to assign the study records to another party or move them to another 
location, written agreement must be obtained from the Sponsor prior to any actions being 
taken. 
9.13 Publication and Disclosure Policy 
This trial will be registered at ClinicalTrials.gov and after study completion, results 
information from this trial will be posted to ClinicalTrials.gov.  In addition, every attempt 
will be made to publish results in peer-reviewed journals.  Publication of the results by the 
Investigator will be subject to mutual written agreement between the Investigator and the 
Sponsor or determined by the publication/steering committee. 


M281  
 
Momenta Pharmaceuticals, Inc. 
Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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10 REFERENCE LIST 
Argenx. Phase 2 clinical proof-of-concept trial of ARGX-113 (efgartigimod) in generalized 
myasthenia gravis. Management call; December 11, 2017. Available from: 
http://phx.corporate-
ir.net/External.File?item=UGFyZW50SUQ9Njg1NTQzfENoaWxkSUQ9Mzk1NjcwfFR5cG
U9MQ==&t=1. Accessed 18 June 2018. 
Blumberg L, Humphries JE, Lasseter KC, Blumberg RS. A humanized IgG4 monoclonal 
antibody that disrupts the interaction of FcRn and IgG for the treatment of IgG mediated 
autoimmune diseases. Poster presented at American Society of Hematology (ASH) 59th 
Annual Meeting and Exposition; 2017 December 9-12; Atlanta, Georgia. 
Burns TM, Sadjadi R, Utsugisawa K, Gwathmey KG, Joshi A, Jones S, et al. International 
clinimetric evaluation of the MG QOL15, resulting in slight revision and subsequent 
validation of the MG-QOL15r. Muscle Nerve. 2016;54:1015-22. 
Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375(26):2570-81. 
Gilhus NE, Skeie GO, Romi F, Lazaridis K, Zisimopoulou P, Tzartos S. Myasthenia gravis – 
autoantibody characteristics and their implications for therapy. Nat Rev Neurol. 
2016;12(5):259-68. 
Hansen JS, Danielsen DH, Somnier FE, Frøslev T, Jakobsen J, Johnsen SP, et al. Mortality in 
myasthenia gravis: A nationwide population based follow up study in Denmark. Muscle 
Nerve. 2016;53(1):73-7. 
Howard JF Jr, Barohn RJ, Cutter GR, Freimer M, Juel V, Mozaffar T, et al. A randomized, 
double blind, placebo controlled phase II study of eculizumab in patients with refractory 
generalized myasthenia gravis. Muscle Nerve. 2013;48(1):76-84. 
Howard JF Jr, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, et al. Safety and 
efficacy of eculizumab in anti-acetylcholine receptor antibody positive refractory generalised 
myasthenia gravis (REGAIN): a phase 3, randomised, double blind, placebo controlled, 
multicentre study. Lancet Neurol. 2017;16(12):976-86. 
Jaretzki A, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, Sanders DB. 
Myasthenia gravis: recommendations for clinical research standards. Task Force of the 
Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. 
Neurology. 2000;55:16-23. 
Kiessling P, Lledo-Garcia R, Watanabe S, Langdon G, Tran D, Bari M, et al. The FcRn 
inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 
study. Sci Transl Med. 2017;9(419). Erratum in: Sci Transl Med. 2017;9(419). 


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Liu L, Garcia AM, Santoro H, Zhang Y, McDonnell K, Dumont J, et al. Amelioration of 
experimental autoimmune myasthenia gravis in rats by neonatal FcR blockade. J Immunol. 
2007;178:5390-8. 
Mantegazza R, Antozzi C. When myasthenia gravis is deemed refractory: clinical signposts 
and treatment strategies. Ther Adv Neurol Disord. 2018;11:1756285617749134. Erratum in: 
Ther Adv Neurol Disord 2018;11:1756286418765591. 
Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? 
Expert Rev Clin Immunol. 2012;8(5):427-38. 
Nixon AE, Chen J, Sexton DJ, Muruganandam A, Bitonti AJ, et al. Fully human monoclonal 
antibody inhibitors of the neonatal fc receptor reduce circulating IgG in non-human primates. 
Front Immunol. 2015;6:176. doi: 10.3389/fimmu.2015.00176. eCollection 2015. 
Robak T, Jarque I, Musteata V, Kiessling P, Massow U, Higginson J, et al. Phase II, 
multiple-dose study of anti-FcRn antibody, rozanolixizumab (UCB7665), in patients with 
primary immune thrombocytopenia: Interim analysis. Blood. 2017;Dec;130(Suppl 1):15. 
Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al. International consensus 
guidance for management of myasthenia gravis. Neurology. 2016;87:419-25. 
Sathasivam S. Diagnosis and management of myasthenia gravis. Progress in Neurology and 
Psychiatry. 2014. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/pnp.315.  
Accessed 21 May 2018. 
Silvestri N, Wolfe G. Treatment refractory myasthenia gravis. J Clin Neuromuscul Dis. 
2014;15(4):167-78. 
US FDA. Guidance for Industry. Suicidal ideation and behavior: Prospective assessment of 
occurrence in clinical trials, Draft Guidance. August 2012. Revision 1. Available from: 
https://www.fda.gov/downloads/Drugs/Guidances/UCM225130.pdf. Accessed on 
11 June 2018. 
Zhang B, Tzartos JS, Belimezi M, Ragheb S, Bealmear B, Lewis RA, et al. Autoantibodies to 
lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch 
Neurol. 2012;69(4):445-51. 
 


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Appendix 1 
Sponsor Signatures 
Study Title: 
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 
Study Number: 
MOM-M281-004 
Amendment 3.2 Date: 
28 August 2019 
 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor.  
 
Signed: 
 
 
 
Date: 
 
 
 
Printed name: Santiago Arroyo, MD, PhD 
Title: 
Chief Medical Officer, Momenta Pharmaceuticals, Inc. 
 
 


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Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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Appendix 2 
Investigator’s Signature 
Study Title: 
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 
Study Number: 
MOM-M281-004 
Amendment 3.2 Date: 
28 August 2019 
I have read the protocol described above.  I agree to conduct the study as described in the 
protocol.  I also agree to conduct this study in compliance with Good Clinical Practice (GCP) 
and all applicable national and local laws and regulations, as well as with the requirements of 
the appropriate Institutional Review Board or independent Ethics Committee (IRB/IEC) and 
any other institutional requirements.  These are stated in “Guidance for Good Clinical 
Practice,” International Council for Harmonisation (ICH) guideline E6(R2) of Technical 
Requirements for Registration of Pharmaceuticals for Human Use, the Declaration of 
Helsinki, and any other applicable regulatory requirements.  No changes will be made to the 
study protocol without prior written approval of the Sponsor and the IRB/IEC. 
 
Signed: 
 
 
 
Date: 
 
 
 
Printed name: ____________________________________ 
Title: 
____________________________________ 
Affiliation: 
____________________________________ 
 


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Appendix 3 
Myasthenia Gravis – Activities of Daily Living 
 


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Clinical Trial Protocol: MOM-M281-004 
 
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Appendix 4 
Quantitative Myasthenia Gravis 
 


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Clinical Trial Protocol: MOM-M281-004 
 
28 August 2019, Amendment 3.2 
 
 
 
 
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Appendix 5 
Revised Myasthenia Gravis Quality of Life – 15 
 


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Appendix 6 
Myasthenia Gravis Foundation of America Post-
Intervention Status 
 
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
Study Title: 
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 
Sponsor 
Momenta Pharmaceuticals, Inc. 
 
