Phase 3 Open-Label Switch Over Study to Assess Safety, Efficacy & PK of Pegunigalsidase Alfa (PRX-102) 2mg/kg IV Every 4 Weeks for 52 Weeks in Fabry Disease Patients Currently Treated With Enzyme Replacement Therapy Fabrazyme® or Replagal™
Phase: PHASE3
Conditions: Fabry Disease
Sponsor: Protalix

Protocol PB-102-F50 
Protalix Ltd. 
EudraCT:  2017-001528-23 
25 Jul 2018 
______________________________________________________________________________ 
CLINICAL STUDY PROTOCOL 
Protocol Title:  A Phase 3, Open Label, Switch Over Study to Assess the Safety, Efficacy and 
Pharmacokinetics of pegunigalsidase alfa (PRX-102) 2 mg/kg Administered by Intravenous 
Infusion Every 4 Weeks for 52 weeks in Patients with Fabry Disease Currently Treated with 
Enzyme Replacement Therapy: Fabrazyme® (agalsidase beta) or Replagal™ (agalsidase alfa) 
Protocol PB-102-F50 
Investigational Product: 
pegunigalsidase alfa (PRX-102), a PEGylated crossed linked 
recombinant human alpha galactosidase-A 
Indication: 
pegunigalsidase alfa (PRX-102) is indicated for long-term 
enzyme replacement therapy in patients with a confirmed 
diagnosis of Fabry disease (alpha galactosidase A 
deficiency) 
Phase: 
Protocol Version: 
3 
Version 1, 27 March 2017 
Version 2, 06 May 2017 
Version 3, 27 Oct 2017 
Version 4, 2 July 2018 
Version 4.1, 25 July 2018 
Name and Affiliation of 
Principal Investigator: 
A list of the Principal Investigators is maintained in the trial 
master file 
Name and Address of Sponsor: 
Protalix Ltd. 
2 Snunit Street 
Science Park 
Carmiel 20100, Israel 
GCP Statement: 
This study will be performed in compliance with GCP, 
including the archiving of essential documents. 
The information in this document is confidential and is proprietary to Protalix, Ltd. It is understood that information 
in this document shall not be disclosed to any third party, in any form, without prior written consent of Protalix. 
NCT03180840

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 SYNOPSIS 
1
TITLE:  A Phase 3, Open Label, Switch Over Study to Assess the Safety, Efficacy and 
Pharmacokinetics of pegunigalsidase alfa (PRX-102) 2.0 mg/kg Administered by Intravenous 
Infusion Every 4 Weeks for 52 weeks in Adult Patients with Fabry Disease Currently Treated 
with Enzyme Replacement Therapy: Fabrazyme® (agalsidase beta) or Replagal™ (agalsidase 
alfa) 
INVESTIGATIONAL PRODUCT:  Pegunigalsidase alfa, a PEGylated crossed linked 
recombinant human alpha galactosidase-A  
INDICATION:  Pegunigalsidase alfa (PRX-102) is indicated for long-term enzyme 
replacement therapy (ERT) in patients with a confirmed diagnosis of Fabry disease (alpha 
galactosidase deficiency). 
PHASE OF DEVELOPMENT:  3 
INVESTIGATIONAL SITES/LOCATIONS:  Multicenter 
OBJECTIVES:  To evaluate the safety, efficacy and pharmacokinetics of pegunigalsidase alfa 
(PRX-102) in patients with Fabry disease currently treated with currently commercially 
available ERT (agalsidase alfa or agalsidase beta). 
STUDY DESIGN:  This is an open-label switchover study to assess the safety, efficacy, and 
pharmacokinetics of pegunigalsidase alfa treatment of 2 mg/kg every 4 weeks in patients 
previously treated with ERT, agalsidase alfa or agalsidase beta, for at least 3 years and on a 
stable dose (>80% labelled dose/kg) for at least the last 6 months. 
Following screening, patients will be enrolled and switched from their current ERT to receive 
intravenous (IV) infusions of pegunigalsidase 2 mg/kg every 4 weeks for 52 weeks (total of 14 
infusions).  
At the time of enrollment, premedication, if used for the agalsidase alfa or agalsidase beta 
infusions before enrollment, will be continued using the same premedication regimen during 
the first infusion with pegunigalsidase alfa and then will be gradually tapered down at the 
Investigator’s discretion during the next infusions based on Appendix 8. 
First infusions of pegunigalsidase alfa will be administered under controlled conditions at the 
investigation site.  Based on Appendix 8, the patients will be able to receive their 
pegunigalsidase alfa infusions at a home care setup once the Investigator and Sponsor Medical 
Monitor agree that it is safe to do so.  
In the case of clear clinical deterioration, the treatment may be changed to 1.0 mg/kg every 2 
weeks at the Investigator’s discretion and discussion with the Medical Monitor. 

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NUMBER OF SUBJECTS (PLANNED):  Up to 30 but not less than 25. Of the enrolled 
patients, up to 6 of the patients will be females (~20%).   
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION:   
Key inclusion criteria: 
Eligible subjects must fulfill the following inclusion criteria: 
1. Age: 18-60 years 
2. A documented diagnosis of Fabry disease 
3. Males: plasma and/or leucocyte alpha galactosidase activity (by activity assay) less than 
lower limit of normal according to the laboratory reference ranges and one or more of 
the characteristic features of Fabry disease  
a. Neuropathic pain 
b. Cornea verticillata 
c. Clustered angiokeratoma 
4. Females: historical genetic test results consistent with Fabry mutations, or in the case of 
novel mutations a first-degree male relative with Fabry disease, and one or more of the 
characteristic features of Fabry disease 
a. Neuropathic pain 
b. Cornea verticillata 
c. Clustered angiokeratoma 
5. Treatment with agalsidase alfa or agalsidase beta for at least 3 years and on a stable 
dose (>80% labelled dose/kg) for at least 6 months 
6. eGFR ≥ 30 mL/min/1.73 m2 by CKD-EPI equation at screening visit 
7. Availability of at least 3 historical serum creatinine evaluations since starting ERT and 
not more than 2 years old 
8. Female patients and male patients whose co-partners are of child-bearing potential agree 
to use a medically accepted, highly effective method of contraception. These include 
combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or transdermal), progestogen-only 
hormonal contraception associated with inhibition of ovulation (oral, injectable, or 
implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), 
bilateral tubal occlusion, vasectomised partner, or sexual abstinence  
9. Patients whose clinical condition, in the opinion of the Investigator, is suitable for 
treatment with ERT every 4 weeks. 
Key exclusion criteria: 
The presence of any of the following excludes a subject from study enrollment: 
1. History of anaphylaxis or Type 1 hypersensitivity reaction to agalsidase alfa or 
agalsidase beta 
2. History of renal dialysis or transplantation  

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3. Linear negative slope of eGFR of ≥ 2 mL/min/1.73 m2 based on at least 4 serum 
creatinine values over approximately 2 years (including the value obtained at the 
screening visit)  
4. History of acute kidney injury in the 12 months prior to screening, including specific 
kidney diseases (e.g., acute interstitial nephritis, acute glomerular and vasculitic renal 
diseases); non-specific conditions (e.g., ischemia, toxic injury); as well as extrarenal 
pathology (e.g., prerenal azotemia and acute post renal obstructive nephropathy) 
5. Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) 
therapy initiated or dose changed in the 4 weeks prior to screening 
6. Urine protein to creatinine ratio (UPCR) at screening > 0.5 g/g or mg/mg or 500 mg/g 
and not treated with an ACE inhibitor or ARB 
7. Females who are pregnant, planning to become pregnant during the study, or are breast 
feeding 
8. Cardiovascular event (myocardial infarction, unstable angina) in the 6-month period 
before screening 
9. Cerebrovascular event (stroke, transient ischemic attack) in the 6-month period before 
screening 
10. Presence of any medical, emotional, behavioral, or psychological condition that, in the 
judgment of the Investigator and/or Medical Director, would interfere with the patient’s 
compliance with the requirements of the study.  
TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION: Upon confirmation of 
eligibility, patients will be switched to pegunigalsidase alfa 2 mg/kg, administered 
intravenously, every 4 weeks. 
Infusion time with pegunigalsidase alfa changes according to the weight of the patient pending: 
patient tolerability, Investigator evaluation, and Sponsor Medical Monitor/Director’s approval 
and after an attempt to taper down gradually used pre-medication as described in Appendix 8. 
 For patients weighing up to (≤) 100 kg, the infusion length will be 4.5 hours and may be 
reduced gradually to 2 hours   
 For patients weighing more than (>) 100 kg, the first infusion length will be 6 hours and 
may be reduced gradually to 3 hours  
DURATION OF TREATMENT:  52 weeks (14 infusions) with the option to be enrolled in an 
open-label extension study upon completion of the study. 
DISCONTINUATION FROM TREATMENT: Reasons for permanent discontinuation 
include the following: 
 Patient experiences two or more Grade 3 toxicities or one or more Grade 4 toxicity 
considered by the Investigator to be associated with pegunigalsidase alfa treatment 
(CTCAE v. 4.03, 2010) 
 Patient experiences progressive hypersensitivity or severe hypersensitivity that is not 

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allayed with pre-treatment 
 Patient requests to discontinue treatment 
 Investigator feels that it is not in the best interest of the patient to continue treatment 
and/or if the Investigator believes that the patient can no longer be compliant with the 
requirements of the study. 
SAFETY ENDPOINTS: 
Changes from baseline in: 
 Clinical laboratory tests 
 Physical examination 
 Assessment of the injection site 
 Electrocardiogram 
 Treatment-emergent adverse events 
 Ability to taper off infusion premedication  
 Requirement for use of premedication overall to manage infusion reactions 
 Treatment-induced anti-pegunigalsidase alfa antibodies 
EFFICACY EXPLORATORY ENDPOINTS: 
 Estimated glomerular filtration rate (eGFRCKD-EPI) 
 Left Ventricular Mass Index (g/m2) by echocardiogram  
 Plasma Lyso-Gb3 
 Plasma Gb3 
 Urine Lyso-Gb3 
 Protein/Creatinine ratio spot urine test 
 Frequency of pain medication use 
 Exercise tolerance (Stress Test) 
 Short Form Brief Pain Inventory (BPI) 
 Mainz Severity Score Index (MSSI) 
 Quality of life EQ-5D-5L 
PHARMACOKINETICS (PK): Blood samples from all patients will be taken for PK analysis 
on Day 1 and at the end of treatment at Visit 14 (week 52). Blood samples will be drawn for an 
additional intermediate PK analysis at Visit 7 (week 24), for all patients who signed inform 
consent to this version (Version 4) before reaching Visit 7 (week 24), or at Visit 11 (week 40) 
for patients who passed Visit 7 at the time of signing the inform consent to this version.  The 
following (but not limited to) PK parameters will be derived from the plasma concentration 
versus time profiles to determine the PK of the study drug: Cmax, Tmax, t1/2, AUC0-t, and AUC0-∞. 
Blood samples will be drawn at the following time points: pre-infusion (baseline); 1 hour after 
the beginning of the infusion; at the end of the infusion, at 1±0.25, 2±0.25, 4±0.25, 8±0.25, 
24±0.5, 48±3, and 96±3 hours post-infusion and at 14±3, 21±3 and 28±3 days post-infusion 

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before next infusion (a total of 13 timepoint within 28 days). 
STATISTICAL ANALYSIS: 
The sample size of approximately 30 patients is adequate to evaluate the safety of switching 
from agalsidase alfa and agalsidase beta to pegunigalsidase alfa in Fabry disease in which 
patient recruitment in clinical trials is difficult. 
The study endpoints will be evaluated by various summary analyses by study visit and by 
change from baseline data for each efficacy endpoint.  Safety and efficacy endpoints will be 
compared to baseline using summary statistics.  Data will not be analyzed by inferential 
statistics. 
An interim analysis may be conducted for administrative purposes. 
 
