A Multi Center Extension Study of PRX-102 Administered by Intravenous Infusions Every 2 Weeks for up to 60 Months to Adult Fabry Patients
Phase: PHASE1
Conditions: Fabry Disease
Sponsor: Protalix

Protocol Number PB-102-F03 
Protalix Ltd. 
Jan 5, 2016 
 _ _____________________________________________________________________________
NCT01981720
 CLINICAL STUDY PROTOCOL
 Protocol Title:  A Multi Center Extension Study of PRX-102  Administered by
 Intravenous Infusions Every 2 Weeks for up to 60 Months to Adult Fabry
 Patients
 Protocol Number: PB-102-F03
Investigational Product: 
PRX-102, a chemically modified human alpha galactosidase, 
expressed in plant cells 
Indication: 
PRX-102 is indicated for long-term enzyme replacement 
therapy in patients with a confirmed diagnosis of Fabry 
disease (alpha galactosidase deficiency) 
Phase: 
Protocol Version: 
Phase 1/2 
Version 2  
Version 3 , 15 Jan 2015 
Version 3B, 26 Jan 2015 (Dallas only) 
Version 3C, 28 Jan 2015 (Virginia and Iowa only) 
Version 3E, 18 Jan 2015 (Spain only) 
Version 4, 05 Jan 2016 
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.

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1 
SYNOPSIS 
TITLE:  A Multi Center Extension Study of PRX-102  Administered by Intravenous 
Infusions Every 2 Weeks for up to 60 Months to Adult Fabry Patients 
INVESTIGATIONAL PRODUCT:  PRX-102, a chemically modified human alpha 
galactosidase, expressed in plant cells 
INDICATION:  PRX-102 is indicated for long-term enzyme replacement therapy in 
patients with a confirmed diagnosis of Fabry disease (alpha galactosidase deficiency) 
PHASE OF DEVELOPMENT:  Phase 1/2 
INVESTIGATIONAL SITES/LOCATIONS:  Multicenter 
OBJECTIVES:  To evaluate the ongoing safety, tolerability, and efficacy parameters of 
PRX-102 in adult Fabry patients who have successfully completed treatment with PRX-
102 in studies PB-102-F01 and PB-102-F02  
STUDY DESIGN:  Patients will be enrolled to receive PRX-102 at the dose of, 1.0 
mg/kg, as an intravenous infusion every 2 weeks (+/- 3 days). The duration of treatment 
will be up to 60 months or until PRX-102 is commercially available to the subject at the 
discretion of the Sponsor and no less than 36 months. 
NUMBER OF SUBJECTS (PLANNED):  up to 16 adult (males and females) Fabry 
patients (≥18 yrs) who completed study PB-102-F02  
MAIN CRITERIA FOR INCLUSION AND EXCLUSION: 
Key inclusion criteria: 
Eligible patients must fulfill the following inclusion criteria: 
1. Completion of study PB-102-F02
2. The patient signs informed consent
3. Female patients of child-bearing potential agree to use a medically acceptable
method of contraception, not including the rhythm method. Acceptable
methods of contraception include hormonal products, intrauterine device, or
male or female condoms. Contraception should be used throughout the
duration of the study and for 3 months after termination of treatment..
Key exclusion criteria: 
The presence of any of the following excludes a patient from study enrollment: 
1. 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

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TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION:  PRX-102 indoses 
of 1.0 mg/kg, intravenously, every 2 weeks. For each patient that received 0.2 or 2 
mg/kg in study PB-102-F02, the dose will be adapted gradually to 1 mg/kg. Study drug 
will be administered at the study clinic or infusion center unless the Medical Director 
and Investigator approve for home care set up, based on the clinical condition of the 
subject and local practices and regulations. 
DURATION OF TREATMENT:  up to 60 months or until the product is commercially 
available to the subject at the discretion of the Sponsor and no less than 36 months. 
DISCONTINUATION FROM TREATMENT:   
Reasons for permanent discontinuation include the following: 
 The patient experiences two or more Grade 3 toxicities or one or more Grade 4 
toxicity that are considered by the investigator to be associated with PRX-102 
treatment (U.S. Department of Health and Human Services, 2010) 
 The patient experiences progressive hypersensitivity or severe hypersensitivity - to 
be treated appropriately and withdrawn from the study 
 The patient requests to discontinue treatment 
 The 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 
 Marketing approval is obtained and the drug is available at the patient country or at 
the discretion of the sponsor 
 
 
EXPLORATORY EFFICACY ENDPOINTS: 
 Gb3 concentrations in plasma sediment at baseline (will be the values from the last 
infusion of study PB-102-F02) and every 3 months up to 24 months and then every 6 
months up to end of study.  
 Globotriaosylsphingosine (Lyso-Gb3) concentration in plasma at baseline (will be 
the values from the last infusion of study PB-102-F02) and every 3 months up to 24 
months and then every 6 months up to end of study.  
 Assessment of gastrointestinal symptoms at baseline (will be the values from the last 
infusion of study PB-102-F02) and every 3 months up to 24 months and then every 6 
months up to end of study. Questionnaire for Evaluation Gastrointestinal 
Symptoms (Dehout et al., 2004) used until Protocol version 4 is approved and 
maybe  substituted by the IBS-SSS questionnaire when  available 
 Kidney functions (eGFR and proteinuria) at baseline (will be the values from the last 
infusion of study PB-102-F02) and every 3 months up to 24 months and then every 6 
months up to end of study.  
 Short Form Brief Pain Inventory (BPI) at baseline (will be the values from the last 
infusion of study PB-102-F02) and every 3 months up to 24 months and then every 6 

