A Randomized, Placebo-control, Parallel Group Study to Evaluate the Effect of Amifampridine Phosphate in Patients With MuSK Antibody Positive Myasthenia Gravis, and a Sample of AChR Antibody Positive Myasthenia Gravis Patients
Phase: PHASE3
Conditions: Myasthenia Gravis, Generalized
Sponsor: Catalyst Pharmaceuticals, Inc.

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CLINICAL STUDY PROTOCOL 
Study Title: 
A Randomized, Placebo-Controlled, Parallel Group Study to 
Evaluate the Effect of Amifampridine Phosphate in Patients 
with MuSK Antibody Positive Myasthenia Gravis, and a 
Sample of AChR Antibody Positive Myasthenia Gravis Patients 
Protocol Number: 
MSK-002 
Investigational Product: Amifampridine phosphate (3,4-diaminopyridine phosphate) 
IND/EUDRACT 
Number: 
106263 / 2015-03127-62 
Indication: 
Musk Antibody Positive Myasthenia Gravis 
External Support: 
Catalyst Pharmaceuticals, Inc. 
Development Phase: 
Phase 3 
Medical Officer: 
Gary Ingenito, MD, PhD 
Study Design: 
Double-blind, Placebo-controlled, Randomized, Parallel Group, 
Withdrawal 
Dose: 
30-80 mg total daily dose or placebo equivalent
Patient Population: 
Patients with MuSK antibody positive Myasthenia Gravis and a 
sample of patients with AChR antibody positive Myasthenia 
Gravis 
Date of Protocol: 
June 27, 2017 
Property of Catalyst Pharmaceuticals, Inc. 
CONFIDENTIAL 
May not be divulged, published, or otherwise disclosed to others without prior written 
approval from Catalyst Pharmaceuticals, Inc. 
This study will be conducted according to the principles of Good Clinical Practice as 
described in the U.S. Code of Regulations and the International Conference on 
Harmonisation Guidelines, including the archiving of essential documents. 

 
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PROCEDURES IN CASE OF AN EMERGENCY 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Medical Monitor 
Gary Ingenito, MD, PhD 
Chief Medical Officer 
Catalyst Pharmaceuticals, Inc. 
355 Alhambra Circle, Suite 1250 
Coral Gables, FL 33134 
Tel: 305-420-3200, ext. 123 
Email: 
gingenito@catalystpharma.com 
Coordinating Investigator 
Renato Mantegazza, MD 
Director Department of 
Neuroimmunology and 
Neuromuscular Diseases 
 
Carlo Besta Neurological 
Institute 
 
Via Celoria 11-201332 Milan, 
Italy 
Clinical Project Lead 
Adriana Manari 
Catalyst Pharmaceuticals, Inc. 
355 Alhambra Circle, Suite 1250 
Coral Gables, FL 33134 
Tel: 305-420-3217 
Email: 
amanari@catalystpharma.com 
Safety Reporting 
 
Jonathan Rubine, MD 
Associate Medical Director 
Catalyst Pharmaceuticals, Inc. 
Tel: 305-420-3233 
Email: 
jrubine@catalystpharma.com 
 

 
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2 
SYNOPSIS 
TITLE OF STUDY: 
A Randomized, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Efficacy of 
Amifampridine Phosphate in Patients with MuSK Antibody Positive Myasthenia Gravis, and a 
Sample of AChR Antibody Positive Myasthenia Gravis Patients 
PROTOCOL NUMBER: 
MSK-002 
STUDY SITE:  
Up to 20 sites in USA, Europe, and Canada 
PHASE OF DEVELOPMENT: 
Phase 3 
STUDY RATIONALE: 
The purpose of this study is to evaluate the safety, tolerability, and efficacy of amifampridine 
phosphate in patients with MuSK antibody positive myasthenia gravis (MuSK-MG), and a sample 
of AChR antibody positive Myasthenia Gravis (AChR-MG) patients.  
OBJECTIVES: 
Primary 
• 
To characterize the overall safety and tolerability of amifampridine phosphate compared with 
placebo in patients with MuSK-MG; and 
• 
To assess the clinical efficacy of amifampridine phosphate compared with placebo in patients 
with MuSK-MG based on change in Myasthenia Gravis Activities of Daily Living Score 
(MG-ADL). 
Secondary 
• 
To assess the clinical efficacy of amifampridine phosphate compared with placebo using the 
Quantitative Myasthenia Gravis (QMG) score. 
• 
To assess the safety and efficacy of amifampridine phosphate compared with placebo in a 
sample of patients with AChR-MG (N equal to 10). 
STUDY DESIGN AND PLAN:  
This randomized (1:1), double-blind, placebo-controlled, parallel group, outpatient study is 
designed to evaluate the safety, tolerability and efficacy of amifampridine phosphate in patients 
diagnosed with MuSK-MG. In addition, a sample of AChR-MG patients (N equal to 10) will be 
assessed for efficacy and safety of amifampridine with the same study design. If it is determined 
that 18 or more of the first 20 screened AChR-MG patients fail to meet inclusion criteria, 
additional screening for AChR-MG patients will be terminated. If the AChR-MG screening failure 
rate is lower, an additional 20 patients will be screened; overall, up to 40 AChR-MG patients may 
be screened to try and enroll 10 in the study. The study is planned to include approximately 60 
male and female MuSK-MG patients and 10 AChR-MG patients. The planned duration of 

 
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participation for each patient is at least 38 days, excluding the screening period, which can last up 
to 14 days. In addition to investigational product (amifampridine phosphate 10 mg tablets or 
matching placebo tablets), patients will continue to receive stable dose of pyridostigmine and/or 
corticosteroid therapy, but no new therapies and no change in dose is permitted during the study. 
All patients who sign an informed consent will be screened for eligibility to participate in the study, 
and those successfully completing screening will have procedures/assessments (see Table 1) 
completed during Run-in, until an optimized stable dose and frequency of amifampridine 
phosphate is established. At the end of 7 days on a stable dose, the patient must show ≥2-point 
improvement in MG-ADL score to be randomized. On Day 0 (randomization), procedures/ 
assessments (see Table 1) will be conducted to confirm eligibility for randomization, including a 
negative urine pregnancy test. 
Open-label Run-in 
Amifampridine dose will be titrated upward every 3 to 4 days, starting at 10 or 15 mg/day, at the 
discretion of the Investigator. Patients will either visit or have telephone/video contact with the site 
for each dose titration and at least one in-person site evaluation at Week 3 of the run-in period. 
When the Investigator determines that the patient has reached the maximal tolerable and 
efficacious dose, the patient should demonstrate they can remain on a stable dose and frequency for 
at least an additional 7 days.  The Open-label Run-in period may be extended if additional time is 
needed for dose titration. At the end of this period, patients must show a ≥2-point improvement in 
MG-ADL from start of Run-in, to be eligible for randomization (Day 0). 
Period 1 (Days 1-10) (+1 day) 
Patients who have successfully completed the open-label run-in and continue to meet all 
inclusion/exclusion criteria will be randomized (1:1 ratio) on Day 0 to receive either amifampridine 
tablets (10 mg as amifampridine phosphate) or placebo tablets for 10 days, beginning on Day 0 
after assessments have been performed on open-label medication. Test medication will be 
dispensed by the site pharmacist, according to the randomization schedule provided. Assessments 
will be performed on Day 10, in the clinic, as listed in Table 1.  
NUMBER OF PATIENTS PLANNED:  
Up to 60 MuSK-MG patients to complete the study, and a sample of 10 AChR-MG patients will be 
sought. 
CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all the following inclusion criteria: 
1. Willing and able to provide written informed consent after the nature of the study has been 
explained and before the start of any research-related procedures. 
2. Male or female ≥18 years of age. 
3. Positive serologic test for anti-MuSK antibodies or anti-AChR antibodies as confirmed at 
Screening or by previous antibody test, with report available. 

 
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4. Confirmatory electromyography (EMG) or EMG report. 
5. Myasthenia Gravis Foundation of America (MGFA) Class II to IV at Screening. 
6. MG-ADL score of ≥6 at Screening, with more than 50% of this score attributed to non-ocular 
items. 
7. Patients receiving steroids and/or pyridostigmine should not have any modification of drug 
regimen during the month before Screening. 
8. Female patients of childbearing potential must have a negative pregnancy test (serum human 
chorionic gonadotropin [HCG] at screening); and must practice an effective, reliable 
contraceptive regimen during the study and for up to 30 days following discontinuation of 
treatment. 
9. Ability to participate in the study based on overall health of the patient and disease prognosis, 
as applicable, in the opinion of the Investigator; and able to comply with all requirements of 
the protocol, including completion of study questionnaires. 
Individuals who meet any of the following Exclusion Criteria are not eligible to participate 
in the study: 
1. Epilepsy and currently on medication. 
2. Concomitant use of medicinal products with a known potential to cause QTc 
prolongation. 
3. Patients with long QT syndromes. 
4. History of thymectomy within 12 months before Screening. 
5. An electrocardiogram (ECG) within 6 months before starting treatment that 
shows clinically significant abnormalities, in the opinion of the Investigator. 
6. Breastfeeding or pregnant at Screening or planning to become pregnant at any 
time during the study.  
7. Patients receiving immunomodulatory treatment (e.g. plasma exchange [PE], 
therapeutic plasma exchange [TPE], intravenous immunoglobulin G [IVIG]) 
should not have any treatment in the previous 4 weeks prior to Randomization 
or at any time during the study. 
8. Use of rituximab or other similar biologic medications for immunomodulation 
within 6 months prior to Screening. 
9. Treatment with an investigational drug (other than amifampridine), device, or 
biological agent within 60 days prior to Screening or while participating in this 
study. 
10. Any medical condition that, in the opinion of the Investigator, might interfere 
with the patient’s participation in the study, poses an added risk for the patient, 
or confound the assessment of the patient. 
11. History of drug allergy to any pyridine-containing substances or any 
amifampridine excipient(s). 

 
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INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE, AND REGIMEN:  
The investigational product (IP) is amifampridine tablets 10 mg, and it will be provided in round, 
white-scored tablets, containing amifampridine phosphate formulated to be the equivalent of 10 mg 
amifampridine base per tablet. Dosing is up to 80 mg/day in 3 or 4 divided doses. 
 
The investigational product, and matching placebo, will be provided by Catalyst Pharmaceuticals, 
Inc., 355 Alhambra Circle, Suite 1250, Coral Gables, Florida, 33134, United States. 
REFERENCE THERAPY, DOSE, ROUTE, AND REGIMEN:  
The reference therapy is a placebo, provided as tablets indistinguishable from amifampridine 
tablets. The placebo will be administered consistent with the dose and dose regimen of the 
investigational product (amifampridine). 
DURATION OF TREATMENT: 
At least 38 days (excluding up to 14-day screening period). The Run-in phase requires that the 
patient must be on a stable dose and dose regimen for the last week of Run-in. 
CRITERIA FOR EVALUATION: 
Safety: 
Safety will be assessed by the incidence of treatment-emergent adverse events (TEAEs), including 
serious adverse events (SAEs). Vital signs, 12-lead ECGs, clinical laboratory tests, physical 
examination, and concomitant medications will also be evaluated.  
Efficacy:  
Efficacy will be assessed by comparison of amifampridine versus placebo for: 
Primary - 
• 
Change from baseline in MG-ADL total score; 
Secondary - 
• 
Change from baseline in QMG total score. 
• 
Proportion of patients with at least a 2-point change from baseline in the MG-ADL score. 
• 
Proportion of patients with at least a 3-point change from baseline in the QMG total score. 
STATISTICAL METHODS: 
Sample Size Determination 
The study is powered with respect to the primary endpoint of change in MG-ADL score from 
baseline for the MuSK-MG group of subjects. The study has approximately 60% power to detect a 
2 point difference between amifampridine and placebo treatment groups for the change in MG-
ADL from baseline (Day 0).  

 
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Safety Analysis 
Safety analyses will be conducted on the safety population (i.e. all patients who receive at least 
1 dose of amifampridine or placebo). The safety analysis will be descriptive and will be presented 
on observed data only. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Only 
treatment-emergent AEs (TEAEs) will be included in the safety analysis. The incidence of TEAEs 
will be summarized by system organ class, preferred term, relationship to treatment, and severity 
by treatment group.  
All other safety measures including ECGs, vital signs, laboratory tests, physical examination and 
concomitant medications data will also be summarized. 
Subgroup analyses for safety will be performed independently on the MuSK-MG and AChR-MG 
groups.  No pooled analyses are planned. 
Efficacy Analysis 
Efficacy analysis will be conducted on 2 datasets: 
• 
Full Analysis Set (FAS): This population consists of all randomized patients who receive 
at least 1 dose of IP (amifampridine or placebo) and have at least one post-treatment 
efficacy assessment. 
• 
Per Protocol (PP): This population is a subset of the FAS population, excluding patients 
with major protocol deviations. The PP population will include all patients who: 
o Have no major protocol deviations or inclusion/exclusion criteria deviations that might 
potentially affect efficacy, and 
o Patients who took at least 80% of the required treatment doses and completed both 
double-blind treatment periods. 
Primary endpoint efficacy analysis of the MuSK-MG group will be analyzed as the change in MG-
ADL from baseline (Day 0) using the Wilcoxon-Mann-Whitney Rank sum test at a two sided α of 
0.05 using the FAS population.  
The first secondary endpoint of the MuSK-MG group will be analyzed as the change in QMG from 
baseline (Day 0) using the Mann-Whitney-Wilcoxon Rank sum test at a two sided α of 0.05 using 
the FAS population. 
The next secondary endpoint of the MuSK-MG group will be analyzed as the proportion of 
subjects with a change of 2 or more points in MG-ADL score from baseline (Day 0), followed by 
proportion of subjects with a change of 3 or more points in the QMG score, using the Fischer’s 
exact test at a two sided α of 0.05 using the FAS population. 
AChR-MG subjects will only be evaluated by descriptive statistics. 
Subgroup analyses for efficacy will be performed independently on the MuSK-MG and AChR-MG 
groups.  No pooled analyses are planned. 
 