 
 

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DOCUMENT APPROVAL 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
applicable regulatory requirements. 
SPONSOR REPRESENTATIVE 
25 July 2018 
_______________________ 
Date 
_______________________ 
Date 
 ___________________________________________
 Signature
PRINCIPAL INVESTIGATOR 
___________________________________________ 
Signature 
Print Name:  ________________________________ 

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TABLE OF CONTENTS 
 
SYNOPSIS ...............................................................................................................................2 
1
 
LIST OF ABBREVIATIONS.................................................................................................11 
2
 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY REQUIREMENTS ........13 
3
 
Institutional Review Board (IRB) ..................................................................................13 
3.1
 
Ethical Conduct of the Study .........................................................................................13 
3.2
 
Subject Information and Consent ..................................................................................13 
3.3
 
INTRODUCTION ..................................................................................................................13 
4
 
Rationale ........................................................................................................................16 
4.1
 
STUDY OBJECTIVES ..........................................................................................................17 
5
 
INVESTIGATIONAL PLAN .................................................................................................17 
6
 
Overall Study Design and Plan – Description ...............................................................17 
6.1
 
Discussion of Study Design ...........................................................................................18 
6.2
 
Selection of Study Population ........................................................................................19 
6.3
6.3.1 Inclusion Criteria ....................................................................................................19 
6.3.2 Exclusion Criteria ...................................................................................................20 
6.3.3 Removal of Subjects from Therapy or Assessment ................................................20 
 
STUDY PRODUCT ...............................................................................................................21 
7
 
Study Medication Supply ...............................................................................................21 
7.1
 
Description and Formulation of Study Product .............................................................21 
7.2
 
Study Drug Dosage and Preparation ..............................................................................21 
7.3
 
Study Drug Administration ............................................................................................22 
7.4
 
Packaging and Labeling .................................................................................................22 
7.5
 
Conditions for Storage and Use .....................................................................................22 
7.6
 
Method of Assigning Subjects to Treatment Groups.....................................................22 
7.7
 
Dispensing, Compliance and Accountability .................................................................23 
7.8
 
Prior and Concomitant Therapy .....................................................................................23 
7.9
 
EFFICACY AND SAFETY ASSESSMENTS ......................................................................23 
8
 
Efficacy Variables ..........................................................................................................23 
8.1
 
Pharmacokinetic Variables ............................................................................................24 
8.2
 
Safety Variables .............................................................................................................24 
8.3
8.3.1 Adverse Events .......................................................................................................25 
8.3.2 Clinical Laboratory .................................................................................................27 
8.3.3 Anti-pegunigalsidase alfa Antibodies .....................................................................27 
8.3.4 Acute Kidney Injury ...............................................................................................28 
 
STUDY PROCEDURES AND FLOW CHART ...................................................................28 
9
 
Study Flow Chart ...........................................................................................................28 
9.1
 
Study Visits ....................................................................................................................29 
9.2
9.2.1 Screening (Visit 0, Visit S, Day -30 ± 10 Days) ....................................................29 
9.2.2 Visit 1 (Baseline, Day 1, 1 ± 3 Days) .....................................................................30 
9.2.3 Week 2 (Day 15±3 days post- 1st infusion) ............................................................32 

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9.2.4 Visit 2 (Week 4 ± 3 days) .......................................................................................32 
9.2.5 Visits  3, 5, 6, 8, 9, 10, 12, and 13 (Weeks  8, 12, 16, 20, 28, 32, 36, 44, 
and 48  3 Days for Each Visit) .............................................................................32 
9.2.6 Visits 4 and 11 (Weeks 12 and 40  3 Days) .........................................................33 
9.2.7 Visit 7 (Week 24  3 Days) ....................................................................................34 
9.2.8 Visit 14 (Week 52  3 Days) ..................................................................................35 
9.2.9 Premature Withdrawal Visit ...................................................................................36 
 STATISTICAL METHODS PLANNED AND SAMPLE SIZE ...........................................36 
10
 Determination of Sample Size .......................................................................................36 
10.1
 Subject Populations ........................................................................................................36 
10.2
10.2.1 Intent-to-Treat (ITT) Population ............................................................................36 
10.2.2 Per Protocol (PP) Population ..................................................................................36 
10.2.3 Safety Population ....................................................................................................36 
 Analysis .........................................................................................................................36 
10.3
10.3.1 Efficacy Variables ..................................................................................................37 
10.3.2 Safety Analysis .......................................................................................................37 
10.3.3 Interim Analysis .....................................................................................................37 
10.3.4 Missing Data ...........................................................................................................37 
 QUALITY CONTROL AND QUALITY ASSURANCE .....................................................38 
11
 Source Data and Records ...............................................................................................38 
11.1
 Reporting of Results ......................................................................................................38 
11.2
 Confidentiality of Subject Data .....................................................................................39 
11.3
 REPORTING AND PUBLICATION .....................................................................................39 
12
 Confidentiality of Study Data ........................................................................................39 
12.1
 REFERENCES .......................................................................................................................40 
13
 APPENDICES ........................................................................................................................43 
14
 Appendix 1.  Vial Label .................................................................................................43 
14.1
 Appendix 2.  Infusion Rate Algorithm ..........................................................................44 
14.2
 Appendix 3.  Pegunigalsidase alfa Evaluation and Treatment Algorithm .....................47 
14.3
 Appendix 4.  The Mainz Severity Score Index (MSSI) .................................................50 
14.4
 Appendix 5.  National Kidney Foundation Guidelines for Chronic Kidney 
14.5
Disease ...........................................................................................................................52 
14.5.1 Estimation of GFR: .................................................................................................52 
14.5.2 CKD-EPI Equation: ................................................................................................52 
 Appendix 6.  QOL Questionnaire - EQ-5D-5L .............................................................53 
14.6
 Appendix 7.  Brief Pain Inventory- BPI (Short Form) ..................................................55 
14.7
 Appendix 8.  Schedule of Premedication, Infusion Rates, and Observation 
14.8
Times Post-Infusion .......................................................................................................57 
 
 
 

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LIST OF TABLES 
Table 1:  Partial AUC/ Cave (by Week) – Modeling Based on Pegunigalsidase alfa Phase 
1/2 Data and Fabrazyme® AUC ~700 µg•min/mL ..........................................................17 
Table 2:  Proposed Regimen of Reduced Premedication, Infusion Length, and Post-
Infusion Observational Period .........................................................................................59 

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 LIST OF ABBREVIATIONS 
2
ACEI 
Angiotensin converting enzyme inhibitor 
AE 
Adverse event 
AKI 
Acute Kidney Injury 
Alpha-GAL-A 
Alpha-Galactosidase-A 
ARB 
Angiotensin II receptor blocker 
AUC0-t 
Area under the concentration-time curve from baseline to a specified time (t) 
AUC0-∞ 
Area under the concentration-time curve from baseline to infinity 
β-hCG 
β-human chorionic gonadotropin (pregnancy test) for females 
BPI 
Brief pain inventory 
Cave 
Average concentration  
C3 
Complement C3 
C4 
Complement C4 
CHO 
Chinese hamster ovary 
CKD 
Chronic kidney disease 
Cmax 
Maximum concentration observed 
CT 
Computed tomography 
DP 
Drug product 
EC 
Ethics Committee 
ECG 
Electrocardiography  
eCRF 
electronic Case Report Form 
eGFR 
Estimated glomerular filtration rate 
ERT 
Enzyme replacement therapy 
FOS 
Fabry Outcome Survey 
Gb3 
Globotriaosylceramide 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
hr 
Hour 
IC 
Informed consent 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
kg 
kilogram 
LLN 
Lower limit of normal 
LVH 
Left ventricular hypertrophy 
LVM 
Left ventricular mass 
Lyso-Gb3 
Globotriaosylsphingosine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PT 
Prothrombin time 
PTT 
Partial Thromboplastin time 
QOL 
Quality of life 

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SAE 
Serious adverse event 
TIA 
Transient ischemic attack 
t1/2 
Terminal plasma half-life, is the time required to divide the plasma concentration by 
two after reaching pseudo-equilibrium 
Tmax 
Time at which the concentration is the maximum value (Cmax) 
USPI 
United States Package Insert 
 
 
 

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ETHICAL CONDUCT OF THE STUDY AND REGULATORY 
3
REQUIREMENTS 
 
Institutional Review Board (IRB) 
3.1
An Institutional Review Board (IRB) or Ethics Committee (EC) will review the study protocol 
and any amendments.  The IRB or EC will also review the informed consent forms, their updates 
(if any), and any written materials given to the subjects. A list of all IRBs and ECs and contact 
information will be included in the study report. 
 
Ethical Conduct of the Study 
3.2
This study will be conducted in accordance with the ethical principles that have their origins in 
the Declaration of Helsinki, in compliance with the approved protocol, GCP and applicable 
regulatory requirements. 
 
Subject Information and Consent 
3.3
The Investigator will obtain a freely given written consent from each subject after an appropriate 
explanation of the aims, methods, anticipated benefits, potential hazards, and any other aspects 
of the study that are relevant to the subject's decision to participate. The consent forms must be 
signed and dated by the subject before he/she is exposed to any protocol-specific procedure. 
The Investigator will explain that the subjects are completely free to refuse to enter the study or 
to withdraw from it at any time, without any consequences for their further care and without the 
need to justify. 
The subject will receive a copy of the subject information and the signed informed consent 
forms.  
The subject will be informed if new information becomes available that may be relevant to 
his/her willingness to continue participation in the study. 
Each subject will be informed that a monitor or a health authority inspector, in accordance with 
applicable regulatory requirements, may review the portions of their source records and source 
data related to the study. Data protection and confidentiality will be handled in compliance with 
local laws. 
 
INTRODUCTION 
4
Fabry disease is a progressive lysosomal storage disease that is seriously debilitating and 
ultimately life-threatening.  It is caused by X-linked deficiency of the enzyme  galactosidase-A (-
GAL-A), and affects both males and females. The disease is characterized by subnormal or 
absent activity of alpha-GAL-A. Clinical onset of the disease typically occurs during childhood 
or adolescence (Schaefer et al., 2009) and will progress to end-stage renal disease, cardiac 
complications, and cerebrovascular problems in the fourth or fifth decade of life (Wilcox et al., 
2008). Although Fabry disease is a X-linked disorder, females are also affected and develop 
manifestations of the disease due to lack of cross-correction between cells with normal alpha-

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GAL-A activity (mutated X chromosome is inactivated) and cells with enzyme deficiency (non-
mutated X chromosome is inactivated). The clinical abnormalities in females are more variable, 
and of later onset compared to males (Schiffmann et al., 2009). 
Fabry disease is regarded as a rare disease and it is estimated that 1 in 40,000 males has the 
disease, whereas the estimated prevalence in the general population is 1 in 117,000 (Meikle et al. 
1999). 
Alpha-GAL-A is a lysosomal enzyme which primarily catalyses the hydrolysis of the glycolipid 
globotriaosylceramide (Gb3) to galactose and lactosylceramide. Fabry disease is characterized 
by massive storage of Gb3, predominantly in cells of the vascular system, cardiomyocytes, 
neuronal cells, and kidney podocytes (Thurberg et al., 2002). Progressive accumulation of Gb3 
and related lipids lead to impaired tissue and organ function. The ultimate consequence of 
glycolipid deposition in the vasculature and other tissues is end-organ failure, particularly the 
kidney, but also heart and cerebrovascular system (Schiffmann et al., 2009). In addition, 
involvement of the central, peripheral, and autonomic nervous systems result in episodes of pain 
and impaired peripheral sensation. Vascular changes in the skin also result in angiokeratomas 
(Hoffmann et al., 2009). The mechanism by which alpha-GAL-A deficiency and glycolipid 
accumulation cause such a wide variety of complications is not well understood. Based on the 
pathology of Fabry disease, the ongoing accumulation of alpha-D-galactosyl moieties, 
particularly of Gb3, appears to be a chronic toxicity state (Schiffmann et al., 2001). A study by 
Aerts et al., reported that globotriaosylsphingosine (lysoGb3), a Gb3 metabolite, is dramatically 
increased in the plasma of male Fabry patients, and plasma and tissues of Fabry mice, and may 
have an important role in the pathogenesis of Fabry disease (Aerts et al., 2008). Increased levels 
of lysoGb3 occur also in symptomatic Fabry females (Van Breemen et al., 2011). 
As Fabry disease is an X-linked disorder, the prevalence of the mutation is predicted to be two 
times higher in women than in men. There is considerable variation in phenotype in 
heterozygous females. However, despite the X-linked nature of the disease, heterozygous and 
therefore tissue-mosaic females can be as severely affected by Fabry disease as hemizygous 
males, experiencing progressive, multi-organ involvement, reduced quality of life, and reduced 
life expectancy. Case-finding studies have reported mutations that are known to be associated 
with Fabry disease in 0.3-2.4% of women who had unexplained stroke, hypertrophic 
cardiomyopathy, or renal failure requiring hemodialysis. A study by Hughes et al., comparing 
men and women with Fabry disease, using data from Fabry Outcome Survey (FOS), showed no 
significant differences between men and women for most clinical features evaluated. Overall, 
both sexes responded to enzyme replacement treatment in a similar way (Hughes et al., 2011). 
Enzyme replacement therapy (ERT), by exogenous administration of purified recombinant 
enzyme, is nowadays among the most successfully employed drug treatments for lysosomal 
storage disorders. The first disorder for which this treatment modality has proven to be effective 
is type 1 Gaucher disease (Barton et al., 1991; Hollak et al., 1995). This success has paved the 
way for the development of ERT for other lysosomal storage disorders, including Fabry disease.  
 