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months up to end of study.  
 Left ventricular mass (LVM) and myocardial fibrosis assessment by cardiac MRI 
every 12 months during the study. (Baseline value will be the evaluation 
performed at the last visit of  study PB-102-F02  
 Cardiac function assessment by echocardiography and stress test every 12 months 
during the study.  Baseline value will be the evaluation performed at last visit of 
study PB-102-F02 
 Mainz Severity Score Index (MSSI) every 6 months during the study. (Baseline 
value will be the evaluation performed at last visit of study PB-102-F02.  
 
SAFETY ENDPOINTS:  
Changes from baseline in: 
 Clinical laboratory tests 
 Physical examination 
 Assessment of the injection site reactions 
 ECG 
 Treatment-emergent adverse events (TEAEs) 
 Anti-PRX-102 antibodies 
 Cerebrovascular disease assessment (clinical and MRI evaluation) at visit 24 M 
and 60 M (total treatment of 3 years and 6 years).   
STATISTICAL ANALYSIS: 
Patients who received at least one dose of study drug will be included in the safety 
analysis.. Results of safety evaluations (including TEAEs, injection site reactions, 
physical examinations, ECG, and laboratory analyses) will be summarized and 
described.  
 
No formal statistical analyses will be performed in this study. Quantitative data will be 
summarized across dose groups by presenting sample size, mean and its standard error, 
standard deviation, median, minimum, and maximum values for both actual and change 
from baseline results. Qualitative data will be summarized across dose groups by 
showing frequency and percentage within each category.  
 
 

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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 
 
___________________________________________ 
 
_______________________ 
Signature 
 
 
 
 
 
 
 
Date 
 
 
 
PRINCIPAL INVESTIGATOR 
 
___________________________________________ 
 
_______________________ 
Signature 
 
 
 
 
 
 
 
Date 
Print Name:  ________________________________ 
 

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TABLE OF CONTENTS 
1 
SYNOPSIS ............................................................................................................................................ 2 
2 
LIST OF ABBREVIATIONS ................................................................................................................ 8 
3 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY REQUIREMENTS ....................... 9 
3.1 
Institutional Review Board (IRB)................................................................................................ 9 
3.2 
Ethical Conduct of the Study ....................................................................................................... 9 
3.3 
Subject Information and Consent ................................................................................................ 9 
4 
INTRODUCTION ............................................................................................................................... 10 
5 
STUDY OBJECTIVES ....................................................................................................................... 13 
To evaluate the ongoing safety, tolerability and efficacy parameters of PRX-102 in adult Fabry 
patients who have successfully completed treatment with PRX-102 in studies PB-102-F01 and 
PB-102-F02. ......................................................................................................................................... 13 
6 
INVESTIGATIONAL PLAN .............................................................................................................. 14 
6.1 
Overall Study Design and Plan – Description ........................................................................... 14 
6.2 
Discussion of Study Design ....................................................................................................... 14 
6.3 
Selection of Study Population ................................................................................................... 14 
6.3.1 
Inclusion Criteria ........................................................................................................... 14 
6.3.2 
Exclusion Criteria .......................................................................................................... 14 
6.3.3 
Removal of Subjects from Therapy or Assessment ...................................................... 15 
7 
STUDY PRODUCT ............................................................................................................................ 16 
7.1 
Study Medication Supply .......................................................................................................... 16 
7.2 
Description and Formulation of Study Product ......................................................................... 16 
7.3 
Study Drug Dosage and Preparation ......................................................................................... 16 
7.4 
Description of Comparator Product ........................................................................................... 16 
7.5 
Study Drug Administration ....................................................................................................... 16 
7.6 
Packaging and Labeling ............................................................................................................ 17 
7.7 
Conditions for Storage and Use ................................................................................................. 17 
7.8 
Method of Assigning Subjects to Treatment Groups ................................................................ 17 
7.9 
Dispensing, Compliance and Accountability ............................................................................ 18 
7.10 Prior and Concomitant Therapy ................................................................................................ 18 
8 
EFFICACY AND SAFETY ASSESSMENTS .................................................................................... 19 
8.1 
Efficacy Variables ..................................................................................................................... 19 
8.2 
Safety Variables......................................................................................................................... 19 
8.2.1 
Clinical Laboratory ....................................................................................................... 19 
8.2.2 
Anti-PRX-102 Antibodies ............................................................................................. 20 
8.2.3 
Adverse Events.............................................................................................................. 20 
9 
STUDY PROCEDURES AND FLOW CHART ................................................................................. 24 
9.1 
Study Flow Chart ....................................................................................................................... 24 
9.2 
Study Visits ............................................................................................................................... 25 
Study visits schedule described below may not correspond in time with the every two 
weeks   infusions schedule, particularly if the subject is being infused at an 
infusion center or at a home set up. ............................................................................... 25 
9.2.1 
Infusion visits ................................................................................................................ 25 
9.2.2 
Study Visits ................................................................................................................... 25 