 
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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................3 
3 TABLE OF CONTENTS .....................................................................................................8 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................12 
5 ETHICS..............................................................................................................................14 
5.1 Independent Ethics Committee / Institutional Review Board ...................................14 
5.2 Ethical Conduct of Study ..........................................................................................15 
5.3 Patient Information and Informed Consent ...............................................................15 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................16 
7 INTRODUCTION .............................................................................................................16 
7.1 Disease Background ..................................................................................................16 
7.2 Amifampridine ..........................................................................................................17 
7.3 Nonclinical Studies ...................................................................................................18 
7.4 Previous Clinical Studies ..........................................................................................19 
7.4.1 
Amifampridine Phosphate in Healthy Subjects ...........................................19 
7.4.2 
Efficacy of Amifampridine .........................................................................21 
7.4.3 
Safety of Amifampridine and Amifampridine Phosphate ...........................22 
7.5 Overall Risks and Benefits ........................................................................................24 
7.6 Study Rationale .........................................................................................................24 
8 STUDY OBJECTIVES ......................................................................................................24 
8.1 Primary Objectives ....................................................................................................24 
8.2 Secondary Objectives ................................................................................................25 
9 INVESTIGATIONAL PLAN ............................................................................................25 
9.1 Overall Study Design and Plan .................................................................................25 
9.2 Selection of Study Population ...................................................................................29 
9.2.1 
Inclusion Criteria .........................................................................................29 
9.2.2 
Exclusion Criteria ........................................................................................29 
9.2.3 
Removal of Patients from Treatment or Assessment ..................................30 
9.2.4 
Patient Identification ...................................................................................31 

 
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9.3 Treatments .................................................................................................................32 
9.3.1 
Treatments Administered ............................................................................32 
9.3.2 
Identity of Investigational Product ..............................................................32 
9.3.2.1 
Product Characteristics and Labeling ..........................................33 
9.3.2.2 
Storage .........................................................................................33 
9.3.3 
Directions for Administration .....................................................................33 
9.3.4 
Method of Assigning Patients to Treatment Groups ...................................34 
9.3.5 
Selection of Doses Used in the Study .........................................................35 
9.3.6 
Blinding .......................................................................................................35 
9.3.7 
Treatment Compliance ................................................................................35 
9.3.8 
Investigational Product Accountability .......................................................35 
9.3.9 
Return and Disposition of Clinical Supplies ...............................................35 
9.4 Prior and Concomitant Medications .........................................................................36 
9.5 Dietary or Other Protocol Restrictions......................................................................36 
9.5.1 
Dietary Restrictions .....................................................................................36 
9.5.2 
Contraception ..............................................................................................37 
9.6 Safety Variables ........................................................................................................37 
9.6.1 
Adverse Events ............................................................................................37 
9.6.2 
Vital Signs ...................................................................................................37 
9.6.3 
Clinical Laboratory Assessments ................................................................37 
9.6.4 
Pregnancy Testing .......................................................................................38 
9.6.5 
Electrocardiogram (ECG) ............................................................................39 
9.6.6 
Physical Examination ..................................................................................39 
9.7 Efficacy Variables .....................................................................................................40 
9.7.1 
Myasthenia Gravis-Specific Activities of Daily Living (MG-ADL) ..........40 
9.7.2 
Quantitative Myasthenia Gravis (QMG) .....................................................40 
10 REPORTING ADVERSE EVENTS .................................................................................40 
10.1 Adverse Events .........................................................................................................40 
10.2 Serious Adverse Events ............................................................................................43 
10.3 Safety Blood Collection ............................................................................................45 

 
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10.4 Pregnancy ..................................................................................................................45 
10.5 Urgent Safety Measures ............................................................................................45 
10.6 Medical Monitor Contact Information ......................................................................46 
11 APPROPRIATENESS OF MEASUREMENTS ...............................................................46 
12 STUDY PROCEDURES ...................................................................................................47 
12.1 Screening Visit ..........................................................................................................47 
12.2 Open-label Run-in .....................................................................................................48 
12.3 Period 1 .....................................................................................................................48 
12.3.1 Day 0 ...........................................................................................................48 
12.3.2 Period 1, Day 10 (or Early Termination Visit) ............................................49 
13 DATA QUALITY ASSURANCE .....................................................................................50 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................50 
14.1 Statistical and Analytical Plans .................................................................................50 
14.1.1 Interim Analyses ..........................................................................................50 
14.2 Analysis Populations .................................................................................................51 
14.3 Primary Endpoints.....................................................................................................51 
14.4 Secondary Endpoints.................................................................................................51 
14.5 Safety Analysis .........................................................................................................52 
14.6 Efficacy Analysis ......................................................................................................52 
14.7 Determination of Sample Size ..................................................................................53 
14.8 Changes in the Conduct of the Study or Planned Analyses ......................................53 
15 COMPENSATION, INSURANCE, AND INDEMNITY .................................................54 
16 CASE REPORT FORMS AND SOURCE DOCUMENTS ..............................................55 
17 STUDY MONITORING AND AUDITING .....................................................................56 
18 RETENTION OF RECORDS ...........................................................................................56 
19 USE OF INFORMATION AND PUBLICATION ...........................................................57 
20 REFERENCES ..................................................................................................................58 
21 INVESTIGATOR RESPONSIBILITIES ..........................................................................61 
21.1 Conduct of Study and Protection of Human Patients ...............................................61 
22 SIGNATURE PAGE .........................................................................................................62 

 
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APPENDIX 1 MYASTHENIA GRAVIS-SPECIFIC ACTIVITIES OF DAILY 
LIVING (MG-ADL) ........................................................................................63 
APPENDIX 2 
 QUANTITATIVE MYASTHENIA GRAVIS (QMG) ..............................64 
 
List of In-text Tables 
 
Table 1. 
Schedule of Events .................................................................................................28 
Table 2. 
Medications Prohibited During Study ...................................................................36 
Table 3. 
Clinical Laboratory Tests .......................................................................................38 
Table 4. 
Categories of Severity for Adverse Events ............................................................42 
Table 5. 
Description of Relationship to Adverse Event Categories ....................................43 
 
List of In-text Figures 
Figure 1. Chemical Structure of Amifampridine Phosphate .................................................33 
 

 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
3,4-DAP 
3,4-diaminopyridine 
Abs 
Antibodies 
ACh 
Acetylcholine 
AChR 
Acetylcholine receptor 
AChR-MG 
Acetylcholine receptor Myasthenia Gravis 
ADL 
Activities of Daily Living 
ADME 
absorption, distribution, metabolism, and excretion 
AE(s) 
adverse event(s) 
AIN 
adult idiopathic nystagmus 
ALS 
amyotrophic lateral sclerosis 
ALT 
alanine aminotransferase  
ANS 
autonomic nervous system 
AST 
aspartate aminotransferase 
ATU 
Autorisations Temporaires d'Utilisation Normative 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve from time 0 to infinity  
CI 
confidence interval 
Cmax 
peak plasma concentration 
CMS 
congenital myasthenia syndromes 
CNS 
central nervous system 
CRA(s) 
clinical research associate(s) 
CRF 
CRO 
case report form 
contract research organization 
CYP450 
cytochrome P450 
DBP 
diastolic blood pressure 
ECG(s) 
electrocardiogram(s) 
eCRF 
electronic case report form 
EEG 
electroencephalogram 
EFNS 
European Federation of Neurological Societies  
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 

 
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HCG 
human chorionic gonadotropin 
hERG 
human Ether-à-go-go Related Gene 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH E6 
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
IEC 
independent ethics committee 
IP 
investigational product 
IRB 
institutional review board 
IVIG 
intravenous immunoglobulin G 
K+ 
potassium ion 
kg 
kilogram 
LEMS 
Lambert-Eaton myasthenic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MG-ADL 
Myasthenia Gravis-Specific Activities of Daily Living 
MG 
Myasthenia Gravis 
MGFA 
Myasthenia Gravis Foundation of America 
MI 
myocardial infarction 
mmHg 
millimeters of mercury 
MS 
multiple sclerosis 
MuSK 
muscle-specific receptor tyrosine kinase 
MuSK-MG 
muscle-specific receptor tyrosine Kinase-Myasthenia Gravis 
NAT 
N-acetyl transferase 
ng/mL 
nanograms per milliliter 
NMJ 
neuromuscular junction 
PE 
plasma exchange 
Pgp 
P-glycoprotein 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PP 
per protocol 
QMG 
quantitative myasthenia gravis 
QT 
QT wave 
QTc 
QT wave corrected for heart rate 
REB 
research ethics board 

 
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SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SGI 
subject global impression 
SOPs 
standard operating procedures 
t1/2 
elimination half-life 
TEAE(s) 
treatment emergent adverse event(s) 
TK 
toxicokinetic 
Tmax 
time to reach maximum plasma concentration 
TPE 
therapeutic plasma exchange 
US 
United States 
 
Definition of Terms:  
Investigational Product (IP): 
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]). The terms “IP” and “study drug” may be 
used interchangeably in the protocol. 
5 
ETHICS 
5.1 
Independent Ethics Committee / Institutional Review Board 
Before initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB), independent ethics committee (IEC), or Research Ethics 
Board (REB) is properly constituted and compliant with International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) and Good Clinical Practice (GCP) requirements, applicable laws and local 
regulations. A copy of the confirmation from the IRB/IEC/REB will be provided to Catalyst 
Pharmaceuticals, Inc. (Catalyst) or its designee. The Investigator will provide the 
IRB/IEC/REB with all appropriate material, including the protocol, Investigator’s Brochure 

 
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or Package Insert, the Informed Consent Form (ICF) including compensation procedures, and 
any other written information provided to the patients, including all ICFs translated to a 
language other than the native language of the clinical site. The study will not be initiated 
and Investigational Product (IP) supplies will not be shipped to the site until appropriate 
documents from the IRB/IEC/REB confirming unconditional approval of the protocol, the 
ICF, and all patient recruitment materials are obtained in writing by the Investigator, and 
copies are received at Catalyst or its designee. The approval document should refer to the 
study by protocol title and Catalyst protocol number (if possible), identify the documents 
reviewed, and include the date of the review and approval. The Investigator is responsible to 
ensure that the appropriate reports on the progress of the study are made to the IRB/IEC/REB 
in accordance with applicable guidance documents and governmental regulations. 
5.2 
Ethical Conduct of Study 
This study will be conducted in accordance with the following: 
• ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 
(ICH E6); and 
• The ethical principles established by the Declaration of Helsinki. 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/IEC/REB and will be conducted by scientifically and medically qualified persons. The 
benefits of the study are in proportion to the risks. The rights and welfare of the patients will 
be respected and the Investigators conducting the study do not find the hazards to outweigh 
the potential benefits. Each patient will provide written, informed consent prior to any 
study-related tests or evaluations are performed. 
5.3 
Patient Information and Informed Consent 
A properly written and executed ICF, in accordance with the Declaration of Helsinki, ICH E6 
(Section 4.8), and other applicable local regulations, will be obtained for each patient before 
entering the patient into the study. The Investigator will prepare the ICF and provide the 
documents to Catalyst, or designee, for review. The IRB/IEC/REB must approve the 
documents before their implementation. A copy of the approved ICF, and if applicable, a 
copy of the approved patient information sheet and all ICFs translated to a language other 
than English must also be received by Catalyst, or designee, prior to any study-specific 
procedures being performed. 

 
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The Investigator will provide copies of the signed ICF to each patient and will maintain the 
original in the record file of the patient. 
6 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Before beginning the study, the Investigator must provide to Catalyst or designee, a fully 
executed and signed US Food and Drug Administration (FDA) Form FDA 1572 and a 
Financial Disclosure Form.  All sub-investigators must be listed on Form FDA 1572 and 
provide a Financial Disclosure Form. 
Clinical research associates (CRAs) or trained designees will monitor the site on a periodic 
basis and perform verification of source documentation for a representative sample of 
patients as well as other required review processes. Principal Investigator (PI) will be 
responsible for the timely reporting of serious adverse events (SAEs) to Catalyst, or 
designee, and the IRB. Catalyst Medical Department (or designee) will be responsible for the 
timely reporting of SAEs to appropriate regulatory authorities, as required. 
Laboratory evaluations will be performed at the local laboratory associated with the study 
site.  
7 
INTRODUCTION 
A comprehensive review of amifampridine phosphate is contained in the Investigator’s 
Brochure supplied by Catalyst (June 2017). Investigators are to review this document before 
initiating this study. 
7.1 
Disease Background 
Myasthenia gravis (MG) is a rare, debilitating, acquired autoimmune disease of the 
neuromuscular junction (NMJ), caused by the failure of neuromuscular transmission, which 
results from the binding of autoantibodies (Abs) to proteins involved in signaling at the NMJ. 
The main proteins affected are acetylcholine receptor (AChR) and muscle-specific receptor 
tyrosine kinase (MuSK). Myasthenia gravis is clinically characterized by weakness and 
fatigability of skeletal muscles, with disease severity varying widely among affected patients. 
MuSK-MG is a disease characterized by a predominance in females, earlier onset than other 
AChR-MG, prominent bulbar involvement, more severe clinical condition, and significant 
resistance to treatment (Pasnoor, 2010).  AChR-MG and MuSK-MG also have a different 
immunopathologic mechanisms, with IgG1 and IgG3 complement binding antibodies 
involved in the former, and IgG4 in the latter. 