 

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Recombinant human alpha-GAL-A can restore enzyme function in patients, and currently two 
ERTs using this enzyme are available; agalsidase-alfa (Replagal™), that was approved in Europe, 
and agalsidase-beta (Fabrazyme®), that was approved both in Europe and in the United States. 
Both recombinant enzymes are comparable in their properties and differ only slightly in glycan 
composition (Blom et al., 2003). They are produced using different protein expression systems 
and are administered at different doses. Fabrazyme® is produced in Chinese Hamster Ovary 
(CHO) cells and is administered by IV infusion every 2 weeks at a dose of 1 mg/kg. Replagal™ is 
produced in a human cell line (stably expressed in human foreskin fibroblast) (Schiffmann et al., 
2000), and is administrated by IV infusion every 2 weeks at a dose of 0.2 mg/kg. Both products 
have shown their efficacy in clinical studies regarding clearance of Gb3 from plasma, kidney 
cells (such as capillary endothelial cells, glomerular endothelial cells, noncapillary endothelial 
cells, and noncapillary smooth muscle cells), and capillary endothelial cells of the cardiac and 
skin (Eng et al., 2001a; Germain et al., 2007; Schaefer et al., 2009). In addition, ERT with both 
products leads to improvement in quality of life, reduction or stabilization of cardiac mass, 
preservation of renal function, and slowing down the decline of glomerular function (Wilcox et 
al., 2004; Schiffmann et al., 2006; Weidemann et al., 2009; Germain et al., 2007; Schiffmann et 
al., 2009).  Although these findings are encouraging, the clinical effects of the current treatment 
of Fabry patients are not as robust as anticipated and show only limited clinical improvement 
(Schaefer et al., 2009; Lidove et al., 2010; El Dib et al., 2011). 
One of the major factors responsible for the limited efficacy of current treatment is the presence 
of irreversible organ damage. Another factor that may contribute to this is the characteristics of 
the current ERTs (such as short circulatory half-life and dose regimens) which seem to be 
insufficient in preventing the chronic toxic effect of Gb3. One way to improve enzyme 
bioavailability may be to extend circulation residence and tissue half-life. A third factor which 
may influence the treatment outcome is the induction of antibodies towards the recombinant 
proteins (Hollak et al., 2009). Emergence of antibodies with in vivo neutralizing capacities is 
frequently encountered in treated Fabry disease patients, resulting in inhibition of enzyme 
activity and adversely affecting Gb3 clearance (Hollak et al., 2009). In early clinical studies, 25 
to 88% of male patients developed these IgG antibodies within the first 6 months of treatment 
(Schiffmann et al., 2006; Eng et al., 2001; Eng et al., 2001a). Regarding treatment outcome, it 
was shown that antibodies against alpha-GAL-A interfere with the clearance of Gb3 from 
plasma, urine (Linthorst et al., 2004; Vedder et al., 2008), and from the tissue (Benichou et al., 
2009). The cross-reactivity of alpha-GAL-A antibodies suggests that it is unlikely that switching 
from one recombinant protein to the other may prevent the immune response and related effects 
(Linthorst et al., 2004; Hollak et al., 2009). Currently, administration of a higher dose of the 
recombinant enzyme is an effective way to overcome the negative effect of the neutralizing 
antibodies (Vedder et al., 2008; Hollak et al., 2009). However, this approach is not considered a 
long-term solution. 
Protalix has developed pegunigalsidase alfa, a chemically modified recombinant human alpha-
GAL-A expressed in plant cell culture. Because of this modification, pegunigalsidase alfa 
exhibits more stabilized enzymatic activity, extended circulation residence time, and enhanced 
bioavailability of the enzyme relative to the commercial drugs.  

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Pegunigalsidase alfa was studied in Fabry disease patients in a Phase 1/2 study (PB-102-F01) for 
12 weeks and continued in a 9-month extension study (PB-102-F02) for a total duration of one 
year.  The results of these studies from 16 patients who completed the extension study, 6 each in 
the 0.2 mg/kg and 1.0 mg/kg treatment groups and four (4) in the 2.0 mg/kg treatment group, 
demonstrated that after receiving one year of pegunigalsidase alfa  treatment: stable cardiac and 
renal function with favorable trends; Gb3 inclusion in kidney peritubular capillaries was 
substantially reduced; a mean reduction in the total score of the Mainz Severity Score Index 
(MSSI; Whybra et al., 2004) for the severity of Fabry disease in general, neurological, 
cardiovascular, and renal systems; a stable or favorable trend in the severity and frequency of 
abdominal pain and frequency of diarrhea in Gastrointestinal Symptoms Assessment (GSA); and 
reduction in pain severity score and pain interference score with the Brief Pain Inventory (BPI) 
scale, indicating an improvement in general activity, walking, working, sleeping, and enjoyment 
in life. 
The most commonly experienced all-cause adverse events (AEs) were fatigue in 6 patients, and 
nausea and vomiting each in 5 patients. The most commonly experienced AEs that were 
considered possibly related to treatment were nausea in 4 patients, chest discomfort, dizziness, 
maculopapular rash, and fatigue each in 2 patients. Two patients experienced a treatment-related 
serious adverse event (SAE): migraine and bronchospasm. The patient who experienced a Grade 
3 hypersensitivity-related bronchospasm led to the patient’s discontinuation from the study per 
protocol. Pegunigalsidase alfa PK parameters and profile in Fabry patients indicate dose 
dependency. The enzyme was found to be available throughout the 2-week infusion intervals 
with a plasma half-life of approximately 80 hrs. The data from these two studies conclude that 
dosing of pegunigalsidase alfa at 1.0 mg/kg every 2 weeks offers an optimal treatment regimen 
for attenuating disease progression in patients with Fabry disease, while indicating the option, 
based on the enzyme amount delivered, for the use of 2.0 mg/kg every 4 weeks to be used in 
patients with mild to moderate Fabry Disease currently treated with ERT.   
 
Rationale 
4.1
The rationale for this open label, switch over study is based on the enhanced PK profile of 
pegunigalsidase alfa. Phase 1/2 study measurements and PK projection modelling data suggest 
pegunigalsidase alfa 2.0 mg/kg every 4 weeks would be beneficial in patients with Fabry Disease 
currently treated with ERT.   
The weekly projected partial AUC and average concentration (Cave) indicate that there should 
be measurable levels of pegunigalsidase alfa at the third and fourth weeks after infusion in the 
same order of magnitude as Fabrazyme® in the first week after infusion (Table 1:  ). 
Calculations enabled the evaluation/estimation of the drug availability on weeks 1, 2, 3, and 4 of 
pegunigalsidase alfa compared to Fabrazyme® every other week following repeated dosing.  The 
half-life (t½) of 2.0 mg/kg pegunigalsidase alfa is ~ 80 hrs vs. ~2 hrs of Fabrazyme® and 
Replagal™ with Cmax values ~10x greater than those published for Fabrazyme® (Fabrazyme® 
USPI 2016). The estimated Cave of 2.0 mg/kg pegunigalsidase alfa every 4 weeks provides a 
concentration of ~90 ng/mL at the 3rd week and ~10 ng/mL at the 4th week post infusion. Both 
values are greater than the negligible 2nd week Cave values for Fabrazyme® (Table 1:  ). 

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Table 1:  Partial AUC/ Cave (by Week) – Modeling Based on Pegunigalsidase alfa Phase 1/2 
Data and Fabrazyme® AUC ~700 µg•min/mL  
  
pegunigalsidase alfa 2 mg/kg 
Fabrazyme® 1 mg/kg 
IV every 2 weeks 
IV every 4 weeks 
IV every 2 weeks 
Time 
(week) 
Partial 
AUC (week) 
(ng•hr/mL) 
Cave 
for week 
(ng/mL) 
Partial 
AUC 
(ng•hr/mL) 
Cave 
for week 
(ng/mL) 
Partial 
AUC 
(ng•hr/mL) 
Cave 
for week 
(ng/mL) 
1 
989,406 
5,889 
989,406 
5,889 
12,000 
71.4 
2 
119,065 
709 
119,065 
709 
nil 
nil 
3 
1,004,012 
5,976 
14,637 
87 
12,000 
71.4 
4 
120,864 
719 
1,799 
11 
nil 
nil 
5 
1,004,233 
5,978 
989,627 
5,891 
12,000 
71.4 
6 
120,892 
720 
119,092 
709 
nil 
nil 
7 
1,004,233 
5,978 
14,640 
87 
12,000 
71.4 
8 
120,892 
720 
1,800 
11 
nil 
nil 
9 
1,004,233 
5,978 
989,627 
5,891 
12,000 
71.4 
10 
120,892 
720 
119,092 
709 
nil 
nil 
11 
1,004,233 
5,978 
14,640 
87 
12,000 
71.4 
12 
120,892 
720 
1,800 
11 
nil 
nil 
Note: Since the projection was done for repeated dosing, the different shading 
indicates the infusion intervals to make it easier to follow. 
This treatment dose and regimen is aimed as a maintenance program for Fabry patients without 
severe clinical symptoms with relatively slowing disease progression. Additionally, it may 
address the clinical needs of early or younger diagnosed patients. 
The unique PK parameters of pegunigalsidase alfa with the proposed dose and regimen have the 
potential to results with a comparable efficacy and safety profile with a reduced immunogenicity 
compared to current ERTs, with greater convenience leading to significant improvement in QOL. 
This has the potential to delay the risk of developing disease complication in mild to moderate 
patients by slow disease progression. This study will provide health care providers and patients 
with Fabry disease alternative treatment options based on the unique characteristics of 
pegunigalsidase alfa. 
 STUDY OBJECTIVES 
5
To evaluate the safety and efficacy of 2.0 mg/kg pegunigalsidase alfa every 4 weeks in patients 
with Fabry disease currently treated with ERT (agalsidase alfa or agalsidase beta). 
 INVESTIGATIONAL PLAN 
6
 
Overall Study Design and Plan – Description 
6.1
This will be an open-label, switch-over study to assess the safety and efficacy of pegunigalsidase 
alfa 2.0 mg/kg administered by intravenous infusion every 4 weeks for 12 months (52 weeks) in 
adult patients with Fabry disease currently treated with ERT: Fabrazyme® (agalsidase beta) or 

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Replagal™ (agalsidase alfa) for at least 3 years and on a stable dose (>80% labelled dose/kg) for 
at least the last 6 months. 
Number of Subjects (Planned):   
Up to 30 but not less than 25 of the enrolled patients, up to 6 of the patients will be females 
(~20%).   
Following screening, patients will be enrolled and switched from their current ERT to receive 
intravenous (IV) infusions of pegunigalsidase alfa 2 mg/kg every 4 weeks for 52 weeks or 14 
infusions.  
At the time of enrollment, if premedication is used for the agalsidase alfa or agalsidase beta 
infusions before enrollment, this premedication will be continued through the first infusion with 
pegunigalsidase alfa and then gradually tapered down at the Investigator’s discretion and based 
on Appendix 8.  
For patients weighing up to (≤) 100 kg, the first infusions of pegunigalsidase alfa will be 
administered under controlled conditions at the investigation site starting at 4.5 hr with the 
option to reduce the IV duration gradually to 2 hr (see Appendix 8). 
For patients weighing more than (>) 100 kg, the first infusions of pegunigalsidase alfa will be 
administered under controlled conditions at the investigation site starting at 6 hr with the option 
to reduce the IV duration gradually to 3 hr (see Appendix 8).   
The first infusions of pegunigalsidase alfa will be administered under controlled conditions at the 
investigation site.  The patient can receive their pegunigalsidase alfa infusions in a home care 
setup once the Investigator and Sponsor Medical Director/Monitor agree that it is safe to do so 
based on Appendix 8.  
In the case of clear clinical deterioration, the treatment may be changed to 1.0 mg/kg every other 
week at the Investigator’s discretion and discussion with the Sponsor Medical Director/Monitor. 
The study will include a screening visit and 14 treatment visits, once every 4 weeks for 52 weeks 
starting on Day 1 (Visit 1).  
 
Discussion of Study Design 
6.2
This study design is based on the unique enhanced PK profile of pegunigalsidase alfa.  The 
weekly projected partial AUC and Cave values, based on the Phase I/II PK profile, indicate that 
there should be measurable levels of pegunigalsidase alfa following 2 mg/kg treatment at the 
third and fourth weeks after infusion in the same order of magnitude as Fabrazyme® in the first 
week post-infusion (Table 1:  ). Calculations enabled the evaluation/estimation of the drug 
availability on weeks 1, 2, 3, and 4 of pegunigalsidase alfa compared to Fabrazyme® every 2 
weeks.  The half-life (t½) of 2.0 mg/kg pegunigalsidase alfa is ~ 80 hrs vs. ~2 hrs of Fabrazyme® 
and Replagal™ with Cmax values ~10-fold higher than those found with Fabrazyme®. The 
estimated Cave of 2.0 mg/kg pegunigalsidase alfa every 4 weeks provides an average 
concentration of ~90 ng/mL at 3 weeks and ~10 ng/mL at 4 weeks post infusion. Both are higher 
than the negligible 2nd week Cave values for Fabrazyme® (Table 1:  ). 