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10 STATISTICAL METHODS PLANNED AND SAMPLE SIZE ........................................................ 28 
10.1 Determination of Sample Size ................................................................................................... 28 
10.2 Subject Populations ................................................................................................................... 28 
10.2.1 Intent-to-Treat (ITT) Population ................................................................................... 28 
10.2.2 Per Protocol (PP) Population ........................................................................................ 28 
10.2.3 Safety Population .......................................................................................................... 28 
10.3 Analysis ..................................................................................................................................... 28 
10.4 Safety Analysis .......................................................................................................................... 29 
10.4.1 Adverse Events.............................................................................................................. 29 
10.4.2 Clinical Laboratory ....................................................................................................... 30 
10.5 Interim Analysis ........................................................................................................................ 30 
11 QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 31 
11.1 Source Data and Records ........................................................................................................... 31 
11.2 Reporting of Results .................................................................................................................. 31 
11.3 Confidentiality of Subject Data ................................................................................................. 32 
12 REPORTING AND PUBLICATION .................................................................................................. 33 
12.1 Confidentiality of Study Data .................................................................................................... 33 
13 Appendices .......................................................................................................................................... 34 
13.1 Appendix 1.  Vial Label ............................................................................................................ 34 
13.2 Appendix 2.  Infusion Rate Algorithm ...................................................................................... 35 
13.3 Appendix 3.  PRX-102 Evaluation and Treatment Algorithm .................................................. 37 
13.4 Appendix 4.  Cardiac MRI ........................................................................................................ 40 
13.4.1 Patients and Sites........................................................................................................... 40 
13.4.2 Magnetic Resonance Imaging (MRI) Data ................................................................... 40 
13.4.3 MRI Evaluation Parameters .......................................................................................... 40 
13.4.4 Sites and Image Data Management ............................................................................... 40 
13.4.5 Image Processing and Centralized Analysis ................................................................. 41 
13.4.6 Data and Report Transfers to Sponsor .......................................................................... 42 
13.4.7 Direct Access to Study Data ......................................................................................... 42 
13.4.8 Unevaluable MRI .......................................................................................................... 42 
13.5 Appendix 5.  The Mainz Severity Score Index (MSSI) ............................................................. 43 
13.5.1 The Mainz Severity Score Index (MSSI) ...................................................................... 43 
13.6 Appendix 6.  Questionnaire for Evaluation Gastrointestinal Symptoms ................................... 45 
13.8 Appendix 7. IBS SSS ................................................................................................................ 46 
13.9 Appendix 8.  Brief Pain Inventory- BPI (Short Form) .............................................................. 47 
13.10 Appendix 9.  References ............................................................................................................ 50 
 

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2 
LIST OF ABBREVIATIONS  
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
Alpha-GAL-A 
Alpha galactosidase-A 
ARB 
Angiotensin 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 
BPI 
Brief pain inventory 
C3 
Complement C3 
C4 
Complement C4 
CHO 
Chinese hamster ovary 
CKD 
Chronic kidney disease 
Cmax 
Maximum concentration observed 
CRF 
Case report form 
CT 
Computed tomography 
EC 
Ethics Committee 
ECG 
Electrocardiography  
eGFR 
Estimated glomerular filtration rate 
ERT 
Enzyme replacement therapy 
Gb3 
Globotriaosylceramide 
GCP 
 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IC 
Informed consent 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
LLN 
Lower limit of normal 
LVH 
Lt. ventricular hypertrophy 
LVM 
Lt. ventricular mass 
Lyso-Gb3 
Globotriaosylsphingosine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
PK 
Pharmacokinetics 
PP 
Per Protocol 
SAE 
Serious adverse event 
SPM 
Study Procedures Manual 
TIA 
Transient ischaemic attack 
t1/2 
Time at which the concentration is half of the maximum value (Cmax) 

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3 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY 
REQUIREMENTS 
3.1 
Institutional Review Board (IRB) 
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 patients. A list of all IRBs and ECs and contact 
information will be included in the study report. 
3.2 
Ethical Conduct of the Study 
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. 
3.3 
Subject Information and Consent 
The investigator will obtain a freely given written consent from each patient after an appropriate 
explanation of the aims, methods, anticipated benefits, potential hazards, and any other aspects 
of the study that are relevant to the patient's decision to participate. The consent forms must be 
signed and dated by the patient before he/she is exposed to any protocol-specific procedure. 
The investigator will explain that the patients 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 patient will receive a copy of the patient information and the signed informed consent forms.  
The patient will be informed if information becomes available that may be relevant to his/her 
willingness to continue participation in the study. 
Each patient 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. 