 
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Although many patients with MuSK-MG are treated with anticholinesterase inhibitors or 
immunosuppressants, they do not respond well to such treatments. Hence, MuSK-MG 
patients may continue to have marked generalized weakness and bulbar signs and symptoms 
of the disease. In these patients, the search for alternative treatment strategies targeting 
different pathophysiologic aspects of the disease is a medical need. 
The use of amifampridine in patients with MuSK-MG has been described for 2 children, who 
achieved some benefit (Skjei, 2013) and 1 adult (Evoli, 2016).  Following 4 months of 
treatment, the authors report the adult patient had obvious improvement of ptosis, decreased 
neck weakness and arm fatigability.  
An Investigator-Sponsored MuSK-MG study in Italy involved a randomized, placebo-
controlled crossover design in patients receiving amifampridine phosphate and placebo.  
Seven MuSK-MG patients were enrolled in the study.  In the open-label run-in period 
amifampridine phosphate dose was titrated upward, at the discretion of the Investigator, for a 
minimum of 3 weeks, with the last week showing stable dose and frequency.  At the end of 
this period, patients must show a 3-point improvement in Myasthenia Gravis Composite 
(MGC) scale to be eligible for randomization. In Treatment Period 1, patients were 
randomized to receive either amifampridine tablets or placebo tablets for 1 week. After 
completion of Treatment Period 1, in Treatment Period 2 patients were administered the test 
medication they did not receive in Treatment Period 1, under double-blind conditions.  In 
Treatment Period 3, they received the same medication as in Treatment Period 1. 
The results of this approximately 50 day study demonstrated the Musk-MG patients had 
statistically significant higher functional performance in all the validated assessment scales 
when they were administered amifampridine compared to placebo.  Overall, the results 
demonstrated a consistent high level of efficacy with amifampridine in MuSK-MG patients, 
and excellent tolerability. 
7.2 
Amifampridine  
Amifampridine (3,4-DAP) is a non-specific voltage-dependent potassium (K+) channel 
blocker. Blockade of K+ channels causes depolarization of the presynaptic membrane and 
slows down or inhibits repolarization. Prolonged depolarization results in opening of slow 
voltage-dependent calcium (Ca2+) channels and allows a subsequent influx of Ca2+. The 
increased concentration of intracellular Ca2+ induces exocytosis of the synaptic vesicles 
containing acetylcholine (ACh), thus releasing an increased level of ACh into the synaptic 
cleft (Maddison, 1998a; Maddison, 1998b). The influx of ACh into the presynaptic cleft 
enhances neuromuscular transmission, providing improved muscle function. 

 
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Over the last 25 years, a considerable amount of clinical experience with amifampridine has 
been gained, which provides a strong body of evidence for its efficacy and safety in the 
treatment of patients with neurologic disorders, including MG, Lambert-Eaton myasthenic 
syndrome (LEMS), multiple sclerosis (MS), congenital myasthenia syndromes (CMS), 
downbeat nystagmus, and amyotrophic lateral sclerosis (ALS). Amifampridine has been 
recommended as first-line symptomatic treatment for LEMS by the European Federation of 
Neurological Societies (EFNS) (Skeie, 2006; Skeie, 2010; Lindquist, 2011) and 
amifampridine tablets 10 mg (as amifampridine phosphate) (Firdapse® Tablets) is marketed 
for the treatment of LEMS in the European Union (including Norway and Iceland), Israel, 
and Switzerland. The collective body of data indicates that amifampridine/ amifampridine 
phosphate is well tolerated up to and including 80 mg/day (Firdapse Investigator Brochure, 
June 2017). 
Recent nonclinical publications are supportive of exploration of amifampridine in myasthenia 
gravis caused by antibodies against muscle-specific kinase (MuSK). Mori and colleagues 
(2012) found that amifampridine (3,4-DAP) significantly improved neuromuscular 
transmission by predominantly increasing ACh release in the neuromuscular junction of 
MuSK-MG mice, demonstrating that the presynaptic defect (plus a smaller postsynaptic 
effect) could contribute to failure of neuromuscular transmission.  In Morsch and colleagues 
study (2013) using a mouse model of MuSK-MG, amifampridine (3,4-DAP) significantly 
enhanced neuromuscular transmission after 1 week of treatment without exacerbating loss of 
endplate AChRs, whereas pyridostigmine exacerbated neuromuscular impairment. Clinical 
evidence also demonstrates that amifampridine produces improvement in MuSK-MG (Evoli, 
2016). 
7.3 
Nonclinical Studies 
An extensive nonclinical program assessed the safety and absorption, distribution, 
metabolism, and excretion (ADME) and pharmacokinetic (PK) properties of amifampridine, 
including: 
• Five safety pharmacology studies in central nervous system (rat), respiratory (rat), and 
cardiovascular (telemeterized dogs, in vitro human Ether-à-go-go Related Gene (hERG) 
and rabbit Purkinje fiber)  
• Pharmacokinetics and mass balance in rat and dog  
• In vitro metabolism in human and animal hepatocytes  
• Human hepatic cytochrome P450 (CYP450) inhibition and induction  

 
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• Human P-glycoprotein (Pgp) interaction  
• Single dose toxicity and toxicokinetic (TK) studies in mouse and rat  
• Repeat dose toxicity and toxicokinetic in rat (28-day, 13-week, and 2 years) and dog 
(28-day and 9-month) 
• Reproductive and developmental toxicity in rat and rabbit 
• Six in vitro and in vivo genotoxicity studies 
The main nonclinical findings were CNS and autonomic nervous system (ANS) effects, the 
development of Schwannomas, and histologic changes in muscle tissues after administration 
of amifampridine.  
7.4 
Previous Clinical Studies 
Amifampridine has been used for over 25 years in patients with multiple neurologic disorders 
including MG, LEMS, MS, CMS, ALS, congenital forms of nystagmus, and adult idiopathic 
nystagmus (AIN). There are a limited number of published controlled trials with 
amifampridine in these disorders. A review of the literature documents that amifampridine is 
a safe and effective treatment in multiple neurologic disorders and is recommended by the 
EFNS for first-line symptomatic treatment of patients with LEMS (Skeie, 2006; Skeie, 2010; 
Lindquist, 2011). 
7.4.1 Amifampridine Phosphate in Healthy Subjects 
A first in human Phase 1 study (DAPSEL Study, 2006) with amifampridine phosphate was 
conducted to investigate the bioavailability/bioequivalence and tolerability of amifampridine 
administered as a phosphate salt or free base. In the first part of the study, a pilot tolerance 
study was conducted in 5 healthy male volunteers who received a single 10-mg dose of 
amifampridine phosphate to determine tolerability. In the second part of the study, 
bioequivalence testing was conducted in 27 healthy male volunteers. Each patient was 
randomized to receive either a single dose (2 × 10 mg tablets) of amifampridine as 
amifampridine phosphate or amifampridine base and received alternate treatment following a 
minimum of 72-hour washout period. 
This study demonstrated bioequivalence for area under the plasma concentration-time curve 
from time 0 to infinity (AUC0-∞), with the 90% confidence interval (CI) for the base/salt ratio 
of 93.1% to 113.3% falling within the predefined limits of 90% to 125% for bioequivalence. 
The mean elimination half-life (t1/2) of amifampridine was 1.8 hours for the phosphate and 
1.6 hours for the free base form. Amifampridine Cmax was 64.8 ng/mL for the phosphate and 

 
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57.0 ng/mL for the free base form. Potentially improved absorption of the phosphate salt 
explained the slightly higher Cmax observed for amifampridine phosphate compared with the 
free base. All adverse events (AEs) were mild or moderate, transitory and fully reversible. 
The nature and frequency of side-effects did not differ between formulations (phosphate salt 
or base). The most common AE (25 of 40 AEs) was paresthesia, which was mainly minor 
peri-oral paresthesia. Since paresthesia is well recognized as an AE occurring in patients 
treated with amifampridine, all were considered as possibly related to investigational product 
(IP) by the Investigator. The only other AE occurring in >1 patient and judged possibly 
related to amifampridine was abdominal pain (4 events). Simple flu (5 events) and feeling of 
discomfort (2 events) were also reported for > 1 patient in the study, however were 
considered not related to amifampridine treatment. 
The only SAEs reported in the study were minor, isolated, and reversible increases in 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which occurred in a 
single patient after administration of 20 mg amifampridine base. Aside from this 1 patient, no 
other laboratory abnormalities were observed. No electrocardiogram (ECG) abnormalities 
were observed. No deaths occurred in the DAPSEL study.  
A Phase 1 study (LMS-001) in healthy volunteers evaluated whether food consumption 
significantly affected the bioavailability of amifampridine phosphate tablets. This was an 
open-label, randomized, single-dose, 2-treatment, 2-period crossover design in 46 healthy 
volunteers. Each patient received 20 mg amifampridine phosphate on 2 occasions, once 
fasting and once after consumption of a standard high fat breakfast. The 2 single 20 mg doses 
of amifampridine phosphate were administered 6 days apart. Data indicate that taking 
amifampridine with food reduces exposures determined by Cmax (maximum serum levels) by 
approximately 40% and AUC by approximately 20%. In addition, the time to maximum 
serum concentrations (Tmax) was increased 2-fold from approximately 38 minutes (fasted) to 
78 minutes (fed). The drug was well tolerated with no serious adverse events and only 1 
severe event, an episode of gastroenteritis unrelated to amifampridine. The most common 
adverse events occurring in ≥ 10% of patients were: oral paresthesia (20 patients; 43%), 
peripheral paresthesias (12; 26%), dizziness (5; 11%), headache (5; 11%), and oral 
hypoesthesia (5; 11%). Abdominal pain, nausea, peripheral paresthesias, dizziness, and 
headache were more commonly reported by patients following administration of 
amifampridine phosphate in the fasted state. 
In both Study LMS-001 and DAPSEL, PK parameters were highly variable with 10-fold 
ranges observed in values of Cmax, AUC, and t½ across patients. In humans, amifampridine is 

 
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exclusively metabolized to a single major metabolite, 3-N-acetyl amifampridine, via N-acetyl 
transferases (NAT) (Catalyst internal in vitro and in vivo studies; data available upon 
request). There are 2 NAT enzymes, NAT1 and NAT2, both of which are principally hepatic 
and both of which are highly polymorphic. These allelic variations lead to slow and fast 
metabolism variations, which have been well characterized in the Caucasian and Asian 
populations, but somewhat less well in African populations (Sabbagh, 2006). Slow 
acetylators are estimated to comprise 50% to 59% of the Caucasian population, with the 
remainder being rapid acetylators (fast + intermediate). Fast acetylators are over represented 
in Asian population (92% of Japanese and 80% of Chinese) while they may be under 
represented in African populations (25%) (Cascorbi, 1995). Slow acetylators will accumulate 
drug to higher levels (i.e. higher Cmax) and clear drug more slowly (i.e. longer t1/2), both of 
which may increase the risk of drug related toxicity (Fukino, 2008; Jetter, 2009). It is 
hypothesized that the high variability in amifampridine phosphate PK may be due to NAT 
polymorphisms with slow and fast acetylator phenotypes. In a study (FIR-001) that evaluated 
the effect of acetylator status in 26 healthy subjects (half with fast and half with slow 
acetylator phenotypes), polymorphisms in the NAT system created 3- to 4-fold differences in 
plasma amifampridine levels. Potentially information relating NAT genotype and 
amifampridine phosphate PK could be used to inform dose selection for individual patients 
and to lower incidence of dose-related side effects. 
7.4.2 Efficacy of Amifampridine 
A Phase 3, randomized, double-blind, placebo-controlled study (LMS-002) evaluated the 
efficacy and safety of amifampridine tablets 10 mg, as amifampridine phosphate (30-80 mg 
total daily dose) versus placebo in patients with LEMS. The study has 4 parts, with the first 
3 parts complete in the clinic (open-label extension ongoing). Patients treated with 
amifampridine phosphate had statistically significant improvement in both primary efficacy 
measures relative to patients treated with placebo. The change in QMG scores from baseline 
(Day 1, Part 2) to Day 14 (Part 3) reached statistical significance (p=0.0452), with the least 
square (LS) mean for QMG score increasing by 2.2 in placebo-treated patients, and 
increasing by 0.4 in amifampridine-treated patients. For the other primary endpoint, subject 
global impression (SGI), patients who were receiving amifampridine on Day 1 reported, on 
average, that they were “pleased” (SGI score of 5.9 ± 1.2) with the test medication while they 
were receiving it. After being switched to placebo tablets, their opinions dropped, on 
average, 2.7 ±2.3 points. The LS mean was -2.6 for the placebo group and -0.8 for the 
amifampridine group, a difference of 1.8 ±0.6 (p=0.0028), corresponding to a patient 
assessment, of “mixed” for the placebo tablets. This substantial change in patients’ 