301 Binney Street 
 
Cambridge, MA 02142 USA 
Name of Test Drug: 
Nipocalimab (M281) 
Protocol Number: 
MOM-M281-004 
Protocol Versions/Dates 
Original Protocol: 13 July 2018 
 
Amendment 1: 26 October 2018 
 
Amendment 2: 11 December 2018 
 
Amendment 3: 04 June 2019 
 
Amendment 3.1: 05 July 2019 
Amendment 3.2: 28 August 2019 (Only applicable for EU) 
Phase: 
2 
Analysis Plan Version 
FINAL Version 1.0 
Analysis Plan Date 
May 22, 2020 
 
 
 
Confidentiality Statement 
Momenta Confidential and Proprietary 
 
 
NCT03772587


PPD
PPD
PPD


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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN APPROVAL ....................................................................2 
TABLE OF CONTENTS ...........................................................................................................3 
LIST OF ABBREVIATIONS ....................................................................................................5 
1 
INTRODUCTION .............................................................................................................7 
2 
OVERVIEW OF STUDY DESIGN ..................................................................................7 
2.1 
Primary Objectives...................................................................................................9 
2.2 
Secondary Objectives...............................................................................................9 
2.3 
Exploratory Objectives ............................................................................................9 
2.4 
Primary Endpoints .................................................................................................10 
2.4.1 
Primary Safety Endpoint ..............................................................................10 
2.4.2 
Primary Efficacy Endpoint ..........................................................................10 
2.5 
Secondary Endpoints .............................................................................................10 
2.6 
Exploratory Endpoints ...........................................................................................10 
3 
SAMPLE SIZE ................................................................................................................11 
4 
RANDOMIZATION, BLINDING, AND REPLACEMENT OF PATIENTS ...............11 
5 
DEFINITIONS OF PATIENT POPULATIONS.............................................................12 
6 
DEFINITIONS, COMPUTATIONS, DATA CONVENTIONS .....................................12 
6.1 
Key Definitions and Computations ........................................................................12 
6.2 
Conventions ...........................................................................................................13 
7 
MISSING DATA AND DROPOUTS .............................................................................14 
7.1 
Partial/Missing Dates .............................................................................................14 
7.2 
Missing MG-ADL, QMG, and MG-QOL15 Individual Item Scores ....................14 
7.3 
Missing MG-ADL and QMG total scores .............................................................15 
8 
DESCRIPTION OF STATISTICAL ANALYSES .........................................................15 
8.1 
General Principles ..................................................................................................15 
8.2 
Patient Enrollment, Disposition, Protocol Deviations ...........................................16 
8.3 
Demographic, Baseline Characteristics, and Medical History ..............................16 
8.4 
Efficacy, Pharmacokinetic and Pharmacodynamic Analyses ................................17 
8.4.1 
Efficacy and Pharmacodynamic Analyses ...................................................17 
8.4.2 
Exploratory Efficacy and Pharmacodynamic Endpoints .............................18 
8.4.3 
Pharmacokinetic (PK) Analysis ...................................................................20 
8.5 
Safety Analysis ......................................................................................................20 
8.5.1 
Adverse Events ............................................................................................20 
8.5.2 
Study Drug Exposure and Dose Modifications ...........................................21 
8.5.3 
Laboratory Tests ..........................................................................................21 
8.5.4 
Vital Signs and Weight ................................................................................22 


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8.5.5 
Physical Examinations .................................................................................22 
8.5.6 
Electrocardiograms (ECG)...........................................................................22 
8.5.7 
Columbia-Suicide Severity Rating Scales (C-SSRS) ..................................23 
8.5.8 
Myasthenia Gravis Exacerbation .................................................................23 
8.5.9 
Concomitant Therapy and Procedures .........................................................23 
9 
TESTING/VALIDATION PLAN AND SOFTWARE SYSTEM ..................................23 
10 INTERIM ANALYSIS ....................................................................................................23 
11 STATISTICAL ANALYSIS CHANGES FROM THE PROTOCOL ............................24 
11.1 
Final Analysis ........................................................................................................24 
11.2 
Interim Analysis .....................................................................................................25 
12 REFERENCE ...................................................................................................................26 
13 SCHEDULE OF STUDY ASSESSMENTS ...................................................................30 
 
 


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LIST OF ABBREVIATIONS 
AChR 
Acetylcholine Receptor 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Class (from WHODRUG dictionary) 
BMI 
Body mass index 
CRF 
Case Report Form 
CMH 
Cochran–Mantel–Haenszel 
COVID-19 
2019 novel coronavirus 
CRF 
Case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CV 
Coefficient of Variation 
DSMB 
Drug Safety Monitoring Board 
ECG 
Electrocardiogram 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practices 
gMG 
generalized Myasthenia Gravis 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
Ig 
Immunoglobulin 
ITT 
Intent to Treat 
K-M 
Kaplan-Meier 
LOCF 
Last observation carried forward 
MCAR 
Missing Completely At Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MG-ADL 
Myasthenia Gravis - Activities of Daily Living 
MGFA 
Myasthenia Gravis Foundation of America 
MGFA-PIS 
Myasthenia Gravis Foundation of America Post-intervention Status 
MG-QoL15r 
Myasthenia Gravis Quality of Life - 15 Scale 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed-effects Model Repeated Measures 
MNAR 
Missing Not At Random 


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MuSK 
Muscle-Specific Kinase 
nADA 
Neutralizing ADA 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per Protocol 
Q2W 
once every 2 weeks 
Q4W 
once every 4 weeks 
QMG 
Quantitative Myasthenia Gravis 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System/Software 
SI 
International System of Units 
TEAE 
Treatment Emergent Adverse Event 
WHODRUG 
World Health Organization Drug  
 


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1 
INTRODUCTION 
This document describes the data analysis specifications for Momenta Pharmaceuticals, Inc. 
protocol MOM-M281-004 entitled “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.” 
This version of the statistical analysis plan (SAP) was prepared in accordance with the latest 
protocol MOM-M281-004 version 3.1 (dated 5 July 2019) and 3.2 (for EU only, dated 
August 28, 2019). The regional version of the protocol does not affect the statistical analysis. 
The purpose of this SAP is to provide a framework in which answers to the protocol 
objectives may be achieved in a statistically rigorous fashion, without bias or analytical 
deficiencies, following methods identified prior to database lock. Specifically, this plan has 
the following purposes: 
To outline the types of analyses and presentations of data that will form the basis for 
conclusions. 
To explain in detail how the data will be handled and analyzed, adhering to commonly 
accepted standards and practices of biostatistical analysis in the pharmaceutical industry.  
Any deviations from these guidelines must be substantiated by sound statistical reasoning 
and documented in writing in the final clinical study report. 
To detail the changes to the planned analysis as a result of the COVID-19 pandemic. 
The original study design included an interim analysis that was to be conducted when 
approximately 30 enrolled patients had completed their Day 57 assessments. The results were 
to be used to adjust the sample size, if necessary, and to guide future development activities. 
Very rapid enrollment towards the end of the enrollment period led the Sponsor instead to 
plan to conduct the interim analysis on all randomized patients.   However, the COVID-19 
global pandemic, which halted study operation prematurely and impeded completion of study 
visits for some patients, rendered execution of this plan infeasible. Therefore, a new interim 
analysis of the data, described in Section 10 of this document, will be implemented.   
2 
OVERVIEW OF STUDY DESIGN 
MOM-M281-004 is a multicenter, randomized, double-blind, placebo-controlled study 
designed to evaluate the safety, tolerability, efficacy, pharmacokinetics (PK), 
pharmacodynamics (PD), and immunogenicity of M281 compared with placebo when 
administered by intravenous (IV) infusion to patients with generalized Myasthenia Gravis 
(gMG). 
Following a Screening Period of up to 4 weeks, approximately 60 eligible patients will be 
randomized 1:1:1:1:1 to one of 5 treatment groups (approximately 12 per group).  The 
randomization will be stratified first by autoantibody type (anti-muscle-specific kinase 


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(MuSK) vs anti-acetylcholine receptor (AChR)), and for patients positive for anti-AChR, the 
randomization will be further stratified by Baseline Myasthenia Gravis - Activities of Daily 
Living (MG-ADL) score (≤10, >10). The treatment groups are as follows: 
• 
Group 1:  placebo once every 2 weeks (Q2W) 
• 
Group 2:  5 mg/kg M281 once every 4 weeks (Q4W) 
• 
Group 3:  30 mg/kg M281 Q4W 
• 
Group 4:  60 mg/kg M281 as a single dose 
• 
Group 5:  60 mg/kg M281 Q2W 
 
During the Treatment Period, patients will attend clinic visits beginning at Baseline (Day 1) 
and every other week for 8 weeks to receive study drug (placebo or M281) and undergo 
safety, efficacy, PK, PD, and immunogenicity assessments.  To maintain the study blind with 
respect to assigned treatment and treatment regimen, all patients will receive an IV infusion 
(either placebo or M281) every other week; thus, all patients will receive a total of 
5 infusions (See Table 1 below).  Patients in the placebo group will receive an infusion Q2W 
beginning on Day 1.  Patients in the M281 5 mg/kg Q4W, and 30 mg/kg Q4W dose groups 
will receive a placebo infusion at the Day 15 and Day 43 visits to maintain blinding of the 
study.  Patients in the M281 60 mg/kg single-dose arm will receive placebo infusions on 
Days 15, 29, 43, and 57.  Only patients in the M281 60 mg/kg Q2W group will not receive 
any placebo infusions. Infusions will be administered on the designated infusion days at the 
study facility after completion of all assessments specified for the given infusion day as 
shown on the Schedule of Study Assessments (Section 13).  The infusions will be 
administered without regard to meal times.  The infusion time is noted in the Infusion 
Manual.  Guidelines for management of infusion reactions are provided in the study manual.  
The date of infusion, start and end times, the volume administered, and the time of the first 
infusion rate change (if applicable) for all doses are to be recorded. 
Pharmacokinetic samples, vital signs, and an electrocardiogram (ECG) will be obtained 
before the start of the infusion.  Patients will be observed for safety after the first 3 infusions 
per the Infusion Manual; if no clinically relevant adverse events (AEs) related to the infusion 
are observed in these first 3 infusions, the post-infusion observation period is no longer 
needed.  The last infusion will be administered at the Day 57 visit.  During the Follow-up 
Period (the 8-week period after the last infusion), clinic visits will be conducted for all 
patients at Day 85 and Day 113 for further safety, efficacy, PK, PD, and immunogenicity 
assessments needed to characterize the anticipated prolonged effects of M281.  Serum 
biomarkers may be explored. 
Upon completion of the study at Day 113, patients have the option to enroll in a separate 
open-label extension study where they would receive treatment with M281. 
An independent Drug Safety Monitoring Board (DSMB) will be responsible for oversight of 
patient safety during the study. 