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Subjects are required to be treated with ERT: Fabrazyme® (agalsidase beta) or Replagal™ 
(agalsidase alfa) for at least 3 years and on a stable dose (>80% labelled dose/kg) for at least 6 
months. 
This study will provide a new treatment option based on the unique characteristic of 
pegunigalsidase alfa for health care providers and patients with Fabry disease in pegunigalsidase 
alfa-treated patients. 
 
Selection of Study Population 
6.3
6.3.1 Inclusion Criteria 
The subjects must fulfill the following inclusion criteria: 
1. Age: 18 – 60 years 
2. A documented diagnosis of Fabry disease. 
3. Males: plasma and/or leucocyte alpha-Galactosidase-A activity (by activity assay) less 
than lower limit of normal per laboratory reference range and one or more of the 
characteristic features of Fabry disease 
a. Neuropathic pain 
b. Cornea verticillata 
c. Clustered angiokeratoma 
4. Females: historical genetic test results consistent with Fabry mutations, or in the case of 
novel mutations a first-degree male relative with Fabry disease, and one or more of the 
characteristic features of Fabry disease 
d. Neuropathic pain 
e. Cornea verticillata 
f. Clustered angiokeratoma 
5. Treatment with agalsidase alfa or agalsidase beta for at least 3 years and on a stable dose 
(>80% labelled dose/kg) for at least the last 6 months 
6. eGFR ≥ 30 mL/min/1.73 m2 by CKD-EPI equation at screening visit 
7. Availability of at least 3 historical serum creatinine evaluations since starting agalsidase 
alfa or agalsidase beta treatment and not more than 2 years 
8. Female patients and male patients whose co-partners are of child-bearing potential agree 
to use a medically accepted, highly effective method of contraception. These include 
combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or transdermal), progestogen-only 
hormonal contraception associated with inhibition of ovulation (oral, injectable, or 
implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), 
bilateral tubal occlusion, vasectomised partner, or sexual abstinence  

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9. Patients whose clinical condition, in the opinion of the Investigator, that are suitable for 
treatment with ERT every 4 weeks. 
6.3.2 Exclusion Criteria 
The presence of any of the following excludes a subject from study enrollment: 
1. History of anaphylaxis or Type 1 hypersensitivity reaction to agalsidase alfa or 
agalsidase beta 
2. History of renal dialysis or transplantation  
3. Linear negative slope of eGFR of ≥ 2 mL/min/1.73 m2 based on at least 4 serum 
creatinine values over approximately 2 years (including the value obtained at the 
screening visit)  
4. History of acute kidney injury in the 12 months prior to screening, including specific 
kidney diseases (e.g., acute interstitial nephritis, acute glomerular and vasculitic renal 
diseases); non-specific conditions (e.g., ischemia, toxic injury); as well as extrarenal 
pathology (e.g., prerenal azotemia, and acute post renal obstructive nephropathy) 
5. Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) 
therapy initiated or dose changed in the 4 weeks prior to screening 
6. Urine protein to creatinine ratio (UPCR) at screening > 0.5 g/g or mg/mg or 500 mg/g 
and not treated with an ACE inhibitor or ARB 
7. Females who are pregnant, planning to become pregnant during the study, or are breast 
feeding 
8. Cardiovascular event (myocardial infarction, unstable angina) in the 6-month period 
before screening 
9. Cerebrovascular event (stroke, transient ischemic attack) in the 6-month period before 
screening 
10. Presence of any medical, emotional, behavioral, or psychological condition that, in the 
judgment of the Investigator and/or Medical Director, would interfere with the patient’s 
compliance with the requirements of the study. 
6.3.3 Removal of Subjects from Therapy or Assessment 
Reasons for permanent discontinuation include the following: 
 The subject experiences two or more Grade 3 toxicities or one or more Grade 4 toxicity 
considered by the Investigator to be associated with pegunigalsidase alfa (CTCAE v. 
4.03, 2010) 
 The subject experiences progressive hypersensitivity or severe hypersensitivity that is not 
allayed with pre-treatment 

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 The subject requests to discontinue treatment 
 Investigator feels that it is not in the best interest of the subject to continue treatment 
and/or if the Investigator believes that the subject can no longer be compliant with the 
requirements of the study 
For any discontinuation, the Investigator will obtain all the required details and document the 
date and the main reason for the premature termination.  If the reason for discontinuation is an 
adverse event, the specific event or the main laboratory abnormality will be recorded in the CRF.  
The Investigator will make thorough efforts to document the outcome.  The Investigator will 
attempt to continue to follow the subject for the full duration of the study or at least for 30 days 
following discontinuation. If circumstances prevent the subject from completing all visits, every 
attempt will be made to complete all procedures listed in Section 9.2.3 for Visit 14 excluding the 
drug infusion. 
 STUDY PRODUCT 
7
 
Study Medication Supply 
7.1
Protalix will provide pegunigalsidase alfa to the sites as needed.  
 
Description and Formulation of Study Product  
7.2
Pegunigalsidase alfa is a purified recombinant, plant cell-expressed chemically modified human 
alpha galactosidase A, which is described in detail in the Investigator’s Brochure. 
The Drug Product (DP) is provided in 15 ml clear glass vials closed with rubber stoppers and 
secured with aluminum flip off caps.  
Each vial contains 10.5 mL of the following contents in liquid form: 
20 mg pegunigalsidase alfa (2.0 mg/mL) 
0.7% NaCl 
25-30 mM Sodium Citrate (pH 5.7 – 6.3). 
 
Study Drug Dosage and Preparation 
7.3
Pegunigalsidase alfa 2.0 mg/kg; the individual dose for each patient will be prepared according 
to the patient’s weight at screening. In the case of clinical deterioration, the treatment may be 
changed to 1.0 mg/kg every two weeks at the Investigator’s discretion and discussion with the 
Medical Monitor. 
Dose of PRX-102 will be adjusted at visit 8 if the weight at visit 7 changes by ≥25% from 
screening weight 
Each dose will be prepared by a pharmacist or nurse at each site. The required amount of enzyme 
will be adjusted with normal saline (0.9% NaCl) to a final volume of 150 mL/infusion for 
patients weighing at screening up to 70 kg, 250 mL/infusion for patients weighing between 70–

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100 kg, and 500 mL/infusion for patients weighing more than 100 kg the volume will be adjusted 
only if dose is changed.  
 
Study Drug Administration 
7.4
For patients weighing up to (≤) 100 kg, the first infusion of pegunigalsidase alfa will be 
administered under controlled conditions at the investigation site starting at 4.5 hrs with the 
option to reduce the IV duration gradually to 2 hrs. 
For patients weighing more than (>) 100 kg, the first infusion of pegunigalsidase alfa will be 
administered under controlled conditions at the investigation site starting at 6 hrs with the option 
to reduce the IV duration gradually to 3 hrs.  
Study drug will be administered by intravenous infusion over 4.5 – 6 hrs. If well tolerated by the 
patient, the infusion rate may be adjusted to 2 – 3 hrs (Appendix 8) according to the individual 
subject’s signs and symptoms (Appendix 2). All changes will be based on Investigator evaluation 
and Sponsor Medical Director approval. 
The first infusions of pegunigalsidase alfa will be administered under controlled conditions at the 
investigation site.  After tapering down premedication, when applicable, and reducing the 
infusion time and observation time (see Appendix 8), the patient can then receive the 
pegunigalsidase alfa infusions at a home care setup once the Investigator and Sponsor Medical 
Director agree that it is safe to do so. 
 
Packaging and Labeling  
7.5
The DP is provided in 15 mL clear glass vials closed with rubber stoppers and secured with 
aluminum flip off caps. The drug product is packaged in vials containing 20 mg pegunigalsidase 
alfa (2 mg/mL), 0.7% NaCl, and 25 – 30 mM Sodium Citrate (pH 5.7 - 6.3). 
Study product is a liquid stored in 15 mL clear injection glass vials (Müller + Müller-Joh. GmbH 
+ Co, Germany). Grey rubber stoppers (formulation 4432/50/Grey) are used for closure (West 
Pharmaceutical Services Deutschland GmbH & Co KG).   
The label is presented in Appendix 1.  Vial Label 
 
Conditions for Storage and Use 
7.6
The proposed storage condition for the pegunigalsidase alfa DP is 5 ± 3°C. The proposed storage 
condition for the infusion bag is 5 ± 3°C, RT, and at 22.5 ± 2.5°C for up to 36 hours. 
 
Method of Assigning Subjects Identification 
7.7
In this open label study, all subjects will receive 2 mg/kg pegunigalsidase alfa once every 4 
weeks:  
A unique screening number (formatted as xxSF50yyy [x: site number, S: screening, F50: 
constant indicating protocol number, y: sequential subject number in the site]) will be assigned to 
each screened subject.  Once a subject is eligible for treatment, including successful completion 

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of screening, sponsor medical director approval but prior to visit 1, a subject enrollment ID 
number will be generated. This ID number will include the site and subject number (formatted as 
xx-F50yyy [xx: site number, F50: constant indicating protocol number, yyy: sequential subject 
number in the study]).   
 
Dispensing, Compliance and Accountability 
7.8
Protalix will provide drug accountability forms to assist the pharmacist in maintaining current 
and accurate inventory records covering receipt, dispensing, and the return of investigational 
drug supplies.  When a shipment is received, the pharmacist will verify the quantities received 
and return the acknowledgment to the Protalix’s CTM (Clinical Trial Material) coordinator. The 
drug will not be used without Protalix’s approval in writing.  The pharmacist investigational drug 
accountability record includes the identification of the person to whom the drug is dispensed, the 
quantity and the date of dispensing and any returned or unused drug, as well as a full record of 
CTM storage temperatures.  This record is in addition to any drug accountability information 
recorded on the Case Report Form (CRF).  These records will be readily available for inspection 
by a monitor and/or Protalix audits and are open to regulatory authority inspection at any time. 
The Investigator is responsible for maintaining accountability for the receipt, dispensing, and 
return of all study medication. 
 
Prior and Concomitant Therapy 
7.9
Medications having the potential to interfere with the evaluation of efficacy are excluded 
throughout the trial. 
The following medications are strictly prohibited during the study: 
 Fabrazyme® (agalsidase beta) 
 Replagal™ (agalsidase alfa) 
 Any other investigational or approved drug for treating Fabry disease. 
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) 
at a stable dose for 4 weeks prior to entry into the study are allowed, but once a subject is 
randomized in the study, initiation of ACEI or ARB therapy is permitted only after discussion 
and approval of the Sponsor Medical Director. 
 EFFICACY AND SAFETY ASSESSMENTS 
8
 
Efficacy Variables 
8.1
 Estimated glomerular filtration rate (eGFRCKD-EPI) (Appendix 5.  National Kidney 
Foundation Guidelines for Chronic Kidney Disease 
 Left Ventricular Mass Index (g/m2) by echocardiogram  
 Plasma Lyso-Gb3 
 Plasma Gb3 

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 Urine Lyso-Gb3 
 Protein/Creatinine ratio spot urine test (UPCR) 
 Frequency of pain medication use 
 Exercise tolerance (Stress Test) 
 Short Form Brief Pain Inventory (BPI) (Appendix 7.  Brief Pain Inventory- BPI (Short 
Form) 
 Mainz Severity Score Index (MSSI) (Appendix 4.  The Mainz Severity Score Index 
(MSSI)) 
 Quality of life EQ-5D-5L (Appendix 6.  QOL Questionnaire - EQ-5D-5L) 
 
Pharmacokinetic Variables 
8.2
Blood samples will be taken from all patients for PK analysis on Day 1 and at the end of the 
study (Visit 14 at week 52). Blood samples will be drawn for an additional intermediate PK 
analysis at Visit 7 (week 24), for all patients who signed inform consent to this version (Version 
4) before reaching Visit 7 (week 24), or at Visit 11 (week 40) for patients who passed Visit 7 at 
the time of signing the inform consent to this version. The following (but not restricted to) PK 
parameters will be derived from the plasma concentration versus time profiles to determine the 
pharmacokinetics of the study drug: Cmax, Tmax, t1/2, AUC0-t, and AUC0-∞. Blood samples (~6 
mL) will be drawn at the following time points: pre-infusion (baseline); 1 hour after the 
beginning of the infusion; at the end of the infusion, at 1±0.25, 2±0.25, 4±0.25, 8±0.25, 24±0.5, 
48±3, and 96±3 hours post-infusion and at 14±3, 21±3 and 28±3 days post-infusion (a total of 13 
timepoint within 28 days). 
 