 
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assessments, to a worsening of their condition while receiving placebo, was considered 
clinically significant. 
In addition to Study LMS-002, 5 randomized, double-blind, placebo-controlled studies and 
1 double-blind study with an active comparator (reported in abstract form only) in 71 patients 
with LEMS are reported in the clinical literature. In all 6 studies, amifampridine (in base 
form) was shown to be more effective for the symptomatic treatment of LEMS compared 
with placebo or active comparator across a number of independent measures of neurological 
function. Supportive data from multiple published uncontrolled investigations and case 
reports demonstrate the long-term benefits of treatment with amifampridine in patients with 
LEMS, and show that removal of patients from drug has led to recurrence of underlying 
symptoms.  Refer to the Firdapse Investigator Brochure (June 2017) for further details on 
these studies. 
7.4.3 Safety of Amifampridine and Amifampridine Phosphate 
Safety data collected from 1,454 patients or healthy volunteers in controlled study LMS-002 
(LEMS), controlled and uncontrolled published studies of LEMS or other neurologic 
conditions, a 3-year safety surveillance study (ATU), and PK studies demonstrate 
amifampridine is well tolerated up to and including 80 mg/day (Firdapse Investigator 
Brochure, June 2017). The most common adverse events observed from the clinical safety 
data were perioral and peripheral paresthesias and gastrointestinal disorders (abdominal pain, 
nausea, diarrhea, epigastralgia).  These events were typically mild or moderate in severity, 
and transient, seldom requiring dose reduction or withdrawal from treatment. In the 
pharmacogenomic study in healthy subjects (classified as either slow acetylators or fast 
acetylators), slow acetylators experienced >80% more drug-related AEs compared with fast 
acetylators (FIR-001). 
Clinically significant or serious adverse events were infrequent in all studies for all 
indications. A total of 12 deaths were reported in the 1,454 patients or healthy subjects. Six 
of 12 deaths were associated with accompanying malignancy (1 of 6 with pulmonary 
embolus as terminal event), 1 due to tracheobronchitis, and 2 due to myocardial infarction 
(MI). Attribution to amifampridine for 2 of 3 deaths from the ATU study was specified as 
unrelated; causality for the third death was not reported. No attribution was specified in the 
academic series, but the author singled out the fatal MI as the only serious incident during 
amifampridine therapy, implying that the 2 deaths due to malignancy, the 1 due to 
malignancy and pulmonary embolus and the 1 due to tracheobronchitis were not related in 
his opinion. The author further states that no pathological findings related to amifampridine 

 
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were found in the patient who died of tracheobronchitis. For 1 of the fatal MIs, the author 
speculates that a “sudden increase of physical activity” with amifampridine may have been a 
contributant (Lundh, 1984; Lundh, 1993); no causality was reported for the other fatal MI 
(Bertorini, 2011). Three deaths occurred in children with CMS, including 2 with fast-channel 
CMS (Beeson, 2005). Although no causal relationship was established with amifampridine, 
the authors advise its use cautiously in children and in fast-channel patients. The other CMS 
death was not thought to be related to amifampridine (Palace, 1991). Overall 7 of 12 deaths 
were not considered related to amifampridine; neither cause nor causality is known for 4 
deaths; and amifampridine may have contributed indirectly to 1 of the MI-related deaths.   
The most frequent clinically significant or serious event was seizure. A total of 10 (0.69%) 
patients out of 1,454 patients or healthy subjects experienced seizures or convulsions after 
treatment with amifampridine. Electroencephalogram (EEG) findings, reported for 3 of the 
10 patients, did not show epileptiform activity. Three of 10 seizures occurred in patients with 
LEMS (3/209; 1.44%), 4 occurred in patients with MS (4/774; 0.5%), 1 occurred in a patient 
with CMS (1/88; 1.14%) (Harper, 2000) and 2 seizures were reported in a literature-based 
study where both MG and LEMS patients were enrolled, but the paper did not state the 
indication (Sanders, 1993; Sanders, 2000; Flet, 2010; McEvoy, 1989; Boerma, 1995; Bever, 
1996).  
Three patients experienced seizures on a daily dose of ≥90 mg/day (n=3; LEMS or MG). No 
other cause was apparent in 2 cases; 1 patient had concurrent toxic serum levels of 
theophylline (McEvoy, 1989; Sanders, 1993). A fourth patient with LEMS had multiple 
seizures following accidental ingestion of 360 mg/day amifampridine for 7 days (prescribed 
dose 60 mg/day) (Boerma, 1995). There were potentially contributing conditions in 6 
patients, specifically, concurrent treatment with theophylline (n=1; LEMS or MG), or 
coexistent brain metastases (n=1; LEMS), epilepsy (n=1; MS) and MS (n=4). In cases where 
follow-up was reported, most seizures did not recur with amifampridine dose reduction or 
treatment withdrawal. In the one accidental overdose case, seizures were controlled with 
intravenous clonazepam and the patient made a full recovery (Boerma, 1995). Note that a 
seizure rate of 4% can be expected in the natural course of patients with MS (Engelsen, 1997; 
Moreau, 1998; Kinnunen, 1987). Among the 774 MS patients treated with amifampridine 
included in the safety assessment of this report, 4 (0.5%) experienced seizures. 
Other clinically significant or SAEs reported in more than 1 patient were palpitations 
(8/1,454; 0.56%), abnormal liver enzymes (6/1,454; 0.41%), QTc prolongation (2/1,454; 
0.14%), and premature ventricular contraction/increased ventricular extrasystoles (2/1,454; 

 
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0.14%). Each of the following serious or clinically significant events was reported in a single 
patient: chorea, paresthesias, paroxysmal supraventricular tachycardia, cardiac arrest, drug-
induced hepatitis, gastroesophageal reflux, increased lipase and amylase, aspiration 
pneumonia with confusion, and urinary tract infection with confusion. 
7.5 
Overall Risks and Benefits 
Data on amifampridine treatment in 1,454 patients or healthy volunteers support the 
favorable safety profile of amifampridine (both base and phosphate formulations) at doses up 
to 80 mg per day. Current data demonstrate that amifampridine phosphate salt has an 
acceptable tolerability profile with a positive risk-benefit in patients treated with 
amifampridine. Refer to the Investigator’s Brochure (June 2017) for further discussion on 
benefit/risk of amifampridine.  
7.6 
Study Rationale 
As discussed above in Section 7.4, a considerable amount of clinical experience is available 
with amifampridine (3,4-diaminopyridine; 3,4-DAP) and, in December 2009, amifampridine 
tablets 10 mg, as amifampridine phosphate, received marketing approval by the European 
Commission as Firdapse® for the symptomatic treatment of patients with LEMS. Case 
reports, animal data and a pilot controlled clinical trial suggest that amifampridine may also 
have clinical utility in patients with MuSK-MG. Thus, the purpose of this study (MSK-002) 
is to demonstrate the safety and efficacy of amifampridine in patients with MuSK-MG. There 
is the possibility that amifampridine phosphate may also have a beneficial effect on AChR-
MG, though immunopathalogically, clinically, and in responsiveness to medication the 
diseases appear different.  To explore this, a sample (N=10) of AChR-MG patients, who 
meet the inclusion criteria, will attempt to be recruited. 
8 
STUDY OBJECTIVES 
8.1 
Primary Objectives 
The primary objectives of the study are: 
• To characterize the overall safety and tolerability of amifampridine compared with 
placebo in patients with MuSK-MG; and  
• 
To assess the clinical efficacy of amifampridine compared with placebo in patients with 
MuSK-MG, and a sample of patients with AChR-MG, based on change from baseline 
in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scores. 

 
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8.2 
Secondary Objectives 
The secondary objectives of the study are: 
• To assess the clinical efficacy of amifampridine compared with placebo by using the 
change from baseline in total Quantitative Myasthenia Gravis (QMG) score; 
• To assess the safety and efficacy of amifampridine compared with placebo in a sample 
of patients with AChR-MG (N equal to 10). 
 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a stratified, randomized (1:1), double-blind, placebo-controlled, parallel group, 
outpatient study designed to evaluate the safety, tolerability and efficacy of amifampridine in 
patients diagnosed with MuSK-MG and a sample of AChR-MG patients. The study is 
planned to be conducted at up to 20 sites in US, Europe, and Canada; and will include about 
60 male and female MuSK-MG patients, and 10 AChR-MG patients. If it is determined that 
18 or more of the first 20 screened AChR-MG patients fail to meet inclusion criteria, 
additional screening for AChR-MG patients will be terminated.  If the AChR-MG screening 
failure rate is lower, an additional 20 patients will be screened; overall, up to 40 AChR-MG 
patients may be screened to try and enroll 10 in the study. 
The planned duration of participation for each patient is at least 38 days excluding the 
screening period, which can last up to 14 days. In addition to amifampridine tablets, 10 mg, 
as amifampridine phosphate, patients will continue to receive stable dose of pyridostigmine 
and/or corticosteroids, but no changes to medications are permitted during the study. 
All patients who sign an informed consent will be screened for eligibility to participate in the 
study: inclusion and exclusion criteria; medical and medication history; complete physical 
exam (including vital signs, height, weight); standard 12-lead ECG; clinical laboratory 
testing; serum pregnancy testing (females of childbearing potential only; result must be 
negative to proceed into the run-in period with open-label IP administration); MuSK or 
AChR antibody testing (if not previously done and report available); EMG (if not previously 
done and report available); and assessment of serious adverse events (SAEs) (Table 1).  
Those patients successfully completing screening will have procedures/assessments (see 
Table 1) conducted at the start of the Run-in period (Day 1, before starting medication) and 
during run-in, until stable dose and frequency of amifampridine is established for at least 7 

 
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days, and at least a 2-point improvement in MG-ADL score is achieved. Screening and the 
start of the Run-in period may be combined into a single visit, in which case overlapping 
procedures/assessments will only need to be performed once. On the last day of the Run-in 
period (Day 0), procedures/assessments, as detailed in Table 1, will be conducted to confirm 
eligibility for randomization, including a negative pregnancy test. Every attempt should be 
made to have the same individual perform all assessments for a patient throughout the study. 
Randomized patients will be assigned to one of 2 treatment groups under double-blind 
conditions; either placebo or amifampridine phosphate.   
Open-label Run-in 
Amifampridine dose will be titrated upward every 3 to 4 days, starting at 10 or 15 mg/day, at 
the discretion of the Investigator. Patients will either visit or have telephone/video contact 
with the site for each dose titration and at least one in-person site evaluation at Week 3 of the 
run-in period.  When the Investigator determines that the patient has reached the maximal 
tolerable and efficacious dose, the patient should demonstrate they can remain on a stable 
dose and frequency for at least an additional 7 days. The Open-label Run-in period may be 
extended if additional time is needed for the dose titration. At the end of this period, patients 
must show at least a 2-point improvement in MG-ADL from start of Run-in, to be eligible for 
randomization (Day 0). 
Randomization 
Patients who continue to meet all the inclusion and exclusion criteria will be randomized on 
the last day of the Run-in period (Day 0). 
Period 1 (Days 1-10) (+1 day) 
Patients who have successfully completed the Open-label Run-in and continue to meet all 
inclusion/exclusion criteria will be randomized (1:1 ratio) on Day 0 to receive either 
amifampridine tablets (10 mg as amifampridine phosphate) or placebo tablets for 10 days, 
under double-blind conditions, (blinded medication to start after assessments obtained on 
open-label medication, on Day 0). Test medication will be dispensed by the site pharmacist, 
according to the randomization schedule provided by Sponsor. All unused medication and 
the container must be brought back to the study site at the end of Period 1. Safety and 
efficacy assessments will be made, in the site clinic, on Day 10 as detailed in the Schedule of 
Assessments in Table 1 and Section 12. 

 
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Table 1. 
Schedule of Events 
Study Assessment  
or Event b 
 
 
 
Run-in 
Period 1 
Screening 
Start a 
Last  
Visit 
(Days 1-10) 
Days 
-14 to -1 
Start of Run-
in 
 
Day 0j end of 
Run-in 
 
Day 10j 
(+1 d) 
Informed consent c 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
Randomization 
 
 
X 
 
Medical history 
X 
 
X d 
 
Complete physical exam e 
X 
 
X 
X 
Vital signs f 
X 
 
X 
X 
12-Lead ECG g 
X 
 
X 
 
Clinical laboratory tests h 
X 
 
X 
 
Pregnancy test i 
X 
 
X 
X 
MuSK and/or AChR Antibody testing 
Xn 
 
 
 
EMG 
Xn 
 
 
 
IP Treatment Administration j 
 
X 
X 
Daily 
Dispense blinded IP k 
 
 
X 
 
IP accountability 
 
X 
X 
X 
Myasthenia Gravis-Specific Activities 
of Daily Living (MG-ADL) 
X 
X l 
X l 
X 
Quantitative Myasthenia Gravis 
(QMG) score 
X 
X l 
X l 
X 
Adverse events/SAEs m 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
Urine drug screen 
 
 
 
X 
Patient Dosing Diary Provided 
 
X 
X 
 
ECG = electrocardiogram; EMG = electromyography; IP = investigational product (amifampridine or 
placebo); SAE = serious adverse event 
a Titrate from starting dose of 10-15 mg/day, every 3 to 4 days with at least one site visit at Week 3.  Last 
week of run-in, study drug dose and frequency must be stable before being eligible for randomization on 
Day 0. 
b All safety assessments (vital signs, ECGs, laboratory tests) are to be performed before the dose taken in 
the study clinic unless specified otherwise. All efficacy assessments will be performed at standardized 
times relative to the dose that must be taken in the study clinic on Days 0 and 10, according to the efficacy 
assessments schedule in Section 9.7 
c Informed consent must be obtained before any study procedures are performed. 
d Any changes since the Screening Visit will be noted. 