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Table 1  Selection and Timing of Infusions for Each Treatment Group 
Treatment Group 
Infusion Timepoints 
Day 1 
Visit 
Day 15 
Visit 
Day 29 
Visit 
Day 43 
Visit 
Day 57 
Visit 
Placebo Q2W 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
M281 5 mg/kg Q4W 
M281 
Placebo 
M281 
Placebo 
M281 
M281 30 mg/kg Q4W 
M281 
Placebo 
M281 
Placebo 
M281 
M281 60 mg/kg single dose 
M281 
Placebo 
Placebo 
Placebo 
Placebo 
Abbreviations:  Q2W = every 2 weeks; Q4W = every 4 weeks. 
 
2.1 
Primary Objectives 
The primary objectives are to evaluate: 
• 
The safety and tolerability of treatment with M281 in patients with gMG who have an 
insufficient clinical response to ongoing, stable standard of care therapy, and 
• 
The efficacy of M281 for gMG as measured by the change in MG-ADL score. 
 
2.2 
Secondary Objectives 
The secondary objectives are to evaluate: 
• 
The efficacy of M281 as measured by changes in the Quantitative Myasthenia Gravis 
(QMG) score and the revised Myasthenia Gravis Quality of Life - 15 Scale 
(MG-QoL15r), 
• 
The PK of M281, and 
• 
The PD activity of M281 as measured by effects on total serum immunoglobulin (Ig)G 
concentrations.  
 
2.3 
Exploratory Objectives 
The exploratory objectives are to: 
• 
Evaluate the PD activity of M281 as measured by effects on serum concentrations of 
IgG1, IgG2, IgG3, IgG4, IgA, IgM, and IgE; 
• 
Evaluate the PD activity of M281 as measured by effects on serum levels of pathogenic 
autoantibodies associated with gMG (anti-AChR and anti-MuSK); 
• 
Characterize pathogenic MG autoantibodies (anti-AChR and anti-MuSK) and their 
potential for disease modification and possible relationship with clinical status; 
• 
Evaluate the immunogenicity of M281 as assessed by the presence of total and 
neutralizing anti-M281 antibodies in patients with gMG; 


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• 
Evaluate the response to treatment with M281 in patients with gMG, as measured by 
exploratory efficacy endpoints, including, but not limited to, use of rescue therapy, time 
to response, duration of response, and number of MG exacerbations; and 
• 
Evaluate the potential relationship between change in MG-ADL score and change in 
anti-AChR levels in patients treated with M281, for patients positive for anti-AChR 
antibodies only. 
 
2.4 
Primary Endpoints 
2.4.1 
Primary Safety Endpoint 
M281 safety and tolerability will be evaluated in terms of the incidence of AEs (including 
Serious AEs (SAEs) and AEs of Special Interest (AESIs)) compared with placebo.  
Analysis of all safety data will be performed on the Safety Population and will be presented 
by the treatment received.  Adverse events will be coded using a standardized medical 
dictionary (Medical Dictionary for Regulatory Activities [MedDRA]).  Analysis of AEs in 
terms of incidence by severity and by relatedness will also be provided.  Prior and 
concomitant medications will be coded by the World Health Organization Drug Dictionary 
Enhanced and will be summarized.  Medical history will be listed by patient and coded using 
MedDRA and will be summarized.  Descriptive statistics and a summary of abnormalities 
using shift tables will be presented for safety laboratory tests, vital signs, ECGs, other 
laboratory parameters, and the Columbia-Suicide Severity Rating Scale (C-SSRS).  For vital 
signs and ECGs, descriptive statistics at each visit and change from Baseline at each visit will 
be provided. Physical examinations will be summarized as shift tables.  Listings will also be 
provided for each type of safety data. 
2.4.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to Day 57 in the total MG-ADL 
score for each treatment group compared with placebo. The details on the statistical analyses 
for the primary efficacy endpoint are described in Section 8.4.1.1. 
2.5 
Secondary Endpoints 
The study’s secondary efficacy endpoints are listed with their corresponding analysis 
methods in Section 8.4.1.2. 
2.6 
Exploratory Endpoints 
The study’s exploratory efficacy endpoints are listed with their corresponding analysis 
methods in Section 8.4.2. 


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3 
SAMPLE SIZE 
Approximately 60 patients will be randomized 1:1:1:1:1 to one of the 5 treatment arms of the 
study.  Allowing for 15% attrition, it is expected that approximately 50 patients (10 per arm) 
will be evaluable for the primary efficacy endpoint. 
The study is designed to have at least 80% power and experiment-wise one-sided type I error 
of 5% to detect a difference from placebo in MG-ADL at Day 57 with 12 patients 
(10 evaluable) per arm in the placebo, M281 5 mg/kg Q4W, M281 30 mg/kg Q4W, and 
M281 60 mg/kg Q2W arms, using a dose-responsive test with the doses sorted in ascending 
order.  The M281 60-mg/kg single-dose arm was not included in the powering as its 
relationship to other doses is not defined.  The change from baseline in MD-ADL in the 
placebo and 60 mg/kg Q2W arms were assumed to be -2 and -6.0 points, respectively, and 
the common standard deviation was assumed to be 3 points.  Additionally, the ratio of 
within- to between-patient variance was assumed to be 0.2.  Power was estimated via 
simulations performed in R 3.4.4 (R Core Team, 2018). 
The study design originally allowed the sample size to be increased by up to 30 additional 
patients based on the results of the interim analysis. However, due to the rapid enrollment 
rate and also due to COVID-19, the need for sample size adjustment will no longer be 
assessed in the interim analysis (see Section 10 and Section 11.2).  
4 
RANDOMIZATION, BLINDING, AND REPLACEMENT OF 
PATIENTS  
Eligible patients will be randomized on Day 1 to a treatment assignment according to a 
randomization schedule generated by the Sponsor or designee.  The study personnel will use 
a web-based interactive response system to obtain the randomization number for each 
eligible patient. 
The study is double-blinded.  The patient, investigator, and Sponsor will be blinded to study 
treatment for the duration of the study.  An unblinded site pharmacist will be responsible for 
preparing the study drug for infusion while the remainder of site personnel will remain 
blinded.  
Laboratory measurements related to expected PD activity and immunogenicity of M281 (i.e., 
total serum IgG and IgG subtypes [IgG1, IgG2, IgG3, and IgG4], anti-AChR and anti-MuSK 
autoantibodies, albumin, and anti-M281 antibodies) will be blinded to the patient, 
investigator, and Sponsor and not provided during study conduct with the exception of total 
serum IgG at the Day 113 Visit if the patient does not enter the MOM-M281-005 open-label 
extension study. 
If an emergency occurs that necessitates knowledge of a patient’s treatment assignment, the 
Investigator can obtain the information via the web-based interactive response system. 
An unblinded interim analysis will be conducted as described in Section 10. An unblinding 
plan detailing the unblinding process will be finalized and signed off before unblinding. 