Safety Variables 
8.3
Safety will be assessed by changes from baseline in: 
 Clinical laboratory tests 
 Physical examination 
 Assessment of the injection site 
 Electrocardiogram 
 Treatment-emergent adverse events 
 Ability to taper off infusion premedication throughout the first 2 months of the study 
 Requirement for use of premedication overall to manage infusion reactions 

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 Treatment-induced anti-pegunigalsidase alfa antibodies (Appendix 3.  Pegunigalsidase 
alfa Hypersensitivity Evaluation and Treatment Algorithm) 
8.3.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject participating in a clinical 
trial. An AE can be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of the study medication, whether or not considered related to the study 
medication. AEs will be collected from the start of treatment until 30 days following the final 
visit dose.  If the subject enters the extension study, the first 30 days of the extension study will 
be considered the observation period for adverse events of this study (PB-102-F50).  Any events 
occurring prior to treatment will be recorded on the medical history page with the event name 
and onset date and end date if not continuing.  Known pre-existing clinically significant 
conditions observed at screening should be recorded as medical history.  
This definition also includes accidental injuries, reasons for any change in medication (drug 
and/or dose) other than planned titration, reasons for admission to a hospital, or reasons for 
surgical procedures (unless for minor elective surgery for a pre-existing condition).  It also 
includes AEs commonly observed and AEs anticipated based on the pharmacological effect of 
the study medication. Any laboratory abnormality assessed as clinically significant by the 
Investigator must be recorded as an AE.  
A treatment-emergent AE is any AE occurring after start of study medication and within the time 
of residual drug effect (30 days after the last administration of the study medication; please note 
the above provision for subjects who enter the extension study), or a pre-treatment AE or pre-
existing medical condition that worsens in intensity after start of study medication and within the 
time of residual drug effect. 
AEs should be recorded as diagnoses, if available. If not, separate sign(s) and symptom(s) are 
recorded. One diagnosis/symptom should be entered per record.  Treatment-related 
hypersensitivity/infusion reactions are defined in Appendix 3.  Pegunigalsidase alfa 
Hypersensitivity Evaluation and Treatment Algorithm and can be defined as a single AE at the 
Investigator’s discretion.   
Note that death is not an event, but the cause of death is.  An exception is the event of sudden 
death of unknown cause. Note that hospitalization is not an event; however, the reason for 
hospitalization is. Procedures are not events; the reasons for conducting the procedures are. In 
general, only the reason for conducting the procedure will be captured as an AE. However, if 
deemed necessary by the Investigator, a procedure can be captured along with the reason for 
conducting the procedure. 
An overdose is not an AE unless it is temporally associated with an unfavorable or unintended 
sign or symptom.   
Each AE is to be classified by the Investigator as serious or non-serious.  A serious adverse event 
(SAE) is any untoward medical occurrence or effect that occurs at any dose:  
 Results in death 

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 Is life-threatening (i.e., an immediate risk of death) 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is associated with a congenital anomaly/birth defect 
 Is an important medical event 
An AE caused by an overdose or medication error is considered serious if a criterion listed in the 
definition above is fulfilled. 
Important AEs that may not result in death, may not be life-threatening, or do not require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject’s safety or may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
SAEs also include any other event that the Investigator or sponsor judges to be serious or which 
is defined as serious by the regulatory agency. 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
trial subject using concise medical terminology.  In addition, each trial subject will be questioned 
about AEs.  The question asked will be “Since you began taking the study medication, have you 
had any health problems?” 
8.3.1.1 Procedures for Assessing, Recording, and Reporting AEs and SAEs 
Throughout the duration of the study, the Investigator will closely monitor each subject for 
evidence of drug intolerance and for the development of clinical or laboratory evidence of AEs.  
All AEs (expected or unexpected) which occur during the course of the study, whether observed 
by the Investigator or by the subject, and whether or not thought to be drug-related, will be 
reported and followed until resolution or until they become stable. 
The description of the AE will include description of the event, start date, stop date, intensity, if 
it was serious, relationship to test drug, change in test drug dosage, if the subject died, and if 
treatment was required. 
AEs with the causality assessed as possible or probable are categorized as related to study 
medication and are called adverse drug reactions. 
All SAEs must be reported immediately (no more than 24 hours after becoming aware of the 
event) by entering the information about the event in the eCRF forms. The Sponsor’s Medical 
Director and Safety Monitor will be notified of the event by the eCRF system. In the case that 
the eCRF system is not available, the Investigator must contact Medical Director (972-54-
2228472) or Safety Monitor (1-(212) 681-2100) to notify the Sponsor of the event. 
 
 

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Events will be recorded as one of the following severity and causality categories below: 
Severity 
Definition 
Mild (Grade 1) 
Awareness of signs or symptoms, but no disruption of usual activity 
Moderate (Grade 2) 
Discomfort sufficient to interfere, but not prevent, daily activity 
Severe (Grade 3) 
Unable to carry out usual activity 
Very severe (Grade 4) 
Incapacitating, requires hospitalization, results in death 
Category 
Definition 
Unrelated 
Clearly and incontrovertibly due only to extraneous causes, and does not meet criteria 
listed under possible or probable. 
Unlikely 
Does not follow a reasonable temporal sequence from administration. May have been 
produced by the subject’s clinical state or by environmental factors or other therapies 
administered. 
Possible 
Follows a reasonable temporal sequence from administration, but may have been also 
produced by the subject’s clinical state, environmental factors or other therapies 
administered. 
Probable 
Clear-cut temporal association with administration with improvement on cessation of 
investigational medicinal product or reduction in dose. Reappears upon rechallenge. 
Follows a known pattern of response to the investigational medicinal product. 
Definitely 
There is evidence of exposure to the test product, for example, reliable history or 
acceptable compliance assessment; the temporal sequence of the AE onset relative to the 
drug is reasonable; the AE is most likely to be explained by the drug treatment than by 
another cause; the challenge is positive; re-challenge (if feasible) is positive; the AE shows 
a pattern consistent with previous knowledge of the drug treatment. 
8.3.2 Clinical Laboratory 
 Hematology: complete blood count; total white blood cell count with differential 
(neutrophils, lymphocytes, monocytes, eosinophils and basophils), total red blood cells 
(hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and 
mean corpuscular hemoglobin concentration), and platelets.  
 Coagulation profile: prothrombin time (PT) and partial thromboplastin time (PTT)  
 Biochemistry: sodium, potassium, glucose, blood urea nitrogen, creatinine, cystatin C, 
calcium, phosphate (inorganic), uric acid, total protein, albumin, bilirubin (total), alkaline 
phosphatase, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, 
lactate dehydrogenase, and creatine phosphokinase   
 Urinalysis: dipstick for presence of blood, glucose, ketones, and protein 
 Vitamin D 
8.3.3 Anti-pegunigalsidase alfa Antibodies 
Anti-pegunigalsidase alfa antibodies will be assessed using a validated analytical method before 
dosing at screening, baseline (Day 1), Week 2 (15±3 days after 1st infusion), Visit 2 (Week 4 ± 3 
days), and in Visits 4 (week 12), 7 (week 24), 11 (week 40), and V14 (week 52). 
Anti-Drug IgE antibodies and tryptase will be assessed in events of hypersensitivity reaction 
following Sponsor request. 

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8.3.4 Acute Kidney Injury 
Episodes of acute kidney injury (AKI) will be considered adverse events.  AKI will be defined 
by a 1.5-fold or greater increase in serum creatinine from the immediately previous laboratory 
value and assessment by the Investigator. The Protalix Medical Director will work with the 
Investigator to ensure that such changes in renal function are thoroughly evaluated.  Refer to 
Missing Data for further description of how episodes of AKI will be handled in data analysis for 
efficacy. 
 STUDY PROCEDURES AND FLOW CHART 
9
 
Study Flow Chart 
9.1
Calendar (week) 
 
Day1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Activity /Visit Number/ Inf 
S 
V1 
2w
eek
s 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Sign IC 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign screening number 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & Specific FD 
history including major 
clinical events 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
Body weight 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
Body height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs5,  
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
review of  medications 
 
Pain medications  
 
Pre-medication Use 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Alfa-galactosidase activity 
in plasma 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alfa-galactosidase activity 
in leucocytes 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine protein/creatinine 
ratio (UPCR) 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
Hematology 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
PT and PTT 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
Serum creatinine and 
Cystatin C 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vitamin D 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy (βHCG) 
for females 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test for 
females 
 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
Urinalysis - dipstick 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
HBsAg, HCV & HIV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Short Form Brief Pain 
Inventory (BPI) 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
Anti-Drug Antibodies 
(IgG)2 
x 
x 
x 
x 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
Plasma PK3 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
Electrocardiography (ECG) 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
Chest X-ray1 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Calendar (week) 
 
Day1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Activity /Visit Number/ Inf 
S 
V1 
2w
eek
s 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Quality of Life (5Q-5D-5L) 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
Mainz Severity Score Index 
(MSSI) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Request patient  approval 
by Medical Monitor 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Monitor approval 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiography 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
Cardiac function 
assessment (stress test) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Brain MRI 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Adverse events 
assessments 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mutation analysis 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine lyso Gb3 
concentration 
 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
Plasma Gb3 concentration2 
 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
Plasma Lyso Gb3 
concentration2 
 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
Study Drug IV infusion8,9 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Observe Patient6 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Call Patient 7 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Will be performed only for patients who have not had the test during the last 3 months before screening 
2 Will be performed pre-infusion 
3 PK Time points: pre-infusion (baseline); 1 hour after the beginning of the infusion; at the end of the infusion, at 1±0.25, 2±0.25, 
4±0.25, 8±0.25, 24±0.5, 48±3, and 96±3 hours post-infusion and at 14±3, 21±3 and 28±3 days post-infusion 
Patients who signed inform consent to this version (Version 4) before reaching Visit 7 (week 24), will perform PK at Visit 7; 
patients who signed inform consent after Visit 7 will perform PK at visit 11 (week 40). 
5 Evaluate vital signs: blood pressure, pulse, temperature and respiration rate; any time pre-infusion, every 30 (±10) minutes 
during the first hour of the infusion, and from the second hour, 60 (±10) minutes up to the end of the clinical observation, and at 
the end of the observation time, if the patient tolerates the infusion. Otherwise, evaluate vital signs every 15 minutes until 
achieving tolerability. 
6 According to Appendix 8 
7 24 hours post dosing first infusion 
8 Evaluate the injection site 
9  In patients who tolerate the infusions well, the infusion rate can be adjusted according to Appendix 8. 
 
 
Study Visits 
9.2
9.2.1 Screening (Visit 0, Visit S, Day -30 ± 10 Days) 
1. Obtain written informed consent from the subject  
2. Assign screening number 
3. Demographics 
4. Medical history and specific Fabry disease history including major clinical events 

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5. Physical examination, including weight and height 
6. Vital signs, including blood pressure, pulse, temperature, and respiration rate 
7. Current medications including (pain medications and pre-medication use) 
8. Laboratory tests  
 Hematology-Local  
 Biochemistry  
 Urinalysis - dipstick 
 Alpha galactosidase activity in plasma 
 Alpha galactosidase activity in leucocytes 
 Urine protein/creatinine ratio (UPCR) - spot urine test 
 PT and PTT 
 Serum creatinine and Cystatin C 
 Vitamin D 
 HBsAg, HCV, & HIV 
 Anti-pegunigalsidase alfa antibodies (IgG) 
 Serum pregnancy test (β-HCG) for female subjects of child-bearing potential 
9. Chest X-ray (if not performed in the last 3 months) 
10. Final enrollment approval will be determined after completion of screening visit and 
filling in Inclusion/exclusion criteria 
11. ECG 
9.2.2 Visit 1 (Baseline, Day 1, 1 ± 3 Days) 
1. Inclusion/exclusion review 
2. Request approval of patient by the Medical Monitor 
3. Physical examination, including weight 
4. Vital signs, including blood pressure, pulse, temperature, and respiration rate 
5. Current medications (pain medications and pre-medication use) 

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6. Laboratory tests 
 Hematology  
 Biochemistry 
 Mutation analysis sample 
 Urine protein/creatinine ratio (UPCR) - spot urine test 
 Serum creatinine and Cystatin C 
 Urinalysis - dipstick 
 Urine lyso Gb3 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Urine pregnancy test for females 
 Anti-pegunigalsidase alfa antibodies (pre-infusion of visit 1)  
 Plasma PK analysis time points: pre-infusion (baseline); 1 hour after the beginning of 
the infusion; at the end of the infusion, at 1±0.25, 2±0.25, 4±0.25, 8±0.25, 24±0.5, 
48±3, and 96±3 hours post-infusion and at 14±3, 21±3 and 28±3 days post-infusion.   
7. Short Form Brief Pain Inventory (BPI) (Appendix 7.  Brief Pain Inventory- BPI (Short 
Form)) 
8. ECG 
9. Quality of Life: 5Q-5L-5D (Appendix 6.  QOL Questionnaire - EQ-5D-5L) 
10. Mainz Severity Score Index (MSSI) (Appendix 4.  The Mainz Severity Score Index 
(MSSI)) 
11. Echocardiography 
12. Cardiac function assessment (stress test) 
13. Brain MRI 
14. Adverse events  
15. Study Drug IV infusion 
16. Perform the following procedures at all pegunigalsidase alfa dosing:  