 
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Table 1. 
Schedule of Events 
Study Assessment  
or Event b 
 
 
 
Run-in 
Period 1 
Screening 
Start a 
Last  
Visit 
(Days 1-10) 
Days 
-14 to -1 
Start of Run-
in 
 
Day 0j end of 
Run-in 
 
Day 10j 
(+1 d) 
e Complete physical examination includes evaluation of all major body systems, including weight at all visits 
and height at Screening only (Section 9.6.6). 
f The time of the last dose should be recorded in relation to taking Vital signs. 
g The time of the last dose should be recorded in relation to performing Standard 12-lead safety ECGs. 
h Clinical laboratory tests include serum chemistry, hematology, and urinalysis. 
i Serum pregnancy tests will be obtained from female patients of childbearing potential only at Screening; 
urine dipstick may be used for the remainder of the study. 
j IP will be administered by the clinic staff during in-clinic visit so assessments can be timed according to IP 
administration.   
k Patients will be provided blinded packages containing amifampridine or placebo depending on their 
randomized sequence of treatment. Collect all open-label medication. 
l Assessment only at the first (Day 1) and last (Day 0) run-in visits. 
m SAE reporting commences when informed consent is signed. Non-serious adverse event reporting 
commences on Day 1 of run-in (Section 10). 
n  If not previously done and report available. 
 

 
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9.2 
Selection of Study Population 
Criteria for participation in the study are provided in Sections 9.2.1 and 9.2.2. 
9.2.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all the following inclusion criteria: 
1. Willing and able to provide written informed consent after the nature of the study has 
been explained and before the start of any research-related procedures. 
2. Male or female ≥18 years of age. 
3. Positive serologic test for anti-MuSK antibodies or anti-AChR antibodies as 
confirmed at Screening or by previous antibody test, with report available. 
4. Confirmatory EMG or EMG report. 
5. Myasthenia Gravis Foundation of America (MGFA) Class II to IV at Screening. 
6. MG-ADL score of ≥6 at Screening, with more than 50% of this score attributed to 
non-ocular items. 
7. Patients receiving steroids or pyridostigmine should not have any modification of 
drug regimen during the month before Screening. 
8. Female patients of childbearing potential must have a negative pregnancy test (serum 
human chorionic gonadotropin [HCG] at screening); and must practice an effective, 
reliable contraceptive regimen during the study and for up to 30 days following 
discontinuation of treatment. 
9. Ability to participate in the study based on overall health of the patient and disease 
prognosis, as applicable, in the opinion of the Investigator; and able to comply with 
all requirements of the protocol, including completion of study questionnaires. 
9.2.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria are not eligible to participate in 
the study: 
1. Epilepsy and currently on medication. 
2. Concomitant use of medicinal products with a known potential to cause QTc 
prolongation. 

 
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3. Patients with long QT syndromes. 
4. History of thymectomy within 12 months before Screening. 
5. An electrocardiogram (ECG) within 6 months before starting treatment that shows 
clinically significant abnormalities, in the opinion of the Investigator. 
6. Breastfeeding or pregnant at Screening or planning to become pregnant at any time 
during the study. 
7. Patients receiving immunomodulatory treatment (e.g. plasma exchange [PE], 
therapeutic plasma exchange [TPE], intravenous immunoglobulin G [IVIG]) should 
not have any treatment in the previous 4 weeks prior to Randomization or at any time 
during the study. 
8. Use of rituximab or other similar biologic medications for immunomodulation within 
6 months prior to Screening. 
9. Treatment with an investigational drug (other than amifampridine) or device within 
30 days before Screening or while participating in this study. 
10. Any medical condition that, in the opinion of the Investigator, might interfere with 
the patient’s participation in the study, poses an added risk for the patient, or 
confound the assessment of the patient. 
11. History of drug allergy to any pyridine-containing substances or any amifampridine 
excipient(s). 
9.2.3 Removal of Patients from Treatment or Assessment 
Patients may withdraw their consent to participate in the study or to receive treatment with IP 
at any time without prejudice. The Investigator must withdraw from the study or from 
treatment with IP any patient who requests to be withdrawn. A patient’s participation in the 
study or treatment with IP may be discontinued at any time at the discretion of the 
Investigator and in accordance with his or her clinical judgment.  
Catalyst must be notified of all patient withdrawals from the study or from treatment with IP 
as soon as possible. Catalyst also reserves the right to discontinue the study at any time for 
either clinical or administrative reasons and to discontinue participation by an individual 
Investigator or site for poor enrollment or noncompliance. 

 
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Reasons for which the Investigator or Catalyst may withdraw a patient from the study 
treatment include, but are not limited to, the following: 
• Patient experiences a serious or intolerable AE; 
• Patient requires medication prohibited by the protocol; and 
• Patient becomes pregnant (refer to Section 10.4 for details on the reporting 
procedures to follow in the event of pregnancy). 
Reasons for which the Investigator or Catalyst may withdraw a patient from the study 
include, but are not limited to, the following: 
• Patient does not adhere to study requirements specified in the protocol; 
• Patient was erroneously admitted into the study or does not meet inclusion criteria; 
and 
• Patient is lost to follow-up. 
If a patient fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the patient cannot be reached by telephone, a certified letter should 
be sent to the patient requesting contact with the Investigator. This information should be 
recorded in the study records. 
The Investigator or designee must explain to each patient, before enrollment into the study, 
that for evaluation of study results, the patient’s protected health information obtained during 
the study may be shared with Catalyst, regulatory agencies, and IRB/IEC/REB. It is the 
Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information, per country-specific regulations, from each patient. If permission to use 
protected health information is withdrawn, it is the Investigator’s responsibility to obtain a 
written request, to ensure that no further data will be collected from the patient and the 
patient will be removed from the study. 
9.2.4 Patient Identification 
Each patient will be assigned a unique patient identifier (2 or 3 digits for the site and 2 or 3 
digits for each patient enrolled). This unique identifier will be on all CRF pages.  
9.2.5 Re-screening 
Re-screening of screen failures will be allowed, if re-screening is approved by the Medical 
Monitor. Justification of the reason for re-screening must be clearly stated in the patient’s 
source documentation. No new consent would be required if re-screened within 30 days. 

 
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Labs do not have to be repeated for 60 days, except for pregnancy test. Patients may be 
replaced if terminated after randomization. 
9.3 
Treatments 
9.3.1 Treatments Administered 
Catalyst or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study.  
Investigational product: Amifampridine tablets 10 mg will be provided in round, white-
scored tablets and containing amifampridine phosphate formulated to be the equivalent of 
10 mg amifampridine base per tablet. The product will be provided in bottles of bulk tablets 
to the pharmacy representative who will dispense an amount for each portion of the study, in 
a patient-specific labeled bottle. 
Placebo: A placebo equivalent will be provided as tablets indistinguishable from the 
amifampridine tablets. The placebo will be administered consistent with the dose regimen of 
amifampridine. The placebo tablets will be provided in bottles of bulk tablets to the 
pharmacy representative, who will dispense an amount, in a patient-specific labeled bottle. 
9.3.2 Identity of Investigational Product 
The chemical name of amifampridine phosphate is: 
• 3,4-pyridinediamine, phosphate (1:1) diamino-3,4-pyridine, phosphate salt 
• 3,4-diaminopyridine phosphate 
The chemical structure is provided in Figure 1. 
Figure 1. Chemical Structure of Amifampridine Phosphate 
 
H3PO4
N
NH2
NH2
4
1
2
3

 
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9.3.2.1 Product Characteristics and Labeling 
Drug product is formulated as a phosphate salt of amifampridine. Tablets were developed to 
provide the equivalent of 10 mg of amifampridine base for oral administration. Each tablet 
contains amifampridine phosphate, microcrystalline cellulose, colloidal anhydrous silica, and 
calcium stearate. The bottles of tablets are labeled “Amifampridine Phosphate Tablets, 
10 mg.” 
The tablets are to be dispensed by the site pharmacy representative into suitably sized 
pharmacy containers for patient use. Placebo will be provided as tablets indistinguishable 
from amifampridine, sent to the research pharmacy representative. The amifampridine tablets 
and placebo tablets will be clearly labeled as to their identity, and the pharmacist is 
responsible for dispensing the amifampridine tablets or placebo tablets, as needed, for each 
patient. 
Each bottle provided to patients will be labeled to include the compound name, site number, 
patient ID number, date dispensed, storage instructions, the statement ‘Caution – New Drug – 
Limited by Federal law to investigational use,’ trial number, manufacturer name and address, 
and area for instructions for use. Any additional regional label requirements and translations 
will be included in accordance with local regulations. 
9.3.2.2 
Storage 
At the study site, all IP must be stored under the conditions specified, 20-25 degrees Celsius 
and in a secure area accessible only to the designated pharmacist and clinical site personnel. 
All IP must be stored and inventoried, and the inventories must be carefully and accurately 
documented according to applicable national and local regulations, ICH GCP, and study 
procedures. 
9.3.3 Directions for Administration 
All doses of study treatment will be taken at home, except one of the doses on the day of the 
in-clinic study visits, when it will be administered by study personnel and will be 
administered in the clinic to facilitate timing of efficacy assessments. Test medication should 
be taken every day at approximately the same time, at the dose and frequency instructed by 
Investigator. On the day of an in-clinic study visit (Days 0 and 10), dose administration will 
be the medication the patient has been taking for the previous days, but administered by the 
study personnel 45 minutes before the first efficacy assessment. If the patient takes the dose 
three times a day, the patient should be given specific instructions on dosing relative to the 

 
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time of their visit to assure a dose will be given during the in-clinic visit within the required 
time window.  All safety assessments will be performed before the dose administered to the 
patient during the in-clinic visit.  Efficacy assessment will be performed at standardized 
times relative to the dose administered in the clinic. 
Assessment 
Start Time  
After Dose 
(+ 10 minutes unless 
otherwise specified) 
MG-ADL 
45 minutes 
QMG 
After MG-ADL 
 
The dose of amifampridine will be individually determined by the Investigator, within the 
bounds of a total daily dose of 30 mg to 80 mg, divided into doses taken 3 to 4 times per day 
as prescribed by the Investigator, based on optimal neuromuscular benefit. The maximum 
single dose is 20 mg. Amifampridine dose will be titrated upward every 3 to 4 days, starting 
at 10 or 15 mg/day, at the discretion of the Investigator. Patients will either visit or have 
telephone/video contact with the site for each dose titration and at least one in-person site 
evaluation at Week 3 of the run-in period. When the Investigator determines that the patient 
has reached the maximal tolerable and efficacious dose, the patient should demonstrate they 
can remain on a stable dose and frequency for at least an additional 7 days.  The Open-label 
Run-in period may be extended if additional time is needed for dose titration. At the end of 
this period, patients must show a ≥2-point improvement in MG-ADL from start of Run-in, to 
be eligible for randomization (Day 0). 
9.3.4 Method of Assigning Patients to Treatment Groups 
Patients will be stratified according to the type of MG (MuSK or AChR), randomized on the 
last day of the open-label run-in period (Day 0), in a 1:1 ratio, to either amifampridine or 
placebo. IP will be administered under double-blind conditions. Randomized patients who 
discontinue after initiation of treatment may be replaced. 
The randomization code will be provided by an Interactive Web Randomization System 
(IWRS) to the site Pharmacist. Details will be included in the Pharmacy Manual.  

 
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9.3.5 Selection of Doses Used in the Study 
The usual amifampridine dose range is 30 to 80 mg total daily dose, given in 3 or 4 divided 
doses, with no single dose >20 mg. Safety of a single maximum dose of 20 mg is based on 
completed animal and in vitro pharmacology, PK, and toxicology studies.  
9.3.6 Blinding 
This is a double-blind, treatment withdrawal study where both the patient and Investigator 
will be blinded to treatment assignment. 
9.3.7 Treatment Compliance 
Patients will be instructed to complete a Dosing Diary of study medication taken and return 
the Diary, all IP containers and remaining test medication at each study visit. Patient 
compliance with the dosing regimen will be assessed by reconciliation of the used and 
unused IP. The quantity dispensed, returned, used, lost, etc., must be recorded on the 
medication dispensing log provided for the study. 
9.3.8 Investigational Product Accountability 
The study site pharmacy representative is responsible for maintaining accurate records 
(including dates and quantities) of IP(s) received, patients to whom IP is dispensed (patient-
by-patient dose specific accounting), IP returned, and IP lost or destroyed. The Investigator, 
study site pharmacy representative or designee must retain all unused or expired study 
supplies until the study monitor (on-site CRA) has confirmed the accountability data. 
9.3.9 Return and Disposition of Clinical Supplies 
Unused IP must be kept in a secure location for accountability and reconciliation by the study 
monitor. The Investigator or designee must provide an explanation for any destroyed or 
missing IP or study materials. 
Unused IP may be destroyed on site, per the site’s standard operating procedures, but only 
after Catalyst has granted approval for drug destruction. The monitor must account for all IP 
in a formal reconciliation process prior to IP destruction. All IP destroyed on site must be 
documented. Documentation must be provided to Catalyst and retained in the Investigator 
study files. If a site is unable to destroy IP appropriately, the site can return unused IP to 
Catalyst upon request. The return of IP or IP materials must be accounted for on a Study 
Drug Return Form provided by Catalyst. 

 
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All IP and related materials should be stored, inventoried, reconciled, and destroyed or 
returned according to applicable regulations and study procedures. 
9.4 
Prior and Concomitant Medications 
All prescription and over-the-counter medications and herbal and nutritional supplements 
taken by a patient for 14 days before the Screening visit will be recorded on the designated 
CRF. Additionally, the stop date of any medications the patient was taking within 6 months 
before Screening that are excluded or restricted by the protocol will be recorded.  
The Investigator may prescribe additional medications during the study, if the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be 
notified of the use of any contraindicated medications immediately thereafter. Any 
concomitant medications added or discontinued during the study should be recorded on the 
CRF. 
Medications prohibited during the study are listed in Table 2.   
Table 2. 
Medications Prohibited During Study 
Immunomodulatory treatment (e.g. plasma exchange [PE], therapeutic plasma exchange [TPE], 
intravenous immunoglobulin G [IVIG]) should not be given in the previous 4 weeks prior to 
Randomization or at any time during the study. 
Rituximab or similar biological medication within 6 months before Screening or during the study. 
Any investigational product (other than amifampridine) or an investigational medical device within 
60 days before Screening. 
 