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4 
INTRODUCTION 
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 alpha 
galactosidase-A (alpha-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-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 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. Progressive accumulation of Gb3, and related lipids, leads 
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 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 2009). A recent 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 haemodialysis. A recent study by Hughes et al, that 
compared men and women with Fabry disease, using data from the Fabry Outcome Survey 

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(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.  
Recombinant human alpha-GAL-A has the ability to restore enzyme function in patients, and 
currently two ERTs using this enzyme are commercially available;  agalsidase-alpha (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 with 
regard to 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 and Guffon et al., 2001; 
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; Germain et al., 2007; Schiffmann 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 maybe 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% (Schiffmann et al., 2006; Eng and Banikazemi et al., 2001; Eng and Guffon et al., 2001) 
of male patients developed these IgG antibodies within the first 6 months of treatment. 
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 

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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 by providing excess enzyme (Vedder et al., 2008; Hollak et al., 
2009). However, this approach is not considered a long-term solution. 
Protalix has developed PRX-102, a chemically modified recombinant human alpha-GAL-A 
expressed in plant cell culture. As a result of this modification, PRX-102 exhibits more stabilized 
enzymatic activity, extended circulation residence time and enhanced bioavailability of the 
enzyme relative to the commercial drug.  
Studies have shown that human alpha-GAL-A is a non-covalently bound homodimeric 
glycoprotein (Garman et al., 2004) and that the dimerization is important for the enzymatic 
activity and stability of the enzyme (Bishop et al., 1988). The chemical modification of PRX-102 
utilises the reagent bis-NHS-PEG and renders PEGylated protein subunits the majority of which 
are crosslinked into homodimers. In addition, the PEGylation modification may have an additive 
value through increasing drug retention time in blood and bioavailability (Veronese et al., 2005; 
Veronese et al., 2008). Preliminary non-clinical data shows that this modification improves 
PRX-102 stability in vitro under lysosomal and plasma conditions, and extends circulation 
residence and bioavailability in vivo, probably due to stabilization of its quaternary structure. 
Therefore, the modifications in PRX-102 have the potential to improve the efficacy of ERT. 

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5 
STUDY OBJECTIVES 
To evaluate the ongoing safety, tolerability and efficacy parameters of PRX-102 in adult Fabry 
patients who have successfully completed treatment with PRX-102 in studies PB-102-F01 and 
PB-102-F02.  

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6 
INVESTIGATIONAL PLAN 
6.1 
Overall Study Design and Plan – Description 
This will be an open-label, dose ranging study to evaluate the ongoing safety, tolerability and 
efficacy parameters of PRX-102 in adult Fabry patients (≥18 years of age).   
Patients will be enrolled to receive 1.0 mg/kg of PRX-102 as an intravenous infusion every 2 
weeks (+/- 3 days) for up to 60 months and no less than 36 months. 
All disease parameters but GB3 in urine, kidney and skin biopsies, which were evaluated during 
study PB-102-F02 will continue to be assessed in this extension protocol (study PB-102-F03).  
 
6.2 
Discussion of Study Design  
The extension study may provide additional information on safety, tolerability and clinical 
outcome in PRX-102-treated patients. 
An interim analysis may be performed after all subjects have completed Month 12, 24, 36 and/or 
48 months.  In these analyses, descriptive statistics methods will be used to summarize available 
efficacy and safety parameters. 
 
6.3 
Selection of Study Population 
6.3.1 
Inclusion Criteria 
The patients must fulfill the following inclusion criteria: 
1. 
Completion of study PB-102-F02 
2. 
The patient signs informed consent 
3. 
Female patients and male patients whose co-partners are of child-bearing potential agree 
to use a medically acceptable method of contraception, not including the rhythm 
method. Acceptable methods of contraception include hormonal products, intrauterine 
device, or male or female condoms. Contraception should be used throughout the 
duration of the study and for 3 months after termination of treatment..  
6.3.2 Exclusion Criteria 
The presence of any of the following excludes a patient from study enrollment: 
1. 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 

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6.3.3 
Removal of Subjects from Therapy or Assessment 
Reasons for permanent discontinuation include the following: 
 The patient experiences two or more Grade 3 toxicities or one or more Grade 4 toxicity 
considered by the investigator to be associated with PRX-102 treatment (U.S. Department 
of Health and Human Services, 2010) 
 The patient experiences progressive hypersensitivity or severe hypersensitivity - to be 
treated appropriately and withdrawn from the study 
 The 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 
 Marketing approval is obtained and the drug is available at the patient country or at the 
discretion of the sponsor 
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 
eCRF.  The Investigator will make thorough efforts to document the outcome.  The Investigator 
will attempt to continue to follow the patient for the full duration of the study or at least for 60 
days following discontinuation.  If circumstances prevent the patient from completing all visits, 
every attempt will be made to complete all procedures listed in Section 9 for last visit (60 
months). 

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7 
STUDY PRODUCT 
7.1 
Study Medication Supply 
The Sponsor will provide the study drug to the study sites as needed.  
7.2 
Description and Formulation of Study Product  
PRX-102 is a purified recombinant, plant cell-expressed chemically modified human alpha 
galactosidase, which is described in detail in the Investigator’s Brochure. 
Each vial contains 10.2 mL of the following contents in liquid form: 
20 mg PRX-102 (2.0 mg/mL) 
0.7% NaCl  
25-30 mM Sodium Citrate (pH 5.7 - 6.3) 
 