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5 
DEFINITIONS OF PATIENT POPULATIONS  
The Intent-to-Treat (ITT) Population will include all randomized patients. Efficacy analysis 
will be performed using the ITT Population in the final analysis. 
The modified Intent-to-Treat (mITT) Population will include all randomized patients who 
have at least one postbaseline efficacy assessment, and whose data are suitable for analysis 
(see Section 11.2 for details). The interim analysis will use the mITT population for efficacy 
analyses.  
The Safety Population will include all patients who received any amount of M281 or 
placebo.  All safety analysis will be performed using the Safety Population. 
The PK Population will include all randomized patients in the Safety Population with at least 
one evaluable plasma concentration of M281. 
The Per Protocol (PP) Population is a subset of the ITT Population and will include patients 
who complete the study with no major protocol deviations impacting safety, efficacy, or PD 
assessments.  Assignment to the PP Population will be determined prior to unblinding the 
study. 
6 
DEFINITIONS, COMPUTATIONS, DATA CONVENTIONS 
6.1 
Key Definitions and Computations 
Start of Treatment 
Date and start time of the first infusion of the study drug. 
Baseline 
Baseline represents the procedures or assessments done prior to the administration of study 
treatment. The Baseline value will be the value obtained closest to and prior to the first 
administration of study treatment (Day 1). These values can occur on the same day as the 
first administration of study treatment (or in the Screening visit), as long as they are 
measured before the study treatment is administered. 
Visit Structure and Visit Names  
Section 13 displays the schedule of study assessments taken from the protocol (pages 25-27) 
that defines the visit structure and visit names. Patient listings and summary tables will 
follow as closely as possible the visit structure and naming conventions outlined in 
Section 13.  
Adverse Event (AE) and Treatment-Emergent Adverse Event (TEAE) 
Reporting of AEs will start following the patient signing the informed consent form and end 
at the final visit.  


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The AEs and SAEs are defined as follows: 
• 
Adverse event is any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality. 
• 
Serious Adverse Event is any adverse event occurring at any dose that results in any of 
the following outcomes: Death, a life-threatening AE, hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious AE when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. 
Treatment-emergent adverse events (TEAE) are defined as any AE occurring during or after 
the initiation of the first infusion of study drug. 
The severity of AE will be graded using Common Terminology Criteria for Adverse Events 
(CTCAE) v.5.0 and the degree of certainty about causality will be graded into definitely, 
probably, possibly related, unlikely to be related, and not related. 
Adverse Event of special interests (AESI) are defined as any CTCAE Grade 3 or higher 
event of severe infection and any CTCAE Grade 3 or higher event of hypoalbuminemia. 
See Section 6.1.1 of the study protocol for more details.   
Anti-drug Antibody Seroconversion 
Anti-drug Antibody (ADA) seroconversion will be considered as any subject who begins 
with an antibody titer below the limit of quantification (including ADA screening assay 
negative) and at any point after Start of Treatment has an antibody titer above the limit of 
quantification. 
6.2 
Conventions 
• 
1 year = 365.25 days. Year is calculated as (days / 365.25) and will be rounded up to 1 
significant digit (tenths) for purposes of presentation. 
• 
1 month = 30.4375 days. Month is calculated as (days / 30.4375) and will be rounded up 
to 1 significant digit (tenths) for purposes of presentation. 
• 
1 pound = 0.454 kg. 
• 
1 inch = 2.54 cm. 
• 
Investigational Product (Study Drug) is M281. 
• 
Study Drug Administration: Duration of treatment is defined as the last dose date minus 
the first dose date of the study treatment plus 1. 
• 
The software used for all summary statistics and statistical analyses will be Statistical 
Analysis System/Software (SAS) Version 9.3 or later. 


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• 
Missing or invalid data will be generally treated as missing, not imputed, unless 
otherwise stated (see Section 7).  
 
7 
MISSING DATA AND DROPOUTS 
All data will be analyzed as they were collected in the clinical database. Hence, missing 
values will generally not be imputed except for in the specific situations described in the 
subsections below. 
7.1 
Partial/Missing Dates  
When tabulating AE data, partial dates will be handled as follows. If the day of the month is 
missing, the onset day will be set to the first day of the month unless it is the same month and 
year as study treatment. In this case, in order to conservatively report the event as treatment-
emergent, the onset date will be assumed to be the date of treatment. If the onset day and 
month are both missing, the day and month will be assumed to be January 1, unless the event 
occurred in the same year as the study treatment. In this case, the event onset will be coded to 
the day of treatment in order to conservatively report the event as treatment-emergent.  A 
missing onset date will be coded as the day of treatment. No imputation will be applied to the 
incomplete AE end date. 
To summarize time since MG diagnosis, partial dates will be handled as follows. If the day of 
the month is missing, the day is set to the fifteenth (15th) of the month.  If the day and month 
are both missing, the day and month will be assumed to be June 15th . 
Imputed dates will be noted in the patient data listings. Any imputed dates undertaken post-
database lock will be fully described in the clinical study report.  
7.2 
Missing MG-ADL, QMG, and MG-QOL15 Individual Item Scores  
In case any individual item scores in MG-ADL, QMG, and MG-QOL15 are missing, the total 
score will be imputed with the following method.  
• 
For any scale, any patient at any timepoint, if the score is missing for 3 or more items, the 
total score for the scale will not be imputed and considered as missing in the analysis.     
• 
If an individual item in any scale for the same patient is missing 3 or more times, the total 
scale score for those timepoints will not be imputed and will be considered as missing in 
the analysis 
• 
Otherwise, for each patient, each missing item score, the missing item score will be 
imputed as the mean of the nonmissing scores of the same item in the timepoints 
immediately before and immediately after the missing score. If there is no data available 
after the timepoint, then the score from the previous timepoint will be carried forward. 
Baseline or screening data can be considered in this algorithm. The calculated mean score 
will be rounded to the nearest integer. The total score of the scale will be recalculated 
from the imputed scores.   
 


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7.3 
Missing MG-ADL and QMG total scores  
MG-ADL and QMG total scores can be missing due to several reasons:  
• 
Patient discontinuation due to AEs, compliance, lack of efficacy, voluntary withdrawal. 
This missing data pattern will be considered Missing Not At Random (MNAR) 
• 
Inability to assess some items (see Section 7.2), This missing data pattern will be 
considered MNAR 
• 
Inability to perform the assessment due to COVID-19 pandemic related operational 
challenges. These missing data will be considered as Missing Completely At Random 
(MCAR) 
Because of mixed missing data patterns, the efficacy analysis will be performed using 
Multiple Imputation Markov Chain Monte Carlo (MCMC) method. The details are provided 
in Section 10. 
8 
DESCRIPTION OF STATISTICAL ANALYSES 
8.1 
General Principles 
Unless otherwise noted, data will be summarized in tabular format by treatment group. All 
study data documented on the case report forms (CRFs) will be included in the study data 
listings.  
All output will be incorporated into Microsoft rtf or Excel files, or Adobe Acrobat portable 
document format (PDF) files, sorted and labeled according to the International Council for 
Harmonisation (ICH) recommendations, and formatted to the appropriate page size(s). 
All data listings that contain an evaluation date will contain a relative study day (Study Day).  
Pre-treatment and on-treatment study days are numbered relative to the day of the first dose 
of study medication, which is designated as Day 1; the preceding day is Day -1, and the day 
before that is Day -2, etc.  
Statistical tests will be two-sided, with a type 1 error rate of 5%, unless otherwise stated (e.g. 
one-sided test for the dose response analyses).  All confidence intervals (if constructed) will 
be constructed at the 95% confidence level. Any inferential statistical tests conducted in this 
study are considered exploratory in nature; therefore, no p-value adjustments for multiplicity 
analyses will be made. 
Tabulations will be produced for appropriate demographic, baseline, efficacy, PK, and safety 
parameters.  Summary (i.e. descriptive) statistics will include number of patients, mean, 
standard deviation, median, range (minimum, maximum) values and, where appropriate, 
coefficient of variation (CV%) for continuous variables and frequencies, and percentages for 
categorical variables.  Time-to-event analyses will be summarized using Kaplan-Meier 
survival analysis and graphs for the estimated median time. 
Missing or invalid data will be generally treated as missing, not imputed, unless otherwise 
stated (see Section 7).  


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8.2 
Patient Enrollment, Disposition, Protocol Deviations  
Patient disposition will be tabulated and will include: 
• 
Number enrolled 
• 
Number of patients in analysis populations (ITT, Safety, and PP)  
• 
Number completing the study treatment and the primary reason for treatment 
discontinuation 
• 
Number completing the study and the primary reason for study discontinuation 
 
A by-patient data listing of study completion information, including the reason for study 
withdrawal, will be presented. 
A protocol deviation is any noncompliance with the clinical trial protocol or Good Clinical 
Practice (GCP). The noncompliance may be either on the part of the patient, the investigator, 
or the study site staff. Protocol deviations will be identified and documented by 
Momenta/designee study monitors/project manager based on reviews of data listings prior to 
database lock.  
The Sponsor or designee will be responsible for producing the final protocol deviation file 
(formatted as a Microsoft Excel file), in collaboration with the data monitoring group as 
applicable; this file will include a description of the protocol deviation.   
All protocol deviations will be presented in a data listing. 
8.3 
Demographic, Baseline Characteristics, and Medical History 
Demographics, baseline characteristics, and medical history will be summarized and 
presented overall and by treatment group for the ITT and Safety Populations. Age, height, 
weight, body mass index (BMI) and baseline MG-ADL, QMG, MG-QoL15r scores will be 
summarized using descriptive statistics (number of patients, mean, standard deviation, 
median, minimum, and maximum). 
The number and percentage of patients in each age, sex, race and ethnicity category, baseline 
Myasthenia Gravis Foundation of America (MGFA) classification, and randomization 
stratum will also be presented. No formal statistical comparisons will be performed. 
MG Disease history will include time since diagnosis, time since symptom onset, number of 
MG crises, and number of past episodes of clinical deterioration which will be summarized 
using descriptive statistics. The antibody status will be presented using the counts and 
percentages. 
Medical history will be coded using MedDRA and will be summarized by treatment group. 
All demographic, baseline, and medical history data, including disease history, previous MG 
medications/therapies, and pregnancy test results will be provided in data listings. 