Concomitant use of amifampridine with medicinal products with atropinic effects may 
reduce the effect of amifampridine, which should be taken into consideration. 
9.5 
Dietary or Other Protocol Restrictions 
9.5.1 Dietary Restrictions 
There are no dietary restrictions for patients during any part of this study. 

 
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9.5.2 Contraception 
Sexually active males and females of childbearing potential and their partners must use 
effective forms of contraception, such as condom for males or occlusive cap (diaphragm or 
cervical/vault caps) for females, during the study.   
9.6 
Safety Variables 
Safety in this study will be determined from evaluation of AEs/SAEs, vital signs 
assessments, clinical laboratory assessments, ECGs, and physical examinations. Pregnancy 
testing is also required for females of childbearing potential. The timing of the required 
evaluations is described in the Schedule of Events in Table 1 and in Section 12. 
9.6.1 Adverse Events 
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10.  
9.6.2 Vital Signs 
Specific visits for obtaining vital signs are provided in Table 1 and in Section 12. Vital signs 
will be measured while in a sitting position, after resting for 5 minutes, and include SBP and 
DBP measured in millimeters of mercury (mmHg), heart rate in beats per minute, respiration 
rate in breaths per minute. Weight (kg) and temperature in degrees Celsius (°C) will also be 
measured. Clinically significant changes from baseline will be recorded as AEs. 
9.6.3 Clinical Laboratory Assessments 
Specific visits for obtaining clinical laboratory assessment samples are provided in Table 1 
for the tests required by Protocol. The scheduled clinical laboratory tests are listed in Table 3. 
All abnormal clinical laboratory result pages should be initialed and dated by an Investigator, 
along with a comment for each abnormal result indicating whether or not it is clinically 
significant. Any abnormal test results determined to be clinically significant by the 
Investigator should be repeated (at the Investigator’s discretion) until the cause of the 
abnormality is determined, the value returns to baseline or to within normal limits, or the 
Investigator determines that the abnormal value is no longer clinically significant. 
Each clinically significant laboratory result should be recorded as an AE. The diagnosis, if 
known, associated with abnormalities in clinical laboratory tests that are considered clinically 
significant by the Investigator will be recorded on the AE CRF. 

 
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Table 3. 
Clinical Laboratory Tests 
Blood Chemistry 
Hematology 
Urine Tests 
Other 
Albumin  
Hemoglobin  
Appearance 
Pregnancy test, if applicable 
Alkaline phosphatase  
Hematocrit  
Color 
ALT (SGPT) 
WBC count 
pH 
 
AST (SGOT) 
RBC count 
Specific gravity 
 
Direct bilirubin 
Platelet count 
Ketones 
 
Total bilirubin 
Differential cell count  
Protein  
 
BUN 
 
Glucose  
 
Calcium 
 
Bilirubin 
 
Chloride 
 
Nitrite 
Total cholesterol 
 
Urobilinogen 
 
CO2 
 
Hemoglobin 
 
Creatine phosphokinase 
 
 
 
Creatinine 
 
Urine drug screen (Day 
10 only) 
 
Glucose 
 
 
 
GGT 
 
 
LDH 
 
 
Phosphorus 
 
 
 
Potassium 
 
 
Total protein  
 
 
 
Sodium  
 
 
 
Uric acid 
 
 
 
 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CO2, carbon 
dioxide; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; RBC, red blood cell; SGOT, serum 
glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase; WBC, white blood cell. 
 
9.6.4 Pregnancy Testing 
Female patients of childbearing potential will have a serum (at Screening) or urine pregnancy 
test at any other time points specified in the Schedule of Events (Table 1 ) and in Section 12. 
Female patients with a positive pregnancy test at Screening do not meet eligibility criteria for 
enrollment. Additional pregnancy tests will be performed at any visit in which pregnancy 
status is in question. 
Refer to Section 10.4 for details on the reporting procedures to follow in the event of 
pregnancy. 

 
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9.6.5 Electrocardiogram (ECG) 
A standard 12-lead safety ECG (single tracing) will be recorded with the patient resting 
comfortably in the supine position at the time points specified in the Schedule of Events 
(Table 1) and in Section 12. Clinically significant changes from baseline will be recorded as 
AEs.  
9.6.6 Physical Examination 
A complete physical examination is to be performed at each clinic visit or, if applicable, at 
early discontinuation from the study. Complete physical examination will include 
assessments of general appearance as well as the following: 
• Head 
• Eyes 
• Ears 
• Nose 
• Throat 
• Cardiovascular 
• Dermatologic 
• Lymphatic 
• Respiratory 
• Gastrointestinal 
• Musculoskeletal 
Weight (kg.) will be measured with each physical examination throughout the study. Height 
(cm.) will be measured at screening only. 
Other body systems may be examined. Clinically significant changes from baseline will be 
recorded as AEs. 

 
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9.7 
Efficacy Variables 
The timing of required evaluation is described in the Schedule of Events in Table 1 following 
the sequence listed below. 
Assessment 
Start Time  
After Dose 
(± 10 minutes unless 
otherwise specified) 
MG-ADL 
45 minutes 
QMG 
After MG-ADL 
 
9.7.1 Myasthenia Gravis-Specific Activities of Daily Living (MG-ADL) 
The MG-ADL is a self-report scale designed to assess the patient’s MG symptoms and 
functional performance of activities of daily living. The MG-ADL consists of 8 items 
(derived from symptom-based components of the original 13-item Quantitative Myasthenia 
Gravis test) to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory 
(1 item) and gross motor or limb (2 items) impairment related to effects from MG 
(Appendix 1). Each of the 8 items is rated using a response scale ranging from 0 (normal) to 
3 (most severe). Lower scores indicate better functional performance. In this trial, the recall 
period for MG-ADL will be the preceding 9 or 10 days.  
9.7.2 Quantitative Myasthenia Gravis (QMG) 
The QMG score will be used to assess the patient’s general body strength and fatigability 
Appendix 2). (The QMG will be administered at the protocol specified time points by the 
same evaluator throughout the study. Detailed instructions for the QMG assessment are 
provided in the MSK-002 Study Reference Manual. 
10 REPORTING ADVERSE EVENTS 
10.1 Adverse Events 
For this protocol, a reportable AE is any untoward medical occurrence (e.g. sign, symptom, 
illness, disease or injury) in a patient administered the IP or other protocol-imposed 
intervention, regardless of attribution. This includes: 
• AEs not previously observed in the patient, that emerge during the study. 

 
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• Pre-existing medical conditions judged by the Investigator to have worsened in 
severity or frequency or changed in character during the study. 
• Complications that occur as a result of non-drug protocol-imposed interventions. 
An adverse drug reaction is any AE for which there is a reasonable possibility that the IP 
caused the AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the IP and the AE. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis. 
The study period during which all non-serious AEs will be reported begins after the first 
administration of study drug through the termination visit or at the early termination visit. 
After informed consent but prior to initiation of study treatment, only SAEs associated with 
any protocol-imposed interventions will be reported. The criteria for determining, and the 
reporting of SAEs is provided in Section 10.2. 
The Investigator should follow all unresolved AEs until the events are resolved or stabilized, 
the patient is lost to follow-up, or it has been determined that the study treatment or 
participation is not the cause of the AE. Resolution of AEs (with dates) should be 
documented on the appropriate CRF page(s) and in the patient’s medical record. 
The Investigator responsible for the care of the patient or qualified designee will assess AEs 
for severity, relationship to IP, and seriousness (refer to Section 10.2 for SAE definition). 
Severity (as in mild, moderate or severe headache) is not equivalent to seriousness, which is 
based on patient/event outcome or action criteria usually associated with events that pose a 
threat to a patient’s life or functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations.  
The Investigator will determine the severity of each AE using grades defined in Table 4 
(the event will be recorded on the source documents and AE CRF). Events that are Grades 4 
and 5 are serious events and require completion of both an SAE form and AE CRF.  

 
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Table 4. 
Categories of Severity for Adverse Events 
Severity 
Description 
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 ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated. 
Note: Grade 4 and 5 
adverse events should 
always be reported as 
serious adverse events 
Grade 5 
Death related to AE. 
Activities of Daily Living (ADL) 
* Instrumental ADLs refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
** Self-care ADLs refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
The Investigator will suggest the relationship of an AE to the IP and will record it on the 
source documents and AE CRF, using the relationship categories defined in Table 5. 

 
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Table 5. Description of Relationship to Adverse Event Categories 
Relationship 
Category 
Description 
Not Related 
Exposure to the IP has not occurred 
OR 
The administration of the IP and the occurrence of the AE 
are not reasonably related in time  
OR 
The AE is considered likely to be related to an etiology other 
than the use of the IP; that is, there are no facts [evidence] or 
arguments to suggest a causal relationship to the IP. 
Possibly 
Related 
The administration of the IP and the occurrence of the AE 
are reasonably related in time 
AND 
The AE could be explained equally well by factors or causes 
other than exposure to the IP. 
Probably 
Related 
The administration of IP and the occurrence of the AE are 
reasonably related in time  
AND 
The AE is more likely explained by exposure to the IP than 
by other factors or causes. 
 
In order to classify AEs and diseases, preferred terms will be assigned by the sponsor to the 
original terms entered in the CRF, using Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. 
10.2 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets 
1 or more of the following criteria: 
• Is fatal 
• Is life threatening 
• Note: Life-threatening refers to an event that places the patient at immediate risk 
of death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death 
• Requires or prolongs in-patient hospitalization 

 
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• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect, that is, an AE that occurs in the child or fetus 
of a patient exposed to IP prior to conception or during pregnancy 
• Is an important medical event or reaction.  
The reporting period for SAEs begins after informed consent is obtained and continues 
through 4 weeks after the last visit.  
Any SAE, whether or not considered related to study drug, must be reported within 24 hours 
of knowledge of the event by forwarding (fax, email) the study-specific SAE Report Form to 
Catalyst. The Investigator should not wait to collect information that fully documents the 
SAE before notifying Catalyst. As additional information becomes available, including but 
not limited to the outcome of the SAE and any medication or other therapeutic measures used 
to treat the event, it must be reported within 24 hours in a follow-up report. 
The Investigator should follow all unresolved SAEs until the events are resolved or 
stabilized, the patient is lost to follow-up, or it has been determined that the study treatment 
or participation is not the cause of the AE. Resolution of AEs (with dates) should be 
documented in the CRF and in the patient’s medical record. 
For some SAEs, Catalyst may follow up by telephone, fax, email, and/or a monitoring visit to 
obtain additional case details deemed necessary to appropriately evaluate the SAE report 
(e.g. hospital discharge summary, consultant report, autopsy report). 
At the last scheduled visit, the Investigator should instruct each patient to report any 
subsequent SAEs that the patient’s personal physician(s) believes might be related to prior 
study treatment. 
The Investigator should notify Catalyst of any death or SAE occurring at any time after a 
patient has discontinued, or terminated study participation, if felt to be related to prior study 
treatment. Catalyst should also be notified if the Investigator should become aware of the 
development of cancer, or of a congenital anomaly, in a subsequently conceived offspring of 
a patient that participated in this study.  
Reporting of SAEs to the IRB/IEC/REB will be done in compliance with the standard 
operating procedures and policies of the IRB/IEC/REB and with applicable regulatory 
requirements. Adequate documentation must be provided showing that the IRB/IEC/REB 
was properly and promptly notified as required. 

 
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10.3 Safety Blood Collection 
Patients who experience a serious or severe AE should have, at the discretion of the 
Investigator, a blood sample drawn for safety labs as soon as possible after the AE. 
Additional blood sampling may be performed at any time during the study if warranted to 
monitor patient safety. 
10.4 Pregnancy 
Pregnancy in a patient or partner should be reported within 24 hours of the site becoming 
aware of the pregnancy by fax or email of the Pregnancy Reporting Form in the study 
reference materials to Catalyst. In addition, pregnancy in a patient is also reported on the End 
of Study CRF. The Investigator must make every effort to follow the patient through 
resolution of the pregnancy (delivery or termination) and to report the resolution on the 
follow-up form (Pregnancy Reporting Form: Additional Information) in the study reference 
materials. In the event of pregnancy in the partner of a study patient, the Investigator should 
make every reasonable attempt to obtain the woman’s consent for release of protected health 
information. 
10.5 Urgent Safety Measures 
The regulations governing clinical trials state that the sponsor and Investigator are required to 
take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
subjects, the sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the subjects against any immediate hazard. The sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/IEC/REB is notified at the same time.” The reporting period for urgent safety measures 
is the period from the time of signing of the ICF through the completion of the last study 
visit. Investigators are required to report any urgent safety measures with 24 hours. 

 
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Examples of situations that may require urgent safety measures include discovery of the 
following: 
• An immediate need to revise IP administration (i.e. modified dose amount or 
frequency not defined in protocol). 
• Lack of study scientific value, or detrimental study conduct or management. 
• Discovery that the quality or safety of IP does not meet established safety 
requirements. 
 
10.6 Medical Monitor Contact Information 
Contact information and additional requirements will be provided in the MuSK-002 Study 
Reference Manual. 
The Investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the study Medical 
Monitor is listed below. 
Gary Ingenito, MD, PhD 
Chief Medical Officer 
Catalyst Pharmaceuticals, Inc. 
Tel: +1 305-420-3223 
Email: gingenito@catalystpharma.com 
 
11 APPROPRIATENESS OF MEASUREMENTS 
The measures of safety used in this study are routine clinical and laboratory procedures. 
The efficacy measures use a variety of approaches to evaluate changes in neuromuscular 
function and muscle strength. These standardized tests have been previously used for 
determination of response to therapeutic intervention in patients with MG and in other 
indications and, thus, are relevant for use in this study in patients with MG. 
 