7.3 
Study Drug Dosage and Preparation 
PRX-102 1.0 mg/kg PRX-102 vials are stored in liquid formulation at 2-8°C (36-46°F).  
The drug concentration is 2.0 mg/mL. 
The individual dose for each patient will be prepared according to patient’s weight and assigned 
dose. The patient’s weight is measured approximately every 6 months up to the end of  study 
(Visits Months: 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60), in order to adjust the amount of drug 
that should be administered. If there has been a change in the patient’s weight, the new measured 
weight will be used to calculate the amount of drug required, as from the following infusion visit.  
The dose will be prepared by a pharmacist or nurse at the study site or at a home care setup in the 
case of home care. The required amount of enzyme will be adjusted with normal saline (0.9% 
NaCl) to a final volume of 150 mL/infusion. For subjects weighing more than 100kg, if the 
clinical conditions permit it, the final volume should be between 250 ml/infusion to 500 
ml/infusion.  
7.4 
Description of Comparator Product  
Not applicable. 
7.5 
Study Drug Administration 
Patients will continue to receive 1 mg/kg PRX-102, administered bi-weekly every 2 weeks (+/- 3 
days) 
 
For each patient that received 0.2 or 2 mg/kg in study PB-102-F02, the dose will be adapted 
gradually: 

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The change in dose will be implemented at the study site only. 
Patients that were treated in group I, 0.2mg/kg,  the dose will be increased by 0.2 mg/kg in every 
third infusion  up to the dosage of 1 mg/kg.    
Patients that were treated in group III, 2mg/kg, the dose will be decreased by 0.25 mg/kg in 
every third infusion up to the dosage of 1 mg/kg. Pre-medication implemented per protocol in 
this treatment group can be discontinued if according to the investigator evaluation the patient 
tolerability to the infusion permit so. Discontinuation of pre-medication should occur towards the 
accommodation of the new dose, at the discretion of the investigator in a stepwise manner.   
During the period of adaptation to the new dose the patient will maintain the same rate of the last 
infusion, and clinical follow up will be at least 2 hours.  
After adjustment to the new dose, when applicable, study drug will be administered at the study 
clinic or infusion center unless the Medical Director and Investigator approve that the patient can 
receive the treatment at a home care setup, based on the clinical condition of the subject and 
local practices and regulations. 
Infusion rate can be adjusted according to patient tolerability (see Appendix 2); All changes in 
infusion rate or volume including the programmed in the protocol, should be agreed between the 
Investigator and the Medical Director 
If the infusions are well tolerated, the infusion rate can be increased by shortening of 30 minutes 
every third infusion, up to 1.5 hours infusion time and not less than that. 
7.6 
Packaging and Labeling 
The drug product is packed in vials containing 20 mg PRX-102 (2.0 mg/mL), 0.7% NaCl and 25-
30 mM Sodium Citrate (pH 5.7 - 6.3). 
Liquid drug is stored in 15 mL clear injection glass vials (Müller + Müller-Joh. GmbH + Co, 
Germany). Grey rubber stoppers (formulation 4432/50/Grey) used for closure (West 
Pharmaceutical Services Duetschland GmbH & Co KG) are sealed with aluminium seals.   
The label for the study drug is presented in Appendix 1. 
7.7 
Conditions for Storage and Use 
The study product is stored at 2-8°C (36-46°F). 
7.8 
Method of Assigning Subjects to Treatment Groups 
The dose of all patients will be 1mg/kg so will be only one treatment group.  

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For each patient recieving 0.2 or 2 mg/kg in study PB-102-F02, the dose will be adapted 
gradually to 1 mg/kg according to the description in paragraph 7.5.   
Patient number will continue to be as assigned in Study PB-102-F02.   
7.9 
Dispensing, Compliance and Accountability 
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 IDP (Investigational Drug Product) 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 
full record of IDP storage temperature.  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. 
7.10 
Prior and Concomitant Therapy 
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-alpha) 
 Any other investigational drug for treating Fabry disease 

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8 
EFFICACY AND SAFETY ASSESSMENTS 
8.1 
Efficacy Variables 
The following efficacy endpoints evaluated in Study PB-102-F02 will continue to be measured 
in this extension study.  Baseline values for this extension study will be the values from the last 
infusion of study PB-102-F02. 
 Gb3 concentrations in plasma at baseline and every 3 months up to visit 24 months, and 
then every 6 months up to end of  study  
 Globotriaosylsphingosine (Lyso-Gb3) concentration in plasma at baseline and every 3 
months up to visit 24 months, and then every 6 months up to end of  study  
 Assessment of gastrointestinal symptoms at baseline and every 3 months up to visit 24 
months, and then every 6 months up to end of study. Questionnaire for Evaluation 
Gastrointestinal Symptoms (Appendix 6-Dehout et al., 2004) will be used until Protocol 
version 4 is approved and may be substituted by the IBS-SSS questionnaire when available 
(Appendix 7).   
 Kidney functions (eGFR and proteinuria) at baseline and every 3 months up to visit 24 
months, and then every 6 months during the rest of the study 
 Short Form Brief Pain Inventory (BPI) at baseline and every 3 months up to visit 24 
months, and then every 6 months up to end of  study (Appendix 8) 
 Left ventricular mass and myocardial fibrosis assessment by cardiac MRI at baseline and 
every 12 months during the study 
 Cardiac function (assessed by echocardiography) and stress test at baseline and every 12 
months during the study 
 Mainz Severity Score Index (MSSI)  at baseline and every 6 months during this study  
 