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 If the patient is typically pre-medicated, include the pre-medication prior to initiating 
the infusion. 
 For a patient weighing up to 100 kg, the infusion length will start at 4.5 hours; for 
patients over 100 kg, the infusion length will start at 6 hours and can be reduced 
pending tolerability (Appendix 8) 
 Evaluate vital signs: blood pressure, pulse, temperature and respiration rate: any time 
pre-infusion, every 30 (±10) minutes during the first hour of infusion, and from the 
second hour, every 60 (±10) minutes up to the end of the clinical observation time, 
and at the end of observation time, if the patient tolerates the infusion. Otherwise, 
evaluate vital signs every 15 minutes.  
 Post dossing clinical observation will start from 4 hours length and can be reduced 
pending tolerability up to one hour (Appendix 8), regardless of the length of the 
infusion. 
 Evaluate the infusion site  
17. Schedule the patient for the next visit 
18. Question the patient on infusion tolerability at 24 hours post-infusion by phone or at the 
site.  
9.2.3 Week 2 (Day 15±3 days post- 1st infusion) 
1. Anti-pegunigalsidase alfa antibodies  
9.2.4 Visit 2 (Week 4 ± 3 days) 
1. Vital signs, including blood pressure, pulse, temperature, and respiration rate 
2. Serum creatinine and Cystatin C (pre-infusion)  
3. Anti-pegunigalsidase alfa antibodies (pre-infusion)  
4. Concomitant medications 
5. Adverse events 
6. Study Drug IV infusion (evaluate the injection site) and post dossing clinical observation 
see Appendix 8. 
7. Remind the patient of the date of his/her next visit. 
 
9.2.5 Visits 3, 5, 6, 8, 9, 10, 12, and 13 (Weeks 8, 12, 16, 20, 28, 32, 36, 44, and 48  3 Days 
for Each Visit) 
8. Vital signs, including blood pressure, pulse, temperature, and respiration rate 

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9. Serum creatinine and Cystatin C (pre-infusion)  
10. Concomitant medications 
11. Adverse events 
12. Study Drug IV infusion (evaluate the injection site) and post dossing clinical observation 
see Appendix 8.  
13. Remind the patient of the date of his/her next visit. 
9.2.6 Visits 4 and 11 (Weeks 12 and 40  3 Days) 
1. Physical examination 
2. Vital signs, including blood pressure, pulse, temperature, and respiration rate 
3. Laboratory tests 
 Hematology 
 Biochemistry 
 Urine protein/creatinine ratio (UPCR) - spot urine test 
 Serum creatinine and Cystatin C (pre-infusion)  
 Urine pregnancy test for females 
 Urinalysis - dipstick 
 Urine lyso Gb3 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Anti-pegunigalsidase alfa antibodies (pre-infusion)  
 Visit 11 (week 40) ONLY; 
o Plasma PK analysis (For patients who signed inform consent to Version 4 
after Visit 7) at the following time points: pre-infusion (baseline); 1 hour after 
the beginning of the infusion; at the end of the infusion, at 1±0.25, 2±0.25, 
4±0.25, 8±0.25, 24±0.5, 48±3, and 96±3 hours post-infusion and at 14±3, 
21±3 and 28±3 days post-infusion.  
4. ECG 
5. Concomitant medications  

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6. Adverse events 
7. Study Drug IV infusion (evaluate the injection site) and post dossing clinical observation, 
see Appendix 8.  
8. Remind the subject of the date of his/her next visit. 
9.2.7 Visit 7 (Week 24  3 Days) 
1. Physical examination, including weight 
2. Vital signs, including blood pressure, pulse, temperature, and respiration rate 
3. Laboratory tests 
 Hematology 
 Biochemistry 
 Urine protein/creatinine ratio (UPCR) - spot urine test 
 Serum creatinine and Cystatin C (pre-infusion)  
 Urine pregnancy test for females 
 Urinalysis - dipstick 
 Urine lyso Gb3 (first morning mid-stream void performed on 2 consecutive days, pre-
infusion) 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Anti-pegunigalsidase alfa antibodies (pre-infusion)  
 Plasma PK analysis (For patients who signed inform consent to Version 4 before 
reaching Visit 7) at the following time points: pre-infusion (baseline); 1 hour after the 
beginning of the infusion; at the end of the infusion, at 1±0.25, 2±0.25, 4±0.25, 
8±0.25, 24±0.5, 48±3, and 96±3 hours post-infusion and at 14±3, 21±3 and 28±3 days 
post-infusion..   
4. BPI (Appendix 7.  Brief Pain Inventory- BPI (Short Form)) 
5. Quality of Life: 5Q-5L-5D (Appendix 6.  QOL Questionnaire - EQ-5D-5L) 
6. ECG 
7. Concomitant medications  
8. Adverse events 

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9. Study Drug IV infusion (evaluate the injection site) and post dossing clinical observation 
see Appendix 8. 
10. Remind the subject of the date of his/her next visit. 
9.2.8 Visit 14 (Week 52  3 Days) 
1. Physical examination, including weight 
2. Vital signs, including blood pressure, pulse, temperature and respiration 
3. Laboratory tests 
 Hematology 
 Biochemistry 
 Urine protein/creatinine ratio (UPCR) - spot urine test 
 Serum creatinine and Cystatin C (pre-infusion)  
 Urine pregnancy test for females 
 Urinalysis - dipstick 
 Urine lyso Gb3 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Anti-pegunigalsidase alfa antibodies (pre-infusion)  
 Plasma PK analysis time points: pre-infusion (baseline); 1 hour after the beginning of 
the infusion; at the end of the infusion, at 1±0.25, 2±0.25, 4±0.25, 8±0.25, 24±0.5, 
48±3, and 96±3 hours post-infusion and at 14±3, 21±3 and 28±3 days post-infusion.   
4. BPI (Appendix 7.  Brief Pain Inventory- BPI (Short Form)) 
5. ECG 
6. Quality of Life: 5Q-5L-5D (Appendix 6.  QOL Questionnaire - EQ-5D-5L) 
7. MSSI (Appendix 4.  The Mainz Severity Score Index (MSSI)) 
8. Cardiac function assessment (stress test) 
9.  Echocardiography 
10. Brain MRI 

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11. Concomitant medications  
12. Adverse events 
13. Study Drug IV infusion (evaluate the injection site) and post dossing clinical observation, 
see Appendix 8. 
9.2.9 Premature Withdrawal Visit 
All attempts should be made to perform all the tests for Visit 14 at the withdrawal visit for 
patients who may discontinue the study before completion. 
 STATISTICAL METHODS PLANNED AND SAMPLE SIZE 
10
 Determination of Sample Size 
10.1
The sample size of approximately 30 subjects was determined pragmatically and is adequate to 
evaluate the safety of switching from agalsidase alfa or beta to 2 mg/kg pegunigalsidase alfa 
every 4 weeks in this orphan disease in which patient recruitment in clinical trials is difficult. 
 Subject Populations 
10.2
10.2.1 Intent-to-Treat (ITT) Population 
Intent-to-treat (ITT) population is defined as patients who received at least one complete dose of 
study medication.  
10.2.2 Per Protocol (PP) Population 
The Per Protocol population is defined as patients who complete the study with no major 
protocol violations.  
10.2.3 Safety Population 
The safety population is defined as all patients who received at least one dose (partial or 
complete) of the study medication. 
 Analysis 
10.3
Demographics.  For continuous variables, n, mean, standard deviation, median, minimum, and 
maximum will be presented.  For categorical variables, frequency counts and percentages will be 
presented.   
Medical History, Vital Signs, and Physical Examination.  For medical history, frequency 
count by treatment will be provided for each body system.   
For physical examination, frequency count of normal or abnormal by treatment will be tabulated 
for each body system.  
Medications.  Summary and/or data listings of the prior, concomitant medication, and class of 
medication will be provided. 

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10.3.1 Efficacy Variables 
For each efficacy variable, the percent change from baseline to each visit of which the specific 
variable is measured will be calculated and summarized with descriptive statistics (n, mean and 
its standard error, median, standard deviation, range, and interquartile range).  
eGFR is calculated from the serum creatinine according to the CKD-EPI formula. Intra-patient 
comparison will be also evaluated. 
10.3.2 Safety Analysis 
10.3.2.1 Adverse Events 
Adverse events (AE) will be coded to system organ class and preferred term using MedDRA 
version 9.1 or higher.  All AEs occurring after the initiation of the study treatment (treatment-
emergent AEs) will be reported, including events present at baseline that worsened during the 
study. 
AEs will be summarized by treatment group to provide visual comparison among the treatment 
groups with respect to incidence of AEs (the number of subjects reporting at least one episode of 
a specific AE), incidence of AEs by severity within body system, incidence of AEs by attribution 
within body system, and incidence of AEs causing withdrawal and incidence of SAEs.  
Regarding severity and attribution summaries, the most extreme outcome (highest severity and 
closest to study drug related) will be used for those subjects who experience the same AE on 
more than one occasion.  
Hypersensitivity reactions will be analyzed as AEs of special interest using descriptive statistics. 
Written narratives will be provided for all serious, unexpected or other significant AEs that are 
judged to be of special interest because of their clinical importance. 
10.3.2.2 Clinical Laboratory 
Clinical Laboratory examinations will be performed prior to and during treatment. 
Descriptive statistics will be presented for the value and abnormality of each of the clinical 
laboratory results by visit and dose group.  Shift tables describing abnormality shifts from 
baseline to after treatment and follow-up will be created. 
10.3.3 Interim Analysis 
An interim analysis may be performed for administrative purposes. 
10.3.4 Missing Data 
No imputation will be made for missing values of safety endpoints except for some AE 
parameters as described above. 
Episodes of Acute Kidney Injury (AKI) will be considered missing data for the purposes of the 
efficacy analysis.  AKI will be defined by a 1.5-fold increase in serum creatinine from the 
immediately previous laboratory value and assessment by the Investigator.  However, prior to 

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data base lock, cases of AKI will be assessed by two independent nephrology experts. Their 
evaluation will include whether they agree that AKI occurred in a patient and whether serum 
creatinine values should be excluded from the eGFR slope calculations for the primary endpoint.  
Excluded serum creatinine values will be considered missing data. 
 QUALITY CONTROL AND QUALITY ASSURANCE 
11
 Source Data and Records 
11.1
Source data are all the information in original records and certified copies of original records of 
clinical findings, observations, laboratory reports, data sheets provided by the sponsor or other 
activities in the study, which are necessary for the reconstruction and evaluation of the study. 
The Investigator will permit study-related monitoring, audit(s), IRB review(s), and regulatory 
inspection(s), with direct access to all the required source records. 
All study records will be retained for a period of time as defined by the regulatory authority for 
the country in which the investigation is conducted. Generally, this means at least 2 years 
following the date on which the drug is approved by the regulatory authority for marketing for 
the purposes that were the subject of the investigation.  In other situations, (e.g., where the 
investigation is not in support of or as part of an application for a research or marketing permit), 
a period of 2 years following the date on which the entire clinical program is completed, 
terminated, or discontinued or the investigational application under which the investigation is 
being conducted is terminated or withdrawn by the regulatory authorities. 
In the event the Investigator retires, relocates, or for any other reason withdraws from the 
responsibility for maintaining records for the period of time required, custody of the records may 
be transferred to any other person who will accept responsibility for the records.  Notice of such 
a transfer must be given in writing to the Sponsor.  The Investigator must contact the Sponsor 
prior to disposal of any records related to this study.  
 Reporting of Results 
11.2
The Case Report Form (eCRF) is an integral part of the study and subsequent reports.  The eCRF 
must be used to capture all study data recorded in the subject’s medical record.  The eCRF must 
be kept current to reflect subject status during the course of the study. 
The monitor is responsible for performing on-site monitoring at regular intervals throughout the 
study to verify adherence to the protocol; verify adherence to local regulations on the conduct of 
clinical research; and ensure completeness, accuracy, and consistency of the data entered in the 
eCRF. 
Protalix Ltd. or its designee will monitor completed eCRFs.  An eCRF will be completed for 
each screened subject. 
All protocol-required information collected during the study must be entered by the Investigator, 
or designated representative, in the Target e*CRF, an internet-based electronic data collection 
system.  All details of the eCRF completion and correction will be explained to the Investigator 
and his team.  The management module of Target e*CRF includes edit check and query 

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systems that seamlessly integrate with the data entry system. All modifications to the data in the 
eCRF are tracked by an electronic audit trail (date and identity of the person making the change 
are instantaneously recorded).  Target e*CRF is 21CFR Part 11 compliant. 
If the Investigator authorizes other persons to make entries in the eCRF, the names, positions, 
and signatures of these persons must be supplied to the Sponsor. 
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected, preferably on the same day that a study subject is seen for an 
examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. By design, an explanation must be provided 
for all missing data, altered data, and/or out of range data. 
The completed eCRF must be reviewed and signed by the Investigator named in the study 
protocol or by a designated sub-Investigator. 
Final monitored and audited eCRFs will be provided by the Sponsor to the sites at the end of the 
study in the format of a PDF file. 
 Confidentiality of Subject Data 
11.3
The Investigator will ensure that the confidentiality of the subjects' data will be preserved. In the 
eCRF or any other documents submitted to the Sponsor, the subjects will not be identified by 
their names, but by their screening and/or enrollment ID numbers (see Section 7.7) in the study. 
The Investigator will maintain documents not meant for submission to the Sponsor (e.g., the 
confidential subject identification code and the signed informed consent documents) in strict 
confidence.  
 REPORTING AND PUBLICATION 
12
 Confidentiality of Study Data 
12.1
Any information relating to the study product or the study, including any data and results from 
the study, will be the exclusive property of the Sponsor. The Investigator and any other persons 
involved in the study will protect the confidentiality of this proprietary information belonging to 
Protalix Ltd. 
 