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8.4 
Efficacy, Pharmacokinetic and Pharmacodynamic Analyses 
8.4.1 
Efficacy and Pharmacodynamic Analyses 
Efficacy analyses will be conducted using the ITT population in the final analysis, and the 
mITT population in the interim analysis. Analysis of Primary and Key Secondary endpoints 
will be repeated for the PP Population and anti-AChR positive patients. 
8.4.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline to Day 57 in the total MG-ADL score 
for each treatment group compared with placebo. 
The primary efficacy endpoint will be evaluated via dose-response analyses, as well as 
mixed-effects model repeated measures (MMRM) analyses, using data at Days 15, 29, 43, 
and 57.  Dose-response analyses will include one-sided tests of linear trend and rank-based 
association.  Models of MG-ADL Day 57 change score versus dose will be explored.  
MMRM analyses will include variables for baseline MG-ADL score, treatment-by-study 
week interaction, and autoantibody type, with variance-covariance structure assumed as 
compound symmetry.  Covariates such as corticosteroids dose, use of immunosuppressants, 
and duration since MG diagnosis may be added to the model, and different variance-
covariance structures may be explored. For MMRM analyses, two-sided tests with type I 
error rate of 5% are used. 
8.4.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints and their corresponding analysis methods are included in 
Table 2. 


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Table 2  Secondary Efficacy Endpoints 
Endpoints 
Analysis Methods 
Total MG-ADL score change from Baseline and difference from placebo 
in relationship to total serum IgG percent of Baseline 
 
Total MG-ADL score change from Baseline and difference from placebo 
during the study as a response to percent change in total serum IgG 
(patients with positive anti-AChR antibodies only) 
 
Total QMG score change from Baseline and difference from placebo in 
relationship to total serum IgG percent of Baseline 
 
Total QMG score change from Baseline and difference from placebo 
during the study as a response to percent change in total serum IgG 
(patients with positive anti-AChR antibodies only) 
Analysis will be described in a 
separate analysis plan. 
Responder analysis:  number of patients with a 2-, 3-, 4-, 5-, 6-, 7-, or 
≥8-point improvement in total MG-ADL score from Baseline to Day 57 
• Responder analysis: number of patients with a 3-, 4-, 5-, 6-, 7-, or 
≥8-point improvement in total QMG score over time after the last 
dose 
Fisher’s exact test comparing 
each active treatment group vs. 
placebo group 
• Change in total QMG score from Baseline to Day 57 
• Change in total MG-QoL15r score from Baseline to Day 57 
• Change in total serum IgG from Baseline to Day 57 
MMRM (same as the primary 
endpoint) 
• Change in total MG-ADL, QMG, and MG-QoL15r scores over time 
after the last dose 
• Change in total serum IgG over time after the last dose 
MMRM (same as the primary 
endpoint) 
• Shift in MGFA classification from Baseline to Day 57 
• Shift in MGFA classification over time after the last dose 
CMH 
Abbreviations: AChR = Acetylcholine Receptor; IgG = Immunoglobulin G; MG-ADL = Myasthenia 
Gravis - Activities of Daily Living; MGFA = Myasthenia Gravis Foundation of America; MMRM = 
Mixed-effects Model Repeated Measures; Myasthenia Gravis Quality of Life - 15 Scale; QMG = 
Quantitative Myasthenia Gravis. 
 
8.4.2 
Exploratory Efficacy and Pharmacodynamic Endpoints 
The exploratory efficacy and PD endpoints and their corresponding analysis methods are 
included in Table 3. 


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Table 3  Exploratory Efficacy and PD Endpoints 
Endpoints 
Analysis Methods 
• 
Change in serum concentration of IgG1, IgG2, 
IgG3, IgG4, IgA, IgM, and IgE over time 
Descriptive statistics only  
• 
Change in gMG-related serum autoantibody 
titers over time 
Descriptive statistics only  
• 
Potency and other characteristics of pathogenic 
MG antibodies may be assayed and possible 
relationship with clinical status may be explored 
Analysis will be performed when the data is 
available 
• 
The incidence of ADA and nADA 
seroconversion over time 
Descriptive statistics only  
• 
Need for increase (rescue) in glucocorticosteroid 
use before Day 57 and before Day 113 
Fisher’s exact test 
• 
Need for rescue therapy before Day 57 and 
before Day 113 
Fisher’s exact test 
• 
Number of patients with clinical deterioration 
before Day 57 and before Day 113 
Fisher’s exact test 
• 
Number of episodes of myasthenic exacerbation 
(hospitalizations, ICU admissions, and length of 
stay) 
CMH 
• 
Number of patients with a durable response, 
defined as ≥4 consecutive weeks with 
improvement ≥2 on MG-ADL 
• 
Number of patients with a durable response, 
defined as ≥4 consecutive weeks with 
improvement ≥3 on QMG 
Fisher’s exact test 
• 
Duration of response, defined as number of 
consecutive weeks that the patient has an 
improvement ≥2 on MG-ADL 
• 
Duration of response, defined as number of 
consecutive weeks that the patient has an 
improvement ≥3 on QMG 
Descriptive statistics only 
• 
Number of patients with change in MGFA 
classification status at Day 57 and over time 
CMH 
• 
A model-based analysis of MG-ADL score 
change from Baseline, change from placebo in 
relationship to anti-AChR titer, for patients 
positive for anti-AChR antibodies only  
Analysis will be described in a separate analysis 
plan. 


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Table 3  Exploratory Efficacy and PD Endpoints 
Endpoints 
Analysis Methods 
• 
A simultaneous model of all score-based 
measurements (QMG, MG-ADL) over time by 
IgG change from Baseline 
Analysis will be described in a separate analysis 
plan. 
• 
Proportion of patients with minimal 
manifestations, and change in status at Day 57 
and Day 113 per MGFA-PIS 
This analysis will not be performed as the data was 
not collected as planned 
• 
Time to response defined as time from first 
infusion to the first time with improvement 
≥2 on MG-ADL 
• 
Time to maximum improvement in MG-ADL 
• 
Time from maximum improvement in MG-ADL 
to rebound 
• 
Time to response defined as time from first 
infusion to the first time with improvement 
≥3 on QMG 
• 
Time to maximum improvement in QMG 
Descriptive statistics 
Abbreviations: AChR = Acetylcholine Receptor; ADA = Antidrug Antibodies; CMH = Cochran–Mantel–
Haenszel ; gMG = Generalized Myasthenia Gravis; ICU = Intensive Care Unit; IgG = Immunoglobulin G; 
MG = Myasthenia Gravis; MG-ADL = Myasthenia Gravis - Activities of Daily Living; MGFA = 
Myasthenia Gravis Foundation of America; MGFA-PIS = Myasthenia Gravis Foundation of America Post-
intervention Status; MMRM = Mixed-effects Model Repeated Measures; Myasthenia Gravis Quality of 
Life - 15 Scale; nADA = Neutralizing Antidrug Antibodies; QMG = Quantitative Myasthenia Gravis. 
 
8.4.3 
Pharmacokinetic (PK) Analysis 
Plasma concentrations of M281 will be summarized by treatment groups and nominal time 
point using descriptive statistics (number of patients, number of samples above the limit of 
quantification, arithmetic mean, standard deviation, coefficients of variation, geometric 
mean, geometric coefficient of variation, median, minimum, and maximum).  No PK 
parameters will be calculated. 
8.5 
Safety Analysis 
Safety analyses will be conducted using the safety population. No inferential statistical tests 
will be done for the safety endpoints. 
8.5.1 
Adverse Events  
Adverse Events will be coded using the latest MedDRA dictionary and displayed in tables 
and listings using System Organ Class and Preferred Term. Severity of AEs was determined 
by study Investigators using CTCAE v5.0 criteria. 