8.2 
Safety Variables 
Safety will be assessed by the frequency, severity, and duration of treatment-emergent adverse 
events (TEAEs), including clinically significant laboratory abnormalities, ECG changes from 
baseline test, brain MRI changes from baseline, physical examination findings, assessment of the 
injection site reactions and existence of Anti PRX-102 antibodies after administration of the 
study drug. 
8.2.1 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 
 Biochemistry: sodium, potassium, glucose, blood urea nitrogen, creatinine, calcium, 
phosphate (inorganic), uric acid, total protein, albumin, bilirubin (total), alkaline 

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phosphatase, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, 
lactate dehydrogenase, and creatine phosphokinase   
 Urinalysis: dipstick for presence of blood, glucose, ketones, and protein 
8.2.2 Anti-PRX-102 Antibodies 
Anti-PRX-102 antibodies, including neutralizing antibodies in patients having a positive IgG 
antibody response, will be assessed using a validated analytical method. 
Anti-PRX-102 antibodies will be assessed every 3 months up to visit 24 months, and then every 
6 months up to end of the study, and 3 months after last infusion. 
8.2.3 Adverse Events 
8.2.3.1 
Adverse Events (AE) and Serious Adverse Events (SAE) 
An adverse event (AE) is any untoward medical occurrence in a patient participating in a clinical 
trial. An adverse event 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 90 days following 
the final visit dose.  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.  Pre-existing, 
known 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 adverse events commonly observed and adverse events 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 adverse event.  
A treatment emergent adverse event is any adverse event occurring after start of study 
medication and within the time of residual drug effect (30 days after the last administration of the 
study medication), or a pre-treatment adverse event or pre-existing medical condition that 
worsens in intensity after start of study medication and within the time of residual drug effect. 
Adverse events 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 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 adverse event. 

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However, if deemed necessary by the Investigator, a procedure can be captured along with the 
reason for conducting the procedure. 
An overdose or medication error is not an adverse event 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 
 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 adverse event caused by an overdose or medication error is considered serious if a criterion 
listed in the definition above is fulfilled. 
Important adverse events 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 patient’s safety or may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Serious adverse events 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 adverse events and all adverse events 
spontaneously reported by the trial patient using concise medical terminology.  In addition, each 
trial patient will be questioned about adverse events.  The question asked will be “Since you 
began taking the study medication, have you had any health problems?” 
8.2.3.2 
Procedures for Assessing, Recording, and Reporting Adverse Events and 
Serious Adverse Events 
Throughout the duration of the study, the Investigator will closely monitor each patient for 
evidence of drug intolerance and for the development of clinical or laboratory evidence of 
adverse events.  All adverse events (expected or unexpected) which occur during the course of 
the study, whether observed by the Investigator or by the patient, 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 adverse event will include description of event, start date, stop date, 
intensity, if it was serious, relationship to test drug, change in test drug dosage, if the patient 
died, and if treatment was required. 

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Events will be coded to one of the following intensity categories below: 
Severity 
Definition 
Grade 1 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL* 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabeling;limiting 
self care ADL** 
Grade 4  
Life threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE.*** 
*Activities of Daily Living (ADL)- Instrumental ADL refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, using the toilet, taking medications, and not bedridden. 
***Grade 5 (Death) is not appropriate for some AEs  
 
Events will be coded into one of the following causality categories as defined below: 
 
Adverse events with the causality assessed as unrelated or unlikely are categorized as not related 
to study medication.   
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 patient’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 patient’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. 

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Adverse events 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 (972-4-
9028162) or Safety Monitor (212-681-2100) to notify the Sponsor of the event. 
SAEs will be reported to all IECs/IRBs according to local requirements and applicable health 
authorities in accordance with applicable regulatory requirements. 
 
The sponsor shall notify the appropriate regulatory authorities as required and all participating 
Investigators of any adverse event associated with the use of the drug that is both serious and 
unexpected.  The Investigator must also notify the IECs/IRBs. 
 
 
8.2.3.3 Pregnancy 
Although pregnancy as such is not considered an AE or SAE, it is the responsibility of the 
Investigator to report to Protalix, by telephone immediately, any pregnancy occurring in a female 
study patient or female partner of a male study patient either during the study or within 42 days 
following the last dose of study drug. Protalix will provide the Investigator with a Pregnancy 
Tracking Form that is to be completed by the study site on a periodic basis and faxed to Protalix. 
The Investigator will follow the pregnancy until the end of the pregnancy. If the pregnancy 
continues to term (delivery), the health of the infant must also be reported to Protalix 
 
 

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9 
STUDY PROCEDURES AND FLOW CHART 
9.1 
Study Flow Chart 
Activity 
Screening  
visit 
(Day 1) 
Infusions 
visits 1-
131(±3days) 
Visit  2 
M  
(±6days) 
Visits: 
 3M  
9 M  
15 M 
21 M 
 
(±6days) 
 
Visits: 
6M 
18 M 
30 M  
42 M  
54M  
(±6days) 
 
Visits : 12 
M 36M 
48 M  
 
(±6days) 
Visits: 
24 M 
60M 
 
(±6 days) 
 
3 
Months 
after last  
infusion4 
 
(±6 
days) 
 
Review Inclusion/ 
exclusion criteria 
x 
 
 
 
 
 
 
 
Sign ICFs  
x 
 
 
 
 
 
 
 