 

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 REFERENCES 
13
Aerts JM, Groener JE, Kuiper S, et al. Elevated globotriaosylsphingosine is a hallmark of Fabry 
disease.  Proc Natl Acad Sci USA. 2008;105:2812-17. 
Barton NW, Brady RO, Dambrosia JM, et al. Replacement therapy for inherited enzyme 
deficiency-macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med. 
1991;324:1464-70. 
Benichou B, Goyal S, Sung C, Norfleet AM, O'Brien F. A retrospective analysis of the potential 
impact of IgG antibodies to agalsidase-β on efficacy during enzyme replacement therapy for 
Fabry disease. Mol Genet Metab. 2009;96:4-12. 
Blom D, Speijer D, Linthorst GE, Donker-Koopman WG, Strijland A, Aerts JM. Recombinant 
enzyme therapy for Fabry disease: absence of editing of human αgalactosidase A mRNA. Am J 
Hum Genet. 2003;72:23-31. 
BPI- Brief Pain Inventory, Short Form. https://www.mdanderson.org/research/departments-labs-
institutes/departments-divisions/symptom-research/symptom-assessment-tools/brief-pain-
inventory.html.  Accessed 18-Jan-2017.  
El Dib RP, Pastores GM.  Enzyme replacement therapy for Anderson-Fabry disease.  Cochrane 
Database Syst Rev. 2011;12:Issue 5, Art No. CD 006663, DOI:10.1002/14651858,CD. 
Eng CM, Banikazemi M, Gordon RE, et al.  A Phase 1/2 clinical trial of enzyme replacement in 
Fabry Disease: Pharmacokinetics, substrate clearance, and safety studies. Am J Hum Genet. 
2001;68:711-22. 
Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human α-
galactosidase A-- replacement therapy in Fabry's disease. N Engl J Med. 2001a;345:9-16. 
Fabrazyme® US Prescribing Information 2016. https://www.fabrazyme.com/healthcare.aspx. 
Accessed 30-Mar-2017. 
Germain DP, Waldek S, Banikazemi et al. Sustained, long-term renal stabilization after 54 
months of agalsidase-β therapy in patients with Fabry disease. J Am Soc Nephrol. 2007;18:1547-
57. 
Hoffmann B, Mayatepek E. Fabry disease - often seen, rarely diagnosed. Dtsch Arztebl Int. 
2009;106:440-7. 
Hollak CE, Aerts JM, Goudsmit R, et al. Individualised low-dose alglucerase therapy for type 1 
Gaucher's disease. Lancet. 1995;345:1474-8. 
Hollak CE, Linthorst GE. Immune response to enzyme replacement therapy in Fabry disease: 
impact on clinical outcome? Mol Genet Metab. 2009;96:1-3. 

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Hughes DA, Barba Romero MA, Hollak CE, Giugliani R, Deegan PB. Response of women with 
Fabry disease to enzyme replacement therapy: comparison with men using data from FOS - the 
Fabry Outcome Survey. Mol Genet Metab. 2011;103:207-14. 
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. 
Ann Intern Med. 2009;150:604-12. 
Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the 
modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann 
Intern Med. 2006;145:247-54. 
Lidove O, West ML, Pintos-Morell, et al. Effects of enzyme replacement therapy in Fabry 
disease - a comprehensive review of the medical literature. Genet Med. 2010;12:668-79. 
Linthorst GE, Hollak CE, Donker-Koopman WE, Strijland A, Aerts JM. Enzyme therapy for 
Fabry disease: neutralizing antibodies toward agalsidase α and beta. Kidney Int. 2004 66:1589-
95. 
Meikle PJ, Hopwood JJ, Clague AE, Carey WF.  Prevalence of lysosomal storage disorders.  
JAMA. 1999;281:249-54.   
National Kidney Foundation. K/DOQI Clinical Practice Guidelines for chronic kidney disease: 
Evaluation, classification and stratification. Am J Kidney Dis. 2002;39:S1-S266. 
Schaefer RM, Tylki-Szymanska A, Hilz MJ. Enzyme replacement therapy for Fabry disease: a 
systematic review of available evidence. Drugs. 2009;69:2179-2205. 
Schiffmann R, Murray GJ, Treco D, et al. Infusion of α-galactosidase A reduces tissue 
globotriaosylceramide storage in patients with Fabry disease. PNAS. 2000;97:365–70. 
Schiffmann R, Kopp JB, Austin HA, et al. Enzyme replacement therapy in Fabry Disease: A 
randomized controlled trial. JAMA. 2001;285:2743-49.  
Schiffmann R, Ries M, Timmons M, Flaherty JT, Brady RO. Long-term therapy with agalsidase 
alfa for Fabry disease: safety and effects on renal function in a home infusion setting. Nephrol 
Dial Transplant. 2006;21:345-54. 
Schiffmann R. Fabry disease. Pharmacol Ther. 2009;122:65-77. 
Thurberg BL, Rennke H, Colvin RB, et al. Globotriaosylceramide accumulation in the Fabry 
kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int. 
2002;62:1933-46. 
U.S. Department of Health and Human Services. National Institutes of Health. National Cancer 
Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: 
May 28, 2009 (v4.03: June 14, 2010). 

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van Breemen MJ, Rombach SM, Dekker N, et al. Reduction of elevated plasma globotriaosyl-
sphingosine in patients with classic Fabry disease following enzyme replacement therapy. 
Biochim Biophys Acta. 2011;1812:70–6. 
Vedder AC, Breunig F, Donker-Koopman WE, et al. Treatment of Fabry disease with different 
dosing regimens of agalsidase: effects on antibody formation and GL-3. Mol Genet Metab. 
2008;94:319-25. 
Weidemann F, Niemann M, Breunig F, et al. Long-term effects of enzyme replacement therapy 
on Fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation. 
2009;119:524-9. 
Whybra C, Kampmann C, Krummenauer F, et al. The Mainz Severity Score Index: a new 
instrument for quantifying the Anderson–Fabry disease phenotype and the response of patients to 
enzyme replacement therapy. Clin Genet. 2004 65:299–307. 
Wilcox WR, Banikazemi M, Guffon N, et al. Long-term safety and efficacy of enzyme 
replacement therapy for Fabry disease. Am J Hum Genet. 2004; 5:65-74. 
Wilcox WR, Oliveira JP, Hopkin RJ, et al. Females with Fabry disease frequently have major 
organ involvement: lessons from the Fabry Registry. Mol Genet Metab. 2008;93:112-28. 
 
 
 

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 APPENDICES 
14
 Appendix 1.  Vial Label 
14.1
Sample labels for the study drug are illustrated below in Figures 1 and 2. Labels will be adapted 
in accordance with local regulatory and language requirements.  
Figure 1:  Outer Package Label (Example) 
 
Figure 2:  Individual Vials Label (Example) 
Study drug name: pegunigalsidase alfa 20 mg/vial for 
intravenous injection only as directed 
10 mL in each vial 
Batch number: ___________ Expiry:  MM-YYYY 
Protocol #: PB-102-F50 
Caution: New Drug – Limited by Federal (or United States) 
law to investigational use. 
Patient number: ____________  
Visit number: ____________ 
Sponsor: Protalix Ltd, 2 Snunit St., Carmiel, Israel, 
Tel: +972-4-9889488 
 
Protocol #: PB-102-F50 
Study drug name: pegunigalsidase alfa (PRX-102) 
20 mg/vial; 10mL in each vial 
Qty: N vials_______ 
For intravenous injections only as directed 
Batch number:   
 
 
   Expiry: MM-YYYY 
 
IND No. 110,161 
Directions for use: 
Store at: 2-8°C (36-46°F) 
Caution: New Drug – Limited by Federal (or United States) law to investigational use. 
  
Sponsor: Protalix Ltd, 2 Snunit St., Carmiel, Israel, Tel: +972-4-9889488 

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 Appendix 2.  Tolerability and Infusion Rate Algorithm 
14.2
The infusion rate (IR) may be adjusted according to individual subject signs and symptoms.  The 
assumptions with respect to adverse experiences to the infusion are: 
1. Most of the subjects will tolerate the infusion without any special symptom or event.  
2. Subjects presenting with signs and symptoms of severe hypersensitivity will be evaluated 
according to the CTCAE Drug Toxicity criteria and there may be a discontinuation of 
treatment according to the protocol. 
3. Subjects may present with signs and symptoms that will respond to reducing the infusion 
rate and may not appear at the next infusion. 
4. Tolerability and the subject-specific infusion rate will be assessed and decided by the 
Investigator according to vital signs and clinical status of the subject. 
Definitions to be applied regarding tolerability of infusions are as follows: 
Good Tolerability 
Partial Tolerability 
Poor Tolerability  
Infusion was performed 
without signs and symptoms 
(such as burning, pruritus, 
flushing, discomfort, or 
change in vital signs). 
Signs and symptoms appeared 
during the infusion and 
resolved after slowing the 
infusion rate or at the end of 
the infusion.  
Signs and symptoms meeting 
the definitions of CTCAE 
Grade 1 or 2 toxicity 
responding to reduction of 
infusion rate or responding to 
treatment (e.g., antihistamine 
for urticaria). 
 

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The specific algorithm for infusion rates to be followed: 
 
Evaluate tolerability of the 
infusion  
Good 
Tolerability 
Tolerability 
achieved 
Adjust IR 
according to 
protocol 
 Reduce IR (by ~25%): 
 
 
 
 
Consider discontinuation 
according to protocol 
following consulting with 
Medical Director 
 
Further reduce IR 
(by ~25%): 
Signs and symptoms 
during the infusion 
Severe or progressive 
hypersensitivity 
Continue same IR 
Consult with Medical 
Director about subsequent 
infusions 
Persistent signs and 
symptoms during the infusion 
or severe hypersensitivity 
Persistent signs and symptoms 
during the infusion 
Tolerability 
achieved 
 
Severe 
hypersensitivity 

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Changes in Infusion Rates According to the Protocol 
The tolerability of the infusions in patients will be determined by signs and symptoms during the 
infusion, observation in the hospital, and by the telephone contact the day after the first infusion. 
The infusion rate may be adjusted according to individual patient signs and symptoms according 
to the above algorithm.  
For patients with good tolerability, an attempt of premedication discontinuation should be done. 
After that, the infusion length and the clinical observation after the infusion could be reduced 
according to Appendix 8. 
The infusion rate should be adjusted according to patient tolerability as described above; 
continuation of the rate of infusion should be agreed upon between the PI and the Medical 
Director. 
 