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Adverse events will be summarized for those events that are considered treatment-emergent, 
where treatment-emergent is defined per protocol as any AE occurring during or after the 
initiation of the first infusion of study drug. 
The number and percentage of patients with any treatment-emergent adverse event (TEAE), 
further identified by maximum severity, with any TEAE assessed by the Investigator as 
related to study drug, with any TEAE with a CTCAE severity Grade ≥ 3, with any treatment-
emergent SAE, with any treatment-related treatment-emergent SAE, with any TEAE leading 
to discontinuation of study drug, with any TEAE leading to death, and with any AE of 
Special Interest will be presented.  In these tabulations, each patient will contribute only once 
(i.e., the maximum severity and the strongest relationship), regardless of the number of 
episodes. AEs with missing relationship will be considered “Related” to study treatment. 
Additional summary tables by System Organ Class and Preferred Term that include all 
TEAEs, TEAEs assessed by the Investigator as related to treatment, treatment-emergent 
SAEs, SAEs assessed by the Investigator as related to treatment, TEAEs by CTCAE severity 
grade, TEAEs with a CTCAE severity Grade ≥ 3, and AEs of Special Interest. TEAEs, sorted 
by Preferred Term in descending order of incidence in the overall safety population will be 
also be presented. 
All AEs occurring on-study will be listed in a patient data listing. By-patient listings will also 
be provided for the following: AEs leading to patient death, SAEs, and AEs leading to 
discontinuation of treatment.  
8.5.2 
Study Drug Exposure and Dose Modifications 
Study drug exposure will be determined by duration and total volume administered and will 
be summarized by treatment group using descriptive statistics.   
Duration of study drug exposure will be calculated by the number of days patients were 
administered study drug, as determined below.   
Duration of Study Drug Exposure = (Date of last dose – Date of first dose) +1 
Study drug administration data for each patient will also be presented in a data listing.  
8.5.3 
Laboratory Tests  
Safety laboratory tests that include hematology, chemistry, coagulation function, and 
urinalysis tests will be evaluated at all scheduled visits.   
Laboratory data will be summarized by NCI-CTCAE v5.0 toxicity grade when possible. The 
CTCAE grade will be calculated for all applicable analytes as described in Table 4 in 
Section 12. 
Clinical laboratory values will be expressed in International System of Units (SI). 


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The actual value and change from baseline to each on-study evaluation will be summarized 
for each clinical laboratory parameter. In the event of repeat values, the worst value per study 
visit will be used.  
Shift tables will be produced that summarize the changes from baseline to worst value, using 
CTCAE toxicity grades for relevant laboratory parameters.    
All laboratory data will be provided in data listings. A subset listing will be presented for 
laboratory results with CTCAE severity ≥ Grade 3.   
8.5.4 
Vital Signs and Weight 
Vital signs (temperature, systolic blood pressure and diastolic blood pressure, and pulse rate) 
will be collected at all scheduled visits with time points of pre-infusion and 30 minutes post-
infusion for the first 3 infusions, and pre-infusion only for the following infusions. 
Vital sign variables and weight will be summarized using descriptive statistics by treatment 
group.   
The actual value and change from baseline to each scheduled visit/time point will be 
summarized using descriptive statistics. Vital sign measurements will be presented for each 
patient in a data listing. 
8.5.5 
Physical Examinations  
Full physical examinations are performed at Screening, Baseline, and Day 113, and a focused 
physical examination at all other visits. A shift table from baseline to the worse post-baseline 
value (abnormal being the worst) will be provided for each body system by treatment group. 
Physical examination results will also be presented in a data listing.   
8.5.6 
Electrocardiograms (ECG) 
Electrocardiograms (ECG) will be collected at all scheduled visits. On infusion days, ECG 
will be assessed immediately prior to the beginning of the infusion. For the first infusion, a 
single 12-lead ECG will also be conducted within 10 minutes after the infusion has been 
completed. 
Electrocardiogram variables measured on a quantitative scale (PR, RR, QRS, QT, QTcB, and 
QTcF) will be summarized using descriptive statistics for the actual value and change from 
baseline to each visit/timepoint by treatment group.  
In addition, a shift table will be provided for interpretation from baseline to the worst post-
baseline value with the number and percentage of patients.  
All ECG tests including overall ECG interpretation will be included in by-patient listings for 
further medical review. 


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8.5.7 
Columbia-Suicide Severity Rating Scales (C-SSRS) 
Post-baseline C-SSRS responses to suicidal ideation and suicidal behavior questions (yes/no) 
will be summarized by treatment group and by visit. A shift table with categories of ‘No 
suicidal ideation or behavior’, ‘Suicidal ideation’, and ‘Suicidal behavior’ will be utilized to 
summarize the change from baseline to worst post-baseline value (suicidal behavior being the 
worst value). 
All C-SSRS data will be presented in by-patient listings. 
8.5.8 
Myasthenia Gravis Exacerbation 
Myasthenia gravis exacerbations were to be collected in the AE page. Myasthenia gravis 
exacerbations will be presented in a by-patient listing.  The counts of exacerbation events by 
treatment will be summarized (number of subjects with an event and number of events). 
8.5.9 
Concomitant Therapy and Procedures  
For the purpose of this analysis, concomitant medications/therapies are defined as those 
medications taken after first dose of study drug.  Specifically, for any medication that did not 
end prior to first dose or the end date is missing or the medication is ongoing, the medication 
will be considered concomitant. Prior medication/therapy is defined as any medication that 
started and ended prior to the first dose of study drug.    
These medications will be coded using World Health Organization Drug (WHODrug) 
Dictionary Version Mar2018.  The number and percentage of patients in the Safety 
population using different concomitant or prior medications will be tabulated separately by 
treatment group and summarized in a table by WHODrug anatomical class (ATC) and 
preferred drug name. These data will also be presented in patient listings.  
9 
TESTING/VALIDATION PLAN AND SOFTWARE SYSTEM 
Statistical Analysis System/Software (SAS) version 9.3 or later will be used to analyze the 
data, and create summary tables, patient data listings, and graphical representations of the 
data. All SAS programs will be validated using industry standard validation procedures. 
10 INTERIM ANALYSIS 
The interim analysis described here represents a change from the protocol specified analysis 
plan due to rapid enrollment and COVID-19 pandemic (see Section 11 for further details).  
Under the current interim analysis plan, all efficacy and safety analyses planned for the 
original final analysis, as detailed in Section 8, will be performed. All efficacy analyses will 
be performed based on the mITT population, and all safety analyses will be performed based 
on the Safety Population. 
The primary and secondary efficacy endpoints will be analyzed using Analysis of Covariance 
(ANCOVA), with the average score collected on Day 43 and Day 57 as the response 
variable, and the stratification factor as covariate. If only one of the assessments (Day 43 or 


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Day 57) is available, then that assessment will be used. For patients who took rescue 
medication, their data after the rescue medication will be disregarded in the efficacy analysis. 
Missing data will be imputed with Last Observation Carried Forward (LOCF) method and 
Multiple Imputation Markov Chain Monte Carlo (MCMC) method. Random seed number 
42365 will be used in MCMC procedure. Individual M281 treatment groups will be 
compared against placebo. Combinations of treatment arms (for example, comparing the 
combination of the highest two groups, 60 mg/kg Q2W and 30 mg/kg Q4W, against placebo) 
may also be explored. All statistical analyses will be evaluated on nominal p-value without 
adjustment of multiple comparison.  
The originally proposed MMRM method will also be performed as a sensitivity analysis. 
The efficacy analysis will be repeated for anti-AChR patients only.  
The efficacy analysis will also be repeated excluding those patients whose data was affected 
by COVID-19. 
11 STATISTICAL ANALYSIS CHANGES FROM THE PROTOCOL 
The study originally had a planned interim analysis after approximately 30 patients had 
completed the Day 57 assessments.  The results were to be used to adjust the sample size, if 
necessary, and to guide future development activities. Very rapid enrollment towards the end 
of the enrollment period led the Sponsor instead to plan to conduct the interim analysis on all 
randomized patients.  However, the COVID-19 pandemic, which halted operation in the 
study and impeded completion of study visits for many patients, made this revised plan 
infeasible and led to the implementation of the current interim analysis described in 
Section 10.   
The COVID-19 pandemic has caused significant changes to the study conduct:   
• 
Study drug administration was stopped April 17, 2020, 8 patients did not receive the final 
Day 57 dose.  
• 
Some patients missed or delayed Day 57, Day 85, or Day 113 visits. 
• 
Some patients had remote visits and as a result MG-ADL was assessed remotely and 
QMG was not assessed. 
• 
Data collection process was disrupted. Data entry and source data verification were 
delayed. 
As a result of these events, the following changes to the planned analysis will be 
implemented in the final and interim analyses. All changes are documented and finalized 
before unblinding. 
11.1 Final Analysis  
The final analysis will be performed as planned in the protocol, with additional missing data 
handling being needed in the primary and secondary efficacy analysis. See Section 7 for 
details.  