 
 
 

 
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12 STUDY PROCEDURES 
12.1 Screening Visit 
An ICF must be signed and dated by the patient, the Investigator or designee, and witness (if 
required) before any study-related procedures are performed. Refer to Section 9.4 for 
prohibited medications. 
After patients have signed an ICF, they will be screened for enrollment into the study. The 
study activities listed below will be performed during the 14 days that constitute the 
Screening visit. 
• Informed Consent; 
• Inclusion/Exclusion criteria; 
• Demographics (sex, race, ethnic origin, age); 
• Medical history, including allergy history; 
• Standard resting 12-lead ECG; 
• Complete physical examination including weight and height;  
• Vital signs (seated position), including systolic blood pressure (SBP), diastolic blood 
pressure (DBP), heart rate, respiration, and body temperature;  
• Clinical laboratory tests including hematology, chemistry, and urinalysis; 
• Serum pregnancy test in females of childbearing potential only; 
• MuSK and/or AChR antibody testing (if not previously done and report available); 
• EMG (if not previously done and report available); 
• MG-ADL assessment; 
• QMG score; 
• SAEs; and 
• Concomitant medications. 

 
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12.2 
Open-label Run-in 
Amifampridine dose will be titrated upward every 3 to 4 days, starting at 10 or 15 mg/day, at 
the discretion of the Investigator. Patients will either visit or have telephone/video contact 
with the site for each dose titration and at least one in-person site assessment at Week 3 of 
the run-in period (Table 1). When the Investigator determines that the patient has reached the 
maximal tolerable and efficacious dose, the patient should demonstrate they can remain on a 
stable dose and frequency for at least an additional 7 days.  The Open-label Run-in period 
may be extended if additional time is needed for dose titration. At the end of this period, 
patients must show a ≥2-point improvement in MG-ADL from start of Run-in, to be eligible 
for randomization (Day 0). 
Patients should be given a Drug Dosing Diary to record each dose of their open-label 
medication and instructions on how to complete the form. 
Additional visits are allowed as necessary. Screening visit and start of Run-in (Day 1) may be 
combined into a single visit. 
12.3 
Period 1 
12.3.1 Day 0 
Patients who are deemed eligible for continuation will have the assessments/procedures listed 
below completed on Day 0 after taking a supervised dose of their medication for that day 
during the clinic visit, so that the assessments can occur in the prescribed relation to the time 
of medication administration.  
• Confirmation of Inclusion/Exclusion criteria; 
• Assessment of AEs/SAEs; 
• Complete physical exam with weight; 
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and body 
temperature; 
• Standard resting 12-lead ECG; 
• Clinical laboratory tests including hematology, chemistry, and urinalysis;  
• Urine pregnancy test in females of childbearing potential only; 
• Concomitant medications; 
• Collect patient Drug Dosing Diary and perform IP accountability of open-label 
medication; 

 
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• Efficacy assessments following in-clinic dose of open-label medication, including: 
o MG-ADL; 
o QMG score. 
 
Order of Assessment at Each 
Study Visit (when applicable) 
Start Time  
After Dose 
(+ 10 minutes unless 
otherwise specified) 
MG-ADL 
45 minutes 
QMG 
After MG-ADL 
 
All open-label IP should be collected from the patient. The pharmacy representative will 
dispense bottles containing amifampridine or placebo tablets, depending on the patient’s 
randomization assignment, for daily outpatient administration for 10 days (Days 1-10), 
starting after completion of all assessments on Day 0.  
Patients should be given a Drug Dosing Diary to record each dose of their double-blind 
medication and instructions on how to complete the form. 
Patients continue administration of blinded study medication (amifampridine or placebo) 
until the Day 10 visit.  
12.3.2 Period 1, Day 10 (or Early Termination Visit) 
Patients will report to the study site on Day 10 (+1 day) and have the assessments/procedures 
listed below completed. Study personnel will administer a dose of the patient’s blinded 
medication at the clinic on Day 10, so assessments can be performed according to the 
specified times in relation to the time of dose administration. The medication administered by 
study personnel should be the same as what the patient has been taking for the last 10 days. If 
the patient is taking study medication 3 or 4 times a day, the visit needs to be arranged such 
that one of the doses is administered by the study site personnel. 
• Assessment of AEs/SAEs; 
• Complete physical exam with weight; 
• Vital signs (seated position), including SBP, DBP, heart rate, respiration, and body 
temperature; 
• Urine pregnancy test in females of childbearing potential only; 

 
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• Urine drug screen; 
• Concomitant medications;  
• Collect patient Drug Dosing Diary and perform IP accountability; 
• Efficacy assessments following in-clinic dose of double-blind medication, including: 
o MG-ADL; 
o QMG score. 
 
Order of Assessment at Each 
Study Visit (when applicable) 
Start Time  
After Dose 
(+ 10 minutes unless 
otherwise specified) 
MG-ADL 
45 minutes 
QMG 
After MG-ADL 
 
13 DATA QUALITY ASSURANCE 
Catalyst personnel or designees will visit the study site before initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, CRFs, monitoring requirements, and procedures for reporting AEs/SAEs.  
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization (if applicable), AE/SAE 
reporting, and drug accountability records. A separate unblinded CRA may verify records at 
the site pharmacy. 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
14.1 Statistical and Analytical Plans 
14.1.1 Interim Analyses 
No interim analyses are planned. 

 
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14.2 Analysis Populations 
The following analysis populations will be defined for the study: 
• Safety Population – The safety population will consist of all subjects who are enrolled 
in the study and have received at least one dose of amifampridine. (Subjects who 
begin the run-in period belong to the Safety Population whether they are randomized 
to a treatment or not.) 
• Full Analysis Set (FAS): This population consists of all randomized subjects who 
receive at least 1 dose of IP (amifampridine or placebo) and have at least one post-
treatment efficacy assessment. Subjects will be compared for efficacy according to 
the treatment to which they were randomized, regardless of the treatment actually 
received. 
• Per Protocol (PP): This population is a subset of the FAS population, excluding 
subjects with major protocol deviations. The PP population will include all FAS 
subjects who: 
o Have no major protocol deviations or inclusion/exclusion criteria deviations that 
might potentially affect efficacy, and 
o Subjects who took at least 80% of the required treatment doses.  
o The PP population will be determined before database lock and unblinding 
subject treatment codes. 
The FAS population will be the primary analysis set for all effectiveness analyses.  The 
safety population will be used for the analysis of all safety variables and baseline 
characteristics. The PP population will be used for selected effectiveness analyses. 
Subgroup analyses for efficacy and safety will be performed independently on the MuSK-
MG and AChR-MG groups.  No pooled analyses are planned. 
14.3 Primary Endpoint(s)  
The primary efficacy endpoint of the study is the change in MG-ADL score from Day 0 
(baseline) for MuSK-MG subjects treated with amifampridine and placebo. 
14.4 
Secondary Endpoints  
The secondary efficacy endpoints of the study are: 

 
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• The change in QMG score from Day 0 (baseline) for MuSK-MG subjects treated 
with amifampridine and placebo. 
• The proportion of subjects with a change of 2, or more, in MG-ADL score for 
MuSK-MG subject treated with amifampridine and placebo. 
• The proportion of subjects with a change of 3, or more, in QMG score for MuSK-
MG subjects treated with amifampridine and placebo. 
14.5 Safety Analysis  
Prior to analysis, all AEs will be coded using the MedDRA coding dictionary. Based on these 
coded terms, TEAEs and SAEs will be summarized using system organ class and preferred 
terms, as well as by relationship to treatment. All AEs will be listed, regardless of whether 
they were study treatment related.     
Vital signs will be summarized using descriptive statistics (mean, standard deviation, median, 
minimum, maximum, and number of non-missing observations) by time point.  Changes 
from baseline will also be summarized by post-dose time point. 
Clinical laboratory parameters will be summarized using descriptive statistics (mean, 
standard deviation, median, minimum, maximum, and number of non-missing observations) 
by time point.  Changes from baseline will also be summarized by post-dose time point.  In 
addition, a shift table will be constructed to show the shifts in laboratory results by parameter 
relative to the normal ranges.  The number and percentage of subjects with the following 
shifts will be presented: normal/normal, normal/low, normal/high, low/low, low/normal, 
low/high, high/low, high/normal, and high/high. Similar shift tables will also be constructed 
for physical exam results. ECG results will be summarized in a shift table with the following 
shifts presented: normal/normal, normal/abnormal, abnormal/normal and 
abnormal/abnormal. A table of descriptive statistics for QTc time by treatment and time 
period will be created. 
Additional safety analyses may be performed as described in the SAP for the study. 
14.6 Efficacy Analysis  
14.6.1 Primary Efficacy Endpoint Analyses 
The MuSK-MG subgroup primary endpoint will be analyzed as the change in MG-ADL from 
baseline (Day 0) using the Wilcoxon-Mann-Whitney Rank sum test at a two-sided α of 0.050 
using the FAS population. Descriptive statistics by treatment for the MG-ADL score for Day 
0, Day 10, and change from Day 0 (baseline) will be presented. 

 
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14.6.2 Secondary Efficacy Endpoint Analyses 
A number of secondary endpoints will be analyzed as described below and in the order 
presented below. 
The first secondary endpoint of the MuSK-MG subgroup endpoint will be analyzed as the 
change in QMG from baseline (Day 0) using the Mann-Whitney-Wilcoxon Rank sum test at 
a two-sided α of 0.05 using the FAS population. Descriptive statistics by treatment for the 
QMG score for Day 0, Day 10, and change from Day 0 (baseline) will be presented. 
The next secondary endpoints of the proportion of subjects in the MuSK-MG subject group 
with a change of 2, or more, in MG-ADL score followed by the proportion of subjects with a 
change of 3, or more, in the QMG score will be analyzed by Fischer's exact test at a two-
sided α of 0.050 and using the FAS subject population.  Totals for the proportions for each 
outcome, by treatment for these endpoints for change from Day 0 (baseline) will be 
presented. 
The same statistical analyses, and in the order presented above for the primary and secondary 
analyses, will be conducted for the per protocol (PP) subject population.  However, if the 
FAS and PP populations are the same, the PP analyses will not be done and the case study 
report will indicate that the FAS and PP populations are the same duplicate analyses were not 
needed and were not done. 
14.7 Determination of Sample Size 
The study is powered with respect to the primary endpoint of change in MG-ADL score from 
baseline for the MuSK-MG group of subjects.  The study has approximately 60% power to 
detect a 2 point difference between amifampridine and placebo treatment groups for the 
change in MG-ADL from baseline (day 0).  AChR-MG subjects are not expected to be 
respond robustly and positively and therefore no attempt will be made to adequately power 
the study for this group of study subjects. 
14.8 Changes in the Conduct of the Study or Planned Analyses 
Any change in study conduct considered necessary by the Investigator will be made only 
after consultation with Catalyst, who will then issue a formal protocol amendment to 
implement the change. The only exception is when an Investigator considers that a patient’s 
safety is compromised without immediate action. In these circumstances, immediate approval 
of the chairman of the IRB/IEC/REB must be sought, and the Investigator should inform 
Catalyst and the full IRB/IEC/REB within 2 working days after the emergency occurs. 

 
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Except for minor administrative or typographical changes, the IRB/IEC/REB must review 
and approve all protocol amendments. Protocol amendments that influence patient risk or the 
study objectives, or require revision of the ICF, must receive approval from the 
IRB/IEC/REB prior to their implementation. 
When a protocol amendment substantially alters the study design or the potential risks or 
burden to patients, the ICF will be amended and approved by Catalyst and the IRB/IEC/REB, 
and all active patients must again provide informed consent. 
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will 
prevail. 
15 COMPENSATION, INSURANCE, AND INDEMNITY 
There will be no charge to study patients to be in this study. Catalyst will pay all costs of 
tests, procedures, and treatments that are part of this study (as included in the site budget). In 
addition, after IRB/IEC/REB approval, Catalyst may reimburse the cost of travel for study-
related visits. Catalyst will not pay for any hospitalizations, tests, or treatments for medical 
problems of any sort, whether or not related to the study patient’s disease that are not part of 
this study. Costs associated with hospitalizations, tests, and treatments should be billed and 
collected in the way that such costs are usually billed and collected. 
The Investigator should contact Catalyst immediately upon notification that a study patient 
has been injured by the IP or by procedures performed as part of the study. Any patient who 
experiences a study-related injury should be instructed by the Investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The patient should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. The 
treating physician should bill the patient’s health insurance company or other third-party 
payer for the cost of this medical treatment. If the patient has followed the Investigator’s 
instructions, Catalyst will pay for reasonable and necessary medical services to treat the 
injuries caused by the IP or study procedures, if these costs are not covered by health 
insurance or another third party that usually pays these costs. In some jurisdictions, Catalyst 
is obligated by law to pay for study-related injuries without prior recourse to third party 
payer billing. If this is the case, Catalyst will comply with the law. 