Concomitant medications3 
x1 
x 
x 
x 
x 
x 
x 
x 
Vital signs3 
x1 
x 
x 
x 
x 
x 
x 
 
Body weight 
x1 
 
 
 
x 
x 
x 
 
Physical examination 
x1 
 
 
x 
x 
x 
x 
 
Adverse events assessments3 
x1 
x 
x 
x 
x 
x 
x 
x 
Blood Chemistry 
x1 
 
 
x 
x 
x 
x 
 
Blood count  
x1 
 
 
x 
x 
x 
x 
 
Urinalysis 
x1 
 
 
x 
x 
x 
x 
 
Spot urine test for proteinuria  
x1 
 
 
x 
x 
x 
x 
 
Plasma Gb3 concentration  
x1 
 
 
x 
x 
x 
x 
 
Plasma Lyso Gb3 concentration 
x1 
 
 
x 
x 
x 
x 
 
Anti PRX-102 Antibodies (IgG)
x1 
 
x 
x 
x 
x 
x 
x 
Electrocardiography (ECG) 
x1 
 
 
 
x 
x 
x 
 
Short form Brief Pain Inventory 
(BPI) 
x1 
 
 
x 
x 
x 
x 
 
Gastrointestinal symptoms 
x1 
 
 
x 
x 
x 
x 
 
Cardiac function assessment  
(echocardiography and stress test) 
 
 
 
 
 
x 
x 
 
Cardiac MRI 
 
 
 
 
 
x 
x 
 
Brain MRI 
 
 
 
 
 
 
x 
 
Mainz Severity Score Index 
(MSSI) 
x1 
 
 
 
x 
x 
x 
 
IV infusion2 
 
x2 
 
 
 
 
 
 
Plasma  PRX-102 level 
(PK) 4 
 
x4(only on 
infusion 1) 
 
 
 
 
 
 
1  values for these evaluations will be transferred from Visit 20 of study PB-102-F02  
2  during all the study, infusions are administered every 2 weeks 
3  should be performed at all visits 
4 Blood sample for last PK timepoint of last infusion (Visit 20) of protocol PB-102-F02 will be drawn 
pre-infusion  
 
 

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9.2 
Study Visits 
Study visits schedule described below may not correspond in time with the every two weeks   
infusions schedule, particularly if the subject is being infused at an infusion center or at a home 
set up. 
9.2.1 
Infusion visits 
PRX-102 will be administered by IV infusion every 2 weeks (±3 days) for up to 60 months 
(131 infusion visits)  
At each infusion, the following activities will be performed: 
1. Concomitant medications  
2. Adverse events 
3. The subjects will be observed clinically for a  minimum of 1 hour after dosing 
4. Vital signs will be evaluated before starting the infusion every 30 minutes during the 
infusion  and at the end of clinical observation  
5. The injection site will be evaluated 
9.2.1.1 
Additional Actions to be performed in Specific infusion visits 
Infusion visit 1 (± 3 days) 
1. Blood sample for last PK timepoint of last infusion (Visit 20) of protocol PB-102-F02 
will be drawn pre-infusion  
9.2.2 
Study Visits 
9.2.2.1 
Screening Visit, Day 1 (Visit 20 of Study PB-102-F02) 
1. Confirm eligibility by review of inclusion/exclusion criteria  
2. Obtain written informed consent from the patient  
9.2.2.2 
Visit 2M (± 6 days) 
1. Blood sample for assessing anti PRX-102 Antibodies will be drawn pre-infusion 
9.2.2.3 
 Visit 3M, 9M, 15M and 21M (± 6 days)  
1.  Physical examination  
2.  Laboratory tests 
 Hematology  
 Biochemistry 
 Urinalysis  
 Spot urine sample for proteinuria 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Anti-PRX-102 antibodies (pre-infusion) 
3.  Short Form Brief Pain Inventory (BPI) (Appendix 8) 

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4. Gastrointestinal symptoms assessment questionnaire(Appendix 6) or IBS-SSS when 
available (Appendix 7) 
9.2.2.4 
Visit 6M, 18 M, 30M, 42M, 54M ( ±6 days)  
1. Physical examination, including body weight  
2. Laboratory tests 
 Hematology  
 Biochemistry 
 Urinalysis  
 Spot urine sample for proteinuria 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Anti-PRX-102 antibodies (pre-infusion) 
3. ECG 
4. Short Form Brief Pain Inventory (BPI) (Appendix 8) 
5. Gastrointestinal symptoms assessment questionnaire (Appendix 6) or IBS-SSS when 
available (Appendix 7) 
6. Mainz Severity Score Index (MSSI) (Appendix 6) 
 
 
9.2.2.5 
Visit 12 M, 36 M, 48 M (± 6 days)  
1. Physical examination, including body weight  
2. Laboratory tests 
 Hematology  
 Biochemistry 
 Urinalysis  
 Spot urine sample for proteinuria 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Anti-PRX-102 antibodies (pre-infusion) 
3. ECG   
4. Cardiac MRI 
5. Cardiac Function assessment (echocardiography and stress test) 
6. Short Form Brief Pain Inventory (BPI) (Appendix 8) 
7. Gastrointestinal symptoms assessment questionnaire (Appendix 6) or IBS-SSS when 
available (Appendix 7) 
8. Mainz Severity Score Index (MSSI) (Appendix 6)  
9.2.2.6 
Visit 24 M, 60 M (± 6 days) 
1. Physical examination, including body weight  
2. Laboratory tests 