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11.2 Interim Analysis  
Unblinding: The interim analysis will be performed and the unblinded aggregated results 
will be disclosed. Individual patient level data will remain blinded to everyone except the 
unblinded team. The unblinding process is described in a separate Unblinding Plan, which is 
also finalized before unblinding.   
Analysis Population: The interim analysis will be based on the mITT population, which 
consists of all randomized patients who had post-baseline efficacy assessments and are 
suitable for analysis. A patient is considered suitable for analysis if the patient data from the 
following list of selected CRFs has been entered and either source verified or remotely 
monitored.  
• 
Demographics form;  
• 
Baseline MG history form;  
• 
Randomization form;  
• 
All MG-ADL and QMG forms up to D43 or the last dosing visit;  
• 
Study drug administration form;  
• 
Central lab samples related to clinical safety and IgG;  
• 
End of treatment form;  
The list of patients suitable for analysis will be established before unblinding. 
The details are described and finalized in the Unblinding Plan. Patients excluded from the 
mITT population and the reason for exclusion will be finalized before unblinding and 
tabulated.  
Scope of Analysis: The primary and secondary efficacy endpoints (MG-ADL and QMG) 
will be regarded as reliable and representative of the entire study population. Safety, other 
efficacy endpoints, and exploratory endpoints will also be analyzed but considered 
preliminary. 
Primary Analysis Method: Details are provided in Section 10. The COVID-19 global 
pandemic has created complex missing data patterns, which may limit the suitability of the 
originally proposed MMRM method. Therefore, the primary analysis method was changed to 
ANCOVA, rules for handling of missing data were specified, and new sensitivity analyses 
were also specified. 
While the original analysis included some flexibility for fine tuning statistical models by 
including baseline covariates, the inclusion of these covariates may no longer be feasible due 
to current data availability. However, such analyses may be performed later when the rest of 
the data becomes available. 
Day 85 and Day 113 Data: Analysis of D85 and D113 data will still be performed but 
caution is required in interpretation as the data might have not been fully verified.  


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12 REFERENCE 
Table 4. CTCAE Toxicity Laboratory Grading Chart 
Panel 
Analyte 
Standard 
Unit 
Directional 
Change of Interest 
Toxicity Grades 
(CTCAE v5.0) 
Hematology 
WBC count 
109/L 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 3.0 × 109/L 
Grade 2: < 3.0 – 2.0 × 109/L 
Grade 3: < 2.0 – 1.0 × 109/L 
Grade 4: < 1.0 × 109/L 
Hematology 
ANC 
109 cells/L 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 1.5 × 109/L 
Grade 2: < 1.5 – 1.0 × 109/L 
Grade 3: < 1.0– 0.5 × 109/L 
Grade 4: < 0.5 × 109/L 
Hematology 
Lymphocyte 
count 
109cells/L 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 0.8 × 109/L 
Grade 2: < 0.8 – 0.5 × 109L 
Grade 3: < 0.5 – 0.2 × 109/L 
Grade 4: < 0.2 × 109/L 
Hematology 
Hemoglobin 
g/L 
Increase 
Grade 0: ≤ ULN 
Grade 1: > 20 g/L + ULN 
Grade 2: > 20 – 40 g/L +ULN 
Grade 3: > 40 + ULN 
Grade 4: Not defined 
 
 
g/L 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 100 g/L 
Grade 2: < 100 – 80 g/L 
Grade 3: < 80  
Grade 4: Not defined 
Hematology 
Platelet count 
109/L 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 75 × 109/L 
Grade 2: < 75 – 50 × 109/L 
Grade 3: < 50 – 25 × 109/L 
Grade 4: < 25 × 109/L 
Chemistry 
Albumin 
g/L 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 30 g/L 
Grade 2: < 30 – 20 g/L 
Grade 3: < 20 g/L 
Grade 4: Not defined 


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Table 4. CTCAE Toxicity Laboratory Grading Chart 
Panel 
Analyte 
Standard 
Unit 
Directional 
Change of Interest 
Toxicity Grades 
(CTCAE v5.0) 
Chemistry 
Alk Phos 
U/L 
Increase 
Grade 0: ≤ ULN 
Grade 1: > ULN – 2.5 × ULN 
Grade 2: > 2.5 – 5.0 × ULN 
Grade 3: > 5.0 – 20.0 × ULN 
Grade 4: > 20.0 × ULN 
Chemistry 
ALT 
U/L 
Increase 
Grade 0: ≤ ULN 
Grade 1: > ULN – 3.0 × ULN 
Grade 2: > 3.0 – 5.0 × ULN 
Grade 3: > 5.0 – 20.0 × ULN 
Grade 4: > 20.0 × ULN 
Chemistry 
AST 
U/L 
Increase 
Grade 0: ≤ ULN 
Grade 1: > ULN – 3.0 × ULN 
Grade 2: > 3.0 – 5.0 × ULN 
Grade 3: > 5.0 – 20.0 × ULN 
Grade 4: > 20.0 × ULN 
Chemistry 
Total Bilirubin 
micromol/L 
Increase 
Grade 0: ≤ ULN 
Grade 1: > ULN – 1.5 × ULN 
Grade 2: > 1.5 – 3.0 × ULN 
Grade 3: > 3.0 – 10.0 × ULN 
Grade 4: > 10.0 × ULN 
Chemistry 
Creatinine 
micromol/L 
Increase 
Grade 0: ≤ ULN 
Grade 1: > ULN – 1.5 × ULN 
Grade 2: > 1.5 – 3.0 × ULN 
Grade 3: > 3.0 – 6.0 × ULN 
Grade 4: > 6.0 × ULN 
Chemistry 
Calcium 
mmol/L 
Increase 
Grade 0: ≤ ULN 
Grade 1: > ULN – 2.9  mmol/L 
Grade 2: > 2.9 – 3.1 mmol/L 
Grade 3: > 3.1 – 3.4 mmol/L 
Grade 4: >3.4 mmol/L 
 
 
 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 2.0 mmol/L 
Grade 2: < 2.0 -1.75 mmol/L 
Grade 3: < 1.75 – 1.50 mmol/L 
Grade 4: < 1.50 mmol/L 


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Table 4. CTCAE Toxicity Laboratory Grading Chart 
Panel 
Analyte 
Standard 
Unit 
Directional 
Change of Interest 
Toxicity Grades 
(CTCAE v5.0) 
Chemistry 
Phosphorus 
mmol/L 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 0.8 mmol/L 
Grade 2: < 0.8 – 0.6 mmol/L 
Grade 3: < 0.6  – 0.3 mmol/L 
Grade 4: < 0.3 mmol 
Chemistry 
Glucose 
mmol/L 
Increase 
Grade 0: ≤ ULN 
Grade 1: > ULN – 8.9  mmol/L 
Grade 2: > 8.9 – 13.9 mmol/L 
Grade 3: > 13.9 – 27.8 mmol/L 
Grade 4: >27.8 mmol/L 
 
 
 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 3.0 mmol/L 
Grade 2: < 3.0 -2.2 mmol/L 
Grade 3: < 2.2 – 1.7 mmol/L 
Grade 4: < 1.7 mmol/L 
Chemistry 
Uric Acid 
umol/L 
Increase 
Grade 0: ≤ ULN 
Grade 1: >ULN – 590 umol/L 
Grade 2: > 590 umol/L 
Grade 3: undefined 
Grade 4: undefined 
Chemistry 
Sodium 
mmol/L 
Increase 
Grade 0: ≤ ULN 
Grade 1: > ULN – 150 mmol/L 
Grade 2: > 150 – 155 mmol/L 
Grade 3: > 155 – 160 mmol/L 
Grade 4: > 160 mmol/L 
 
 
 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 130 mmol/L 
Grade 2: Not defined 
Grade 3: < 130 – 120 mmol/L 
Grade 4: < 120 mmol/L 
Chemistry 
Potassium 
mmol/L 
Increase 
Grade 0: ≤ ULN 
Grade 1: > ULN – 5.5 mmol/L 
Grade 2: > 5.5 – 6.0 mmol/L 
Grade 3: > 6.0 – 7.0 mmol/L 
Grade 4: > 7.0 mmol/L 


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Table 4. CTCAE Toxicity Laboratory Grading Chart 
Panel 
Analyte 
Standard 
Unit 
Directional 
Change of Interest 
Toxicity Grades 
(CTCAE v5.0) 
 
 
 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 3.0 mmol/L 
Grade 2: Not defined 
Grade 3: < 3.0 – 2.5 mmol/L 
Grade 4: < 2.5 mmol/L 
Chemistry 
Magnesium 
mmol/L 
Increase 
Grade 0: ≤ ULN 
Grade 1: > ULN – 1.23 mmol/L 
Grade 2: Not defined 
Grade 3: > 1.23 – 3.30 mmol/L 
Grade 4: > 3.30 mmol/L 
 