 
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16 CASE REPORT FORMS AND SOURCE DOCUMENTS 
The CRO data management department or designee will perform all data management 
activities, including the writing of a data management plan outlining the systems and 
procedures to be used. 
Electronic case report forms (eCRFs) will be provided. The eCRF system, and procedures, 
and electronic signatures follow ICH requirements and applicable laws and local regulations. 
All system users will be trained on the eCRF before being granted system access. In the 
event of an entry error, or if new information becomes available, users will correct the value 
by deselecting the erroneous response and then selecting or entering the factual response. The 
documented audit trail will include the reason for the change, the original value, the new 
value, the time of the correction and the identity of the operator. 
In the application, study data on the eCRFs will be verified to the source data, which 
necessitates access to all original recordings, laboratory reports, and patient records. 
In addition, all source data should be attributable (signed and dated). The Investigator must 
therefore agree to allow direct access to all source data. Patients must also allow access to 
their medical records, and patients will be informed of this and will confirm their agreement 
when giving informed consent. The Investigator must review and electronically sign the 
completed eCRF casebook to verify its accuracy. A CRA designated by Catalyst will 
compare the eCRFs in the application with the original source documents at the study site 
and evaluate them for completeness and accuracy before designating them as “Source Data 
Verified” in the application. If an error is discovered at any time or a clarification is needed, 
the Data Manager, CRA, or designee, will create an electronic query on the associated field. 
Site personnel will then answer the query by either correcting the data or responding to the 
query. The Data Manager or CRA will then review the response and determine either to close 
the query or re–query the site if the response does not fully address the question. This process 
will be repeated until all open queries are answered and closed. 
The CRO’s data management department may receive electronic transfers of laboratory data 
from the site’s local laboratory as well as other data from third-party vendors as appropriate.  
The Investigator will then electronically sign the casebook, specifying that the information 
on the eCRFs is accurate and complete. An electronic copy of each site’s casebooks will be 
sent to each site for retention with other study documents.  

 
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17 STUDY MONITORING AND AUDITING 
Qualified individuals approved and/or designated by Catalyst will monitor all aspects of the 
study according to GCP and SOPs for compliance with applicable government regulations. 
The Investigator agrees to allow these monitors direct access to the clinical supplies, 
dispensing, and storage areas and to the clinical files, including original medical records, of 
the study patients, and, if requested, agrees to assist the monitors. The Investigator and staff 
are responsible for being present or available for consultation during routinely scheduled site 
visits conducted by Catalyst or its designees.  
Members of Catalyst’s GCP Quality Department or designees may conduct an audit of a 
clinical site at any time before, during, or after completion of the study. The Investigator will 
be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other regulatory agencies may also conduct an audit of the 
study. If informed of such an inspection, the Investigator should notify Catalyst immediately. 
The Investigator will ensure that the auditors have access to the clinical supplies, study site 
facilities, original source documentation, and all study files. 
18 RETENTION OF RECORDS 
The Investigator must retain all study records required by Catalyst and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a Catalyst 
representative before disposal of any study records, and must notify Catalyst of any change 
in the location, disposition or custody of the study files. The Investigator/institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (e.g. patient charts) 
as well as any original source documents that are electronic as required by applicable 
regulatory requirements.  
All study records must be retained for at least 2 years after the last approval of a marketing 
application in an ICH region and until (1) there are no pending or contemplated marketing 
applications in an ICH region or (2) at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IP. The Investigator/institution should retain 
patient identifiers and records for at least 15 years after the completion or discontinuation of 
the study. Patient files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice. These documents should be retained 

 
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for a longer period, however, if required by the applicable regulatory requirements or by a 
Catalyst agreement. Catalyst must be notified and will assist with retention should 
Investigator/institution be unable to continue maintenance of patient files. It is the 
responsibility of Catalyst to inform the Investigator /institution as to when these documents 
no longer need to be retained. 
19 USE OF INFORMATION AND PUBLICATION 
Catalyst recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and at seminars or conferences. 
The details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this study will be described in the Clinical Trial 
Agreement between Catalyst and the institution of the Investigator. 

 
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20 REFERENCES 
Bertorini TE, Rashed H, Zeno M, et al. Effects of 3-4 diaminopyridine (DAP) in motor 
neuron diseases. J Clin Neuromusc Dis 12[3], 129-137. 2011. 
 
Beeson D, Hantaï D, Lochmüller H, Engel AG.  126th International Workshop: Congenital 
Myasthenic Syndromes, 24–26 September 2004, Naarden, The Netherlands.  Neuromuscul 
Disord 2005;15:498-512. 
 
Bever CT, Anderson PA, Leslie J, Panitch HS, et al. Treatment with oral 3,4 diaminopyridine 
improves leg strength in multiple sclerosis patients: results of a randomized, double-blind, 
placebo-controlled, crossover trial. Neurology 47[6], 1457-1462. 1996.  
 
Boerma CE, Rommes JH, van Leeuwen RB, Bakker J. Cardiac arrest following an iatrogenic 
3,4-diaminopyridine intoxication in a patient with Lambert-Eaton myasthenic syndrome. J 
Toxicol Clin Toxicol 33[3], 249-251. 1995.  
 
Cascorbi I, Drakoulis N, Brockmoller J, Maurer A, et al. Arylamine N-acetyltransferase 
(NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation 
with phenotypic activity. Am J Hum Genet 57[3], 581-592. 1995.  
 
Engelsen BA, Gronning M. Epileptic seizures in patients with multiple sclerosis. Is the 
prognosis of epilepsy underestimated? Seizure 6[5], 377-382. 1997. 
 
Evoli A, Alboini PE, Damato V, Iorio R. 3,4-Diaminopyridine may improve myasthenia 
gravis with MuSK antibodies. Neurology. 2016;86(11):1070–1 
 
Flet L, Polard E, Guillard O, Leray E, et al. 3,4-Diaminopyridine safety in clinical practice: 
an observational, retrospective cohort study. J Neurol . 2010.  
 
Fukino K, Sasaki Y, Hirai S, Nakamura T, et al. Effects of N-acetyltransferase 2 (NAT2), 
CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of 
isoniazid and metabolites in tuberculosis patients. J Toxicol Sci 33[2], 187-195. 2008.  
 
Harper CM, Engel AG.  Treatment of 31 congenital myasthenic syndrome (CMS) patients 
with 3,4-diaminopyridine (DAP).  Neurology 2000;54(Suppl 3):A395 
 
Jetter A, Kinzig M, Rodamer M, Tomalik-Scharte D, et al. Phenotyping of N-
acetyltransferase type 2 and xanthine oxidase with caffeine: when should urine samples be 
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Kinnunen E, Koskenvuo M, Kaprio J, Aho K. Multiple sclerosis in a nationwide series of 
twins. Neurology 37[10], 1627-1629. 1987. 
 
Lindquist S, Stangel M. Update on treatment options for Lambert-Eaton myasthenic 
syndrome: focus on use of amifampridine. Neuropsychiatr Dis Treat 7, 341-349. 2011. 
 
Lundh H, Nilsson O, Rosen I, Johansson S. Practical aspects of 3,4-diaminopyridine 
treatment of the Lambert-Eaton myasthenic syndrome. Acta Neurol Scand 88[2], 136-140. 
1993.  
 
Lundh H, Nilsson O, Rosen I. Treatment of Lambert-Eaton syndrome: 3,4-diaminopyridine 
and pyridostigmine. Neurology 34[10], 1324-1330. 1984.  
 
Maddison P, Newsom-Davis J, Mills KR. Effect of 3,4-diaminopyridine on the time course 
of decay of compound muscle action potential augmentation in the Lambert-Eaton 
myasthenic syndrome. Muscle Nerve 21[9], 1196-1198. 1998a. 
 
Maddison P, Newsom-Davis J, Mills KR. Distribution of electrophysiological abnormality in 
Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 65, 213-217. 1998b. 
 
McEvoy KM, Windebank AJ, Daube JR, Low PA. 3,4-Diaminopyridine in the treatment of 
Lambert-Eaton myasthenic syndrome. N Engl J Med 321[23], 1567-1571. 1989.  
 
Moreau T, Sochurkova D, Lemesle M, Madinier G, et al. Epilepsy in patients with multiple 
sclerosis: radiological-clinical correlations. Epilepsia 39[8], 893-896. 1998. 
 
Palace J, Wiles CM, Newsom-Davis J. 3,4-Diaminopyridine in the treatment of congenital 
(hereditary) myasthenia. J Neurol Neurosurg Psychiatry 54[12], 1069-1072. 1991. 
 
Pasnoor M, Wolfe GI, Nations S, Trivedi J, et al. Clincal findings in MuSK-antibody positive 
myasthenia gravis: A U.S. experience.  Muscle & Nerve 41, 370 - 374. 2010 
 
Sabbagh A, Darlu P. SNP selection at the NAT2 locus for an accurate prediction of the 
acetylation phenotype. Genet Med 8[2], 76-85. 2006.  
 
Sanders DB, Massey JM, Sanders LL, Edwards LJ. A randomized trial of 3,4-
diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology 54[3], 603-607. 2000.  
 
Sanders DB, Howard JF Jr, Massey JM. 3,4-Diaminopyridine in Lambert-Eaton myasthenic 
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Skjei KL, Lennon VA, Kuntz NL: Muscle specific kinase autoimmune myasthenia gravis in 
children: A case series. Neuromuscul Disorders 2013 Nov;23(11):874-882 
 
Skeie GO, Apostolski S, Evoli A, Gilhus NE, et al. Guidelines for the treatment of 
autoimmune neuromuscular transmission disorders. Eur J Neurol 17[7], 893-902. 2010. 
 
Skeie GO, Apostolski S, Evoli A, Gilhus NE, et al. Guidelines for the treatment of 
autoimmune neuromuscular transmission disorders. Eur J Neurol 13[7], 691-699. 2006.  

 
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21 INVESTIGATOR RESPONSIBILITIES 
21.1 Conduct of Study and Protection of Human Patients 
The Investigator will ensure that: 
• He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of patients. 
• He or she will personally conduct or supervise the study. 
• He or she will inform any potential patients, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in compliance with ICH E6 
(Section 4.8), and other applicable local regulations, are met.  
• He or she will report to the sponsor adverse experiences that occur during the 
investigation in compliance with the standard operating procedures and policies of the 
IRB/IEC/REB and with applicable regulatory requirements. 
• He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments. 
• He or she will ensure that adequate and accurate records are kept in accordance with 
ICH and GCP requirements and to ensure those records are available for inspection. 
• He or she will ensure that the IRB/IEC/REB complies with ICH and GCP 
requirements, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human patients or others are 
reported to the IRB/IEC/REB. Additionally, he or she will not make any changes in 
the research without IRB/IEC/REB approval, except where necessary to eliminate 
apparent immediate hazards to human patients. 
• He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent ICH and GCP requirements. 
• He or she agrees to comply with electronic signature requirements in accordance with 
ICH requirements and applicable laws and local regulations. 

 
MSK-002 
 
Page 62 
 
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27 June 2017 
22 SIGNATURE PAGE 
Protocol Title:  
A Randomized, Placebo-Controlled, Parallel Group Study to Evaluate the Effect of 
Amifampridine Phosphate in Patients with MuSK Antibody Positive Myasthenia Gravis, 
and a Sample of AChR Antibody Positive Myasthenia Gravis Patients 
Protocol Number: MSK-002  
I have read the forgoing protocol and agree to conduct this study as outlined. I agree to 
conduct the study in compliance with all applicable regulations and guidelines, including 
ICH E6, as stated in the protocol, and other information supplied to me. 
 
 
 
 
Investigator Signature 
                                             Date 
 
Printed name:  
 
 
Accepted for Catalyst: 
On behalf of Catalyst, I confirm that Catalyst, as a sponsor will comply with all obligations 
as detailed in all applicable regulations and guidelines. I will ensure that the Investigator is 
informed of all relevant information that becomes available during the conduct of this 
protocol.  
 
 
 
Medical Monitor Signature 
 
Date 
Printed name: 
Gary Ingenito, MD, PhD 
 
Chief Medical Officer 
 
Catalyst Pharmaceuticals, Inc. 
 

 
MSK-002 
 
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APPENDIX 1: MYASTHENIA GRAVIS-SPECIFIC ACTIVITIES OF DAILY 
LIVING (MG-ADL) 
The MG-ADL is a self-report scale designed to assess the patient’s MG symptoms and 
functional performance of activities of daily living. Eight items as listed below will be 
assessed by the patient at the protocol specified time points (see Table 1 ). 
 
 
 
 
 
 
Score 
Grade 
0 
1 
2 
3 
(0, 1, 2, 3) 
1.Talking  
Normal  
Intermittent 
slurring of 
nasal speech 
Constant 
slurring or 
nasal, but can 
be understood 
Difficult to 
understand 
speech 
 
2. Chewing 
Normal 
Fatigue with 
solid food 
Fatigue with 
soft food 
Gastric tube 
 
3.Swallowing 
Normal  
Rare episode of 
choking 
Frequent 
choking 
necessitating 
changes in diet 
Gastric tube 
 
4.Breathing  
Normal 
Shortness of 
breath with 
exertion 
Shortness of 
breath at rest 
Ventilator 
dependence 
 
5. Impairment of 
ability to brush 
teeth or comb hair 
 
None 
Extra effort, but 
no rest 
periods needed 
Rest periods 
needed  
Cannot do one 
of these 
functions 
 
6.Impairment of 
ability to arise 
from a chair 
None  
Mild, 
sometimes uses 
arms 
Moderate, 
always uses 
arms 
Severe, requires 
assistance 
 
7. Double vision  
None 
Occurs, but not 
daily 
Daily, but not 
constant 
Constant 
 
8. Bothersome 
eyelid droop  
None  
Occurs, but not 
daily 
Daily, but not 
constant 
Constant 
 
 
 
 
 
 
MG-ADL 
score 
 
 
 
 
 
(items 1-8) 
 
 
 
 
 

 
MSK-002 
 
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APPENDIX 2 : QUANTITATIVE MYASTHENIA GRAVIS (QMG) 
The QMG assesses the patient’s general body strength and fatigability. The QMG will be 
administered at the protocol specified time points (see Table 1 ) by the same evaluator 
throughout the study.