 

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 Appendix 3.  Pegunigalsidase alfa Hypersensitivity Evaluation and Treatment 
14.3
Algorithm 
During and after infusion of pegunigalsidase alfa, the following algorithm will be followed to 
monitor and manage the occurrence of hypersensitivity, anaphylaxis, or anaphylactoid reactions. 
Clinical signs 
Early 
 Sensation of warmth and itching 
 Feelings of anxiety  
Moderate 
 Pruritus 
 Flushing 
 Urticaria 
 Chest discomfort 
 Mild hypotension 
Progressive 
 Erythematous or massive urticarial rash 
 Edema of face, neck, soft tissues 
Severe 
 Hypotension 
 Bronchospasm (wheezing) 
 Laryngeal edema (dyspnea, stridor, aphonia, drooling) 
 Arrhythmias 
Treatment algorithm: 
With the onset of any of the above clinical signs, immediately discontinue study medication 
administration and initiate the following monitoring. 
 Continuous electrocardiographic monitoring 
 Continuous pulse oximetry 
 Measure blood pressure every 5 minutes 
 Perform chest auscultation every 5 minutes 
 Collect blood samples for tryptase (29-33), antibodies and C3, C4. Tryptase samples need 
to be withdrawn at: 
o 1st sample taken 0.25-3 hours after onset of symptoms 
o 2nd sample taken between 3-6 hours  
o 3rd sample taken 24-48 hours to verify the return to baseline. 
Treat as follows: 
Urticaria or edema of the face, neck, or soft tissues 

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 Epinephrine 1:1000 solution, 0.5 mL subcutaneously, repeat as needed every 5-10 minutes 
 Antihistamines 
 Corticosteroids 
Hypotension (systolic blood pressure [SBP] ≤ 90 mmHg) 
 Isotonic sodium chloride solution, 1 L every 30 minutes as needed to maintain SBP > 90 
mmHg 
 Epinephrine 1:10,000 solution given IV at 1 μg/minute initially, then 2-10 μg/minute to 
maintain SBP > 90 mmHg 
 Norepinephrine 4 mg in 1 L 5% dextrose in water given IV at 2-12 μg/min to maintain 
SBP > 90 mmHg 
 Glucagon 1 mg in 1 L 5% dextrose in water given IV at 5-15 μg/minute for refractory 
hypotension 
Bronchospasm 
 Oxygen by face mask at 6-8 L/minute to maintain oxygen saturation at > 90% 
 Epinephrine 1:1000 solution, 0.5 mL subcutaneously 
 Albuterol 0.5 mL of 0.5% solution in 2.5 mL of sterile saline every 15 minutes up to three 
doses 
 Inhaled beta-agonists 
 Corticosteroids 
Laryngeal edema 
 Epinephrine 1:1000 solution, 0.5 mL subcutaneously, repeat as needed every 5 to 10 
minutes 
 Corticosteroids 
If symptoms resolve within a single study visit and the Investigator determines the symptoms 
were not an occurrence of progressive or severe hypersensitivity, anaphylaxis, or anaphylactoid 
reactions, then administration of the drug may continue according to the algorithm provided 
above, and at the discretion of the Investigator and Medical Director.  
Premedication 
Premedication for subsequent pegunigalsidase alfa infusions may be considered at the discretion 
of the Investigator and Medical Director for subjects experiencing early clinical signs of 
hypersensitivity or rash/urticaria that responds promptly to oral antihistamine administration (see 
also Appendix 2.  Tolerability and Infusion Rate Algorithm for adjustment of infusion rate).  The 
premedication will be administered according to the following steps as needed to prevent 
progressive hypersensitivity: 
1. Antihistamine (H1 blocker: diphenhydramine, hydroxyzine, cetirizine, loratadine, 
desloratadine) at a standard dose 12 hours and 2 hours before the start of the infusion. 
2. H1 blocker plus H2 blocker (ranitidine, cimetidine, famotidine) at standard doses 12 
hours and 2 hours before the start of the infusion. 

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3. H1 blocker plus H2 blocker plus prednisone up to 50 mg administered 12 hours and 2 
hours before the start of the infusion. 

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 Appendix 4.  The Mainz Severity Score Index (MSSI) 
14.4
The MSSI score has been proven representative in patients with ‘classic’ Fabry disease and is 
useful for monitoring clinical improvement in patients receiving enzyme replacement therapy 
(Whybra et al., 2004). 
The MSSI scoring system is composed of four sections that cover the general, neurological, 
cardiovascular and renal signs and symptoms of Fabry disease. Each section includes a group of 
signs and symptoms that are associated with Fabry disease. 
The MSSI will be performed at baseline (Visit 1) and every 6 months throughout the study. 
The Mainz Severity Score Index (MSSI) 
General Score 
Neurological Score 
Sign/symptom 
Rating 
MSSI 
score 
Sign/symptom 
Rating 
MSSI 
score 
Characteristic facial 
appearance 
No 
0 
Tinnitus 
No 
0 
 
Yes 
1 
 
Mild 
1 
Angiokeratoma 
None 
0 
 
Severe 
2 
 
Some 
1 
Vertigo 
No 
0 
 
Extensive 
2 
 
Mild 
1 
Edema 
No 
0 
 
Severe 
2 
 
Yes 
1 
Acroparesthesia 
No 
0 
Musculoskeletal 
No 
0 
 
Occasional 
3 
 
Yes 
1 
 
Chronic 
6 
Cornea verticillata 
No 
0 
Fever pain crisis 
No 
0 
 
Yes 
1 
 
Yes 
2 
Diaphoresis 
Normal 
0 
Cerebrovascular 
No 
0 
 
Hypo/Hyper 
1 
 
Ischemic lesions (in 
MRI/CT) 
1 
 
Anhidrosis 
2 
 
TIA/migraine etc. 
3 
Abdominal pain 
No 
0 
 
Stroke 
5 
 
Yes 
2 
Psychiatric/ 
psychosocial 
 
 
Diarrhea/ 
constipation 
No 
0 
Depression 
No 
0 
 
Yes 
1 
 
Yes 
1 
Hemorrhoids 
No 
0 
Fatigue 
No 
0 
 
Yes 
1 
 
Yes 
1 
Pulmonary 
No 
0 
Reduced activity 
level 
No 
0 
 
Yes 
2 
 
Yes 
1 
New York Heart 
Association (NYHA) 
classification* 
No 
0 
 
 
 
 
Class I 
1 
 
 
 
 
Class II 
2 
 
 
 
 
Class III 
3 
 
 
 
 
Class IV 
4 
 
 
 
Maximum Score 
 
18 
Maximum Score 
 
20 

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Cardiovascular Score 
Renal Score 
Sign/symptom 
Rating 
MSSI 
score 
Sign/symptom 
Rating 
MSSI 
score 
Changes in cardiac 
muscle thickness 
No 
0 
Evidence of renal 
dysfunction 
No proteinuria 
0 
 
Thickening of 
wall/septum 
1 
 
Proteinuria 
4 
 
LVH seen on ECG 
6 
 
Tubular 
dysfunction/low 
GFR or creatinine 
clearance 
8 
 
Cardiomyopathy 
(<15) 
8 
 
End-stage renal 
failure (serum 
creatinine levels 
>3.5 mg/dl) 
12 
 
Severe 
cardiomyopathy 
(>15) 
12 
 
Dialysis 
18 
Valve insufficiency 
No 
0 
 
 
 
 
Yes 
1 
 
 
 
ECG abnormalities 
No 
0 
 
 
 
 
Yes 
2 
 
 
 
Pacemaker 
No 
0 
 
 
 
 
Yes 
4 
 
 
 
Hypertension 
No 
0 
 
 
 
 
Yes 
1 
 
 
 
Maximum Score 
 
20 
Maximum Score 
 
18 
* Limitation on physical activity according to NYHA classification is as follows. Class I: none; Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnea or anginal pain, but echocardiography reveals heart 
involvement. Class II: slight; comfortable at rest, but ordinary physical activity results in fatigue, etc. Class III: 
marked; comfortable at rest, but less than ordinary physical activity causes fatigue, etc. Class IV: unable to carry out 
any physical activity without discomfort; symptoms of cardiac insufficiency or of anginal syndrome may be present 
even at rest and physical activity increases discomfort.  
Abbreviations: CT, computed tomography; ECG, electrocardiogram; GFR, glomerular filtration rate; LVH, left 
ventricular hypertrophy; MRI, magnetic resonance imaging; TIA, transient ischemic attack. 
 
 

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 Appendix 5.  National Kidney Foundation Guidelines for Chronic Kidney Disease 
14.5
Stages of Chronic kidney disease (National Kidney Foundation, 2002): 
 Stage 1- Kidney damage with normal or elevated GFR (≥ 90) 
 Stage 2- Kidney damage with mild reduction in GFR (60-89) 
 Stage 3- Kidney damage with moderate reduction in GFR (30-59) 
 Stage 4- Kidney damage with severe reduction in GFR (15-29) 
 Stage 5- Kidney failure (<15 or dialysis) 
14.5.1 Estimation of GFR: 
Estimates of GFR are the best overall indices of the level of kidney function. The level of GFR 
should be estimated from prediction equations that take into account the serum creatinine 
concentration and some or all of the following variables: age, gender, race, and body size. 
Among adults, the CKD-EPI equation provides a clinically useful estimate of GFR (Levey et al., 
2009).  This equation provides an estimate of GFR standardized for body surface area. 
14.5.2 CKD-EPI Equation:  
The CKD-EPI equation (Levey et al., 2009) performed better than the MDRD (Modification of 
Diet in Renal Disease Study; Levey et al., 2006) equation, especially at higher GFR, with less 
bias and greater accuracy. When looking at NHANES (National Health and Nutrition 
Examination Survey) data, the median estimated GFR was 94.5 vs. 85.0 mL/min per 1.73 m2, 
and the prevalence of chronic kidney disease was 11.5% vs 13.1%. The CKD-EPI equation, 
expressed as a single equation, is: 
GFR = 141 * min(Scr/κ,1)α * max(Scr/κ,1)-1.209 * 0.993Age * 1.018 [if female] * 1.159 [if 
black/African American] 
Scr: serum creatinine (mg/dL),  
κ: 0.7 for females and 0.9 for males,  
α: -0.329 for females and –0.411 for males,  
min: indicates the minimum of Scr/κ or 1, and  
max: indicates the maximum of Scr/κ or 1. 

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 Appendix 6.  QOL Questionnaire - EQ-5D-5L 
14.6
 

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 Appendix 7.  Brief Pain Inventory- BPI (Short Form) 
14.7
The short form of the Brief Pain Inventory (BPI) will be performed at baseline and Visits 7 and 
10. 
(https://www.mdanderson.org/research/departments-labs-institutes/departments-divisions/ 
symptom-research/symptom-assessment-tools/brief-pain-inventory.html) 
 

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 Appendix 8.  Schedule of Premedication, Infusion Rates, and Observation Times 
14.8
Post-Infusion  
Proposed schedule to: 
1. Taper down premedication 
2. Increase infusion rate 
3. Reduce  observation time after infusion 
The schedule below, will guide the sites on the process to taper down premedication, increase the 
infusion rate up to minimal time of infusion allowed by the protocol based on the tolerability of 
the patient, and reduce the observation time after infusion.  At the end of the process, the patient 
may be offered to continue therapy in a home care setup based on the Investigator evaluation and 
discussion with the Medical Director. 
General considerations: 
1. Patients whose weight is up to (≤)100 kg, the length of first infusion will be 4.5 hours. 
2. Patients whose weight is more than (>) 100 kg, the length of first infusion will be 6 
hours. 
3. Clinical follow-up (observation) after the infusion in all rates will be 4 hours for the first 
infusion. 
4. Patients who received the previous ERT with premedication will have the first infusion of 
pegunigalsidase alfa with the same protocol of premedication as with the previous ERT. 
5. All changes can be implemented only if there is good tolerability of the previous change. 
6. In the case of questionable tolerability, the continuation of the process will be discussed 
between the Investigator and the Medical Director. 
1. Taper down premedication 
The principle in the process is: 
On the first infusion: the subject will continue the premedication as  in previous ERT tratment. 
On the next  infusion, one of the medications used as premedication will be removed. If well 
tolerated, on the next infusion, additional medication used as premedication will be removed 
(when applicable).  This regimen will continiue up to tapering down all premedications, or best 
tolerability to the infusion is achieved. 

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2. Reduce infusion time  
The principle in the process is: 
Reduction in the infusion time will start after an attempt was done to taper down the 
premedication based on patient tolerability.  The length of infusion will be reduced by 0.5 hour 
as described in Table 2 to achieve the best tolerated infusion length or an infusion of 2 hours (for 
patients ≤ 100 kg weight) or 3 hours (for patients weighing more than 100 kg). 
3. Reduce observation time after infusion  
The principle in the process is: 
The process for reducing observation time after the infusion will start after the attempt of 
tapering down the premedication was finalized (when one of the results could be the patient will 
remain on premedication).  Until then, the post-infusion observation will be 4 hours. 
On the next upcoming visit, the observation time will be reduced by 0.5 hour in each infusion up 
to 2 hours and then reduced to 1 hour post-infusion.  
4. Referring the patient to home care set-up 
The patients will be able to join the home care program once the patient is clinically stable with 
no additional changes in premedication, infusion rate, and observation time.  
The changes require discussion and approval by the Medical Monitor/Director. 
Table 2 represents a proposed regimen to achieve the goal of reducing premedication, infusion 
length, and post infusion observation; Other regimens need to be discussed and approved by the 
Medical Monitor/Director. 
 
 

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Table 2:  Proposed Regimen of Reduced Premedication, Infusion Length, and Post-
Infusion Observational Period 

Protocol PB-102-F50 
Protalix Ltd. 
EudraCT:  2017-001528-23 
25 Jul 2018 
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