 
 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 0.5 mmol/L 
Grade 2: < 0.5 – 0.4 mmol/L 
Grade 3: < 0.4 – 0.3 mmol/L 
Grade 4: < 0.3 mmol/L 
Urinalysis 
pH 
 
Decrease 
Grade 0: ≥ LLN 
Grade 1: < LLN – 7.3 
Grade 2: Not defined 
Grade 3: < 7.3 
Grade 4: Not defined 
 
 


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13 SCHEDULE OF STUDY ASSESSMENTS 
Study Day  
Screening Perioda 
-Day -28 to Day -1 
Treatment Period 
Follow-Up Period  
(No Study Treatment) 
Baseline 
(Day 1)b 
Day 15b 
Day 29b 
Day 43b 
Day 57b 
Day 85 
Day 113 
Visit Window (± Days) 
-- 
-- 
± 1  
± 3  
± 3  
± 3  
± 7  
± 7  
Informed Consent 
X 
 
 
 
 
 
 
 
Site Visit 
X 
X 
X 
X 
X 
X 
X 
X 
Med History and Demographics 
X 
 
 
 
 
 
 
 
Vital Signsc  
X 
X 
X 
X 
X 
X 
X 
X 
Weight  
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Physical Examinationd 
Xd 
Xd 
X  
X  
X  
X  
X  
Xd  
12-Lead ECGe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe  
X 
X  
C-SSRS 
X 
X 
 
X 
 
X 
X 
 
Efficacy Assessmentsf 
 
MG-ADL 
X 
X 
X 
X 
X 
X 
X 
X 
QMG 
X 
X 
X 
X 
X 
X 
X 
X 
MG-QoL15r 
 
X 
X 
X 
X 
X 
X 
X 
MGFA Clinical Classification 
X 
X 
 
 
 
X 
 
X 
MGFA-PIS – selected elements 
 
 
 
 
 
X 
 
X 
Pregnancy test (women of 
childbearing potential, and 
menopausal females if FSH is not 
elevated)g 
X  
X 
  
  
 
  
 
 


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Study Day  
Screening Perioda 
-Day -28 to Day -1 
Treatment Period 
Follow-Up Period  
(No Study Treatment) 
Baseline 
(Day 1)b 
Day 15b 
Day 29b 
Day 43b 
Day 57b 
Day 85 
Day 113 
Visit Window (± Days) 
-- 
-- 
± 1  
± 3  
± 3  
± 3  
± 7  
± 7  
Blood sample for FSH 
(menopausal females only)g 
X 
 
 
 
 
 
 
 
QuantiFERON-Gold TB Testh 
X 
 
 
 
 
 
 
 
Blood sample for HIV-1 & 2, 
Hepatitis B (HBV core antibody), 
Hepatitis C 
X 
 
 
 
 
 
 
 
Blood sample for anti-AChR and 
anti-MuSK autoantibody levelsi  
Xi 
X 
X 
X 
X 
X 
X 
X 
Blood sample for exploratory 
biomarkers 
-- 
X 
 
X 
 
X 
X 
X 
Safety Laboratory Testingj 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for total and 
neutralizing anti- M281 
antibodies   
 
X 
X 
X 
X 
X 
X 
X 
Blood sample for levels of total 
IgG and IgG subclasses 
X 
X 
X 
X 
X 
X 
X 
Xk 
Blood sample for IgA, IgM, and 
IgE levels 
 
X 
 
X 
 
X 
 
X 
Confirm Patient Eligibility and 
Randomizel 
 
X 
 
 
 
 
 
 
Serum PKm 
 
Xm 
Xm 
Xm 
Xm 
Xm 
X 
 
Study Drug Infusionb 
 
X 
X 
X 
X 
X 
 
 
AEs / Prior and Concomitant 
Medications/Rescue Therapyn  
Monitored throughout the study 


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Study Day  
Screening Perioda 
-Day -28 to Day -1 
Treatment Period 
Follow-Up Period  
(No Study Treatment) 
Baseline 
(Day 1)b 
Day 15b 
Day 29b 
Day 43b 
Day 57b 
Day 85 
Day 113 
Visit Window (± Days) 
-- 
-- 
± 1  
± 3  
± 3  
± 3  
± 7  
± 7  
Abbreviations:  AE = adverse event; anti-AChR= anti-acetylcholine receptor autoantibody; anti-MuSK = anti-muscle-specific kinase autoantibody; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HBV= hepatitis B virus; HCV = 
hepatitis C virus; HIV= human immunodeficiency virus; Ig = immunoglobulin; MG = myasthenia gravis; MG-ADL= Myasthenia Gravis – Activities of 
Daily Living; MGFA-PIS = Myasthenia Gravis Foundation of America Post-intervention status; MG-QoL15r= revised Myasthenia Gravis Quality of Life – 
15 Scale; PD = pharmacodynamic; PK = pharmacokinetics; QMG = Quantitative Myasthenia Gravis scale; TB= tuberculosis. 
a 
Patients who fail to meet all the entry criteria may be retested as noted in Section 4 of the Study Protocol and in the study manual, and/or rescreened after a 
period of at least 4 weeks. Details for rescreening procedures will be provided in the study manual.  
b 
Infusion to be administered as specified in the Infusion Manual. Patients will be observed for safety after the first 3 infusions per the Infusion Manual; if no 
clinically relevant AEs related to the infusion are observed in these first 3 infusions, the post-infusion observation period is no longer needed.  
c 
Vital signs (temperature, recumbent systolic blood pressure and diastolic blood pressure, and pulse rate) will be measured immediately prior to the start of 
each infusion.  For the first infusion, vital signs will also be measured after completion of the infusion as specified in the Infusion Manual. 
d 
Full physical examinations to be performed at Screening, Baseline, and Day 113, and a focused physical examination at all other visits.  Focused physical 
examinations should determine if there has been any change in neurologic function, upper respiratory tract (ears, nose, throat, and sinuses), eyes and lungs, 
abdomen, or skin. 
e 
12-lead ECGs will be conducted at every scheduled visit. On infusion days, the ECG will be taken immediately prior to the beginning of the infusion. For 
the first infusion, a single 12-lead ECG will also be conducted within 10 minutes after the infusion has been completed.  
f 
The patient’s acetylcholinesterase inhibitor dose must be withheld for approximately 10 hours or longer prior to performing the MG assessments (including 
those conducted during the Screening Period to determine patient eligibility).  All MG assessments must be done starting at approximately the same time of 
day as performed at Screening, and prior to study drug administration on infusion days.  The applicable MG assessments must be performed in the order 
shown in this Schedule of Study Assessments.  Patients may take their dose of acetylcholinesterase inhibitor once the MG assessments are completed.  
g 
Women of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to infusion of 
study drug.  Menopausal women must have an elevated follicle-stimulating hormone level (FSH) at Screening; if the FSH is not elevated, menopausal 
women must have a negative serum pregnancy test to be eligible, and a negative urine pregnancy test on Day 1 prior to infusion of study drug.  
h 
Patients with a positive QuantiFERON®-TB Gold test result are excluded from this study.  Patients with an equivocal QuantiFERON®-TB Gold test result at 
Screening will be allowed one retest; if the retest is negative, the patient is eligible.  If the retest is positive or equivocal, the patient is excluded from this 
study. 
i 
If the patient receives the first dose of M281 before the Screening results are available and the results are subsequently negative, the patient may be replaced. 
j 
Includes chemistry, hematology, coagulation function (including prothrombin time), and urinalysis. 


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k 
For patients who do not enroll in the open-label extension study, if the total serum IgG is not at least 600 mg/dL at this visit, the investigator must continue 
to regularly follow the patient until total serum IgG is 600 mg/dL or higher. 
l 
Confirmation of patient eligibility on Day 1 is based on the Baseline QMG and MG-ADL scores, Baseline C-SSRS, review of medications/therapies, and 
negative urine pregnancy test (performed at the study center) for women of childbearing potential before first administration of study drug.  Menopausal 
women must have an elevated FSH or negative serum pregnancy test at Screening and negative urine pregnancy test on Day 1 before first administration of 
study drug to be eligible.  
m 
On infusion days, blood samples for measurement of M281 serum concentrations will be taken immediately prior to the beginning of the infusion. After the 
first infusion and after the infusion on Day 57, blood samples for measurement of M281 serum concentrations will also be taken post-infusion (as specified 
in the Infusion Manual).  
n 
All medications/therapies to be collected from the time of informed consent throughout the patient’s participation in the study.  Reporting of AEs will start 
following the patient signing the informed consent form.  Administration of rescue therapy for worsening of MG-related symptoms should also be recorded.