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 Hematology  
 Biochemistry 
 Urinalysis  
 Spot urine sample for proteinuria 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Anti PRX-102 antibodies (IgG) 
3. ECG 
4. Gastrointestinal symptoms assessment questionnaire (Appendix 6)  or IBS-SSS when 
available (Appendix 7) 
5. Short Form Brief Pain Inventory (BPI) (Appendix 8) 
6. Cardiac MRI 
7. Mainz Severity Score Index (MSSI)  (Appendix 6) 
8. Cardiac Function assessment (echocardiography and stress test) 
9. Brain MRI 
 
9.2.2.7 
Three months after last infusion (±6 days) 
Anti PRX-102 Antibodies  
9.2.2.8 
Premature Withdrawal Visit 
All attempts should be made to perform all the tests for last Visit for patients withdrawing before 
this Visit (including Anti-PRX-102 antibodies three months after last infusion). 

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10 STATISTICAL METHODS PLANNED AND SAMPLE SIZE 
10.1 
Determination of Sample Size 
The sample size was determined pragmatically since the number of patients that can be recruited 
in a reasonable period of time for this rare disease is limited. In addition, sample size in this 
extension study depends upon the number of patients who complete Study PB-102-F02 and 
enroll into this study 
10.2 
Subject Populations 
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. Primary and secondary analyses will be performed on these participants as 
well.  
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. 
10.3 
Analysis 
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 by dose group.   
Medical History, Vital Signs, and Physical Examination.  For medical history, frequency 
count by treatment will be provided for each body system by dose group.   
For physical examination, frequency count of normal or abnormal by treatment will be tabulated 
for each body system by dose group.  
Medications.  Summary and/or data listings of the prior, concomitant medication, and class of 
medication will be provided by dose group. 
Efficacy Variables.  For each efficacy variable, the percent change from baseline to each visit 
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).   

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 Efficacy evaluation will include: 
 Gb3 in plasma median percentage change and interquartile range from baseline to Month 
12 , 24, 36, 48 and 60 months  (total treatment of 2, 3, 4, 5 and 6 years respectively)  
 Lyso-Gb3 in plasma median percentage change and interquartile range from baseline to  
Month 12 , 24, 36, 48 and 60 months  (total treatment of 2, 3, 4, 5 and 6 years 
respectively)  
 Improvement in gastrointestinal symptoms from baseline to Month 12 , 24, 36, 48 and 60 
months  (total treatment of 2, 3, 4, 5 and 6 years respectively)  
 Proteinuria median percentage change and interquartile range from baseline to Month 12, 
24, 36, 48 and 60 months  (total treatment of 2, 3, 4, 5 and 6 years respectively)  
 eGFR median percentage change and interquartile range from baseline to Month 12  and , 
24, 36, 48 and 60 months  (total treatment of 2, 3, 4, 5 and 6 years respectively)  
 Descriptor scores for the Short Form Brief Pain Inventory (BPI) will be summarized for 
baseline, Month 12 , 24, 36, 48 and 60 months  (total treatment of 2, 3, 4, 5 and 6 years 
respectively)  
 MSSI scores at baseline, Month 12 , 24, 36, 48 and 60 months  (total treatment of 2, 3, 4, 
5 and 6 years respectively)  
 Left ventricular mass and myocardial fibrosis severity will be summarized for Baseline of 
Study PB-102-F01, Months 3 and 9 of PB-102-F02 (total treatment of 6 and 12 months 
respectively) and Months 12 , 24, 36, 48 and 60 months  (total treatment of 2, 3, 4, 5 and 
6 years respectively)  
 Cardiac function, evaluated by echocardiography and stress test, will be summarized for 
Baseline of Study PB-102-F01, Months 3 and 9 of PB-102-F02 (total treatment of 6 and 
12 months respectively) and Months 12 , 24, 36, 48 and 60 months  (total treatment of 2, 
3, 4, 5 and 6 years respectively)  
 
10.4 
Safety Analysis 
Safety will be assessed by evaluation of adverse events, injection site reactions, clinical 
laboratory results brain MRI and anti-PRX-102 antibodies. 
10.4.1 
Adverse Events 
Adverse events will be coded to system organ class and preferred term using MedDRA version 
14.1.  All adverse events occurring after the initiation of the study treatment (treatment emergent 
adverse events) will be reported, including events present at baseline that worsened during the 
study. 
Adverse events will be summarized by treatment group to provide visual comparison among the 
treatment groups with respect to incidence of adverse events (the number of patients reporting at 
least one episode of a specific adverse event), incidence of adverse events by severity within 

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body system, incidence of adverse events by attribution within body system, and incidence of 
adverse events causing withdrawal and incidence of serious adverse events.  Regarding severity 
and attribution summaries, the most extreme outcome (highest severity and closest to study drug 
related) will be used for those patients who experience the same adverse event on more than one 
occasion.  
Hypersensitivity reactions will be analyzed as adverse events of special interest using descriptive 
statistics.  
Written narratives will be provided for all serious, unexpected or other significant adverse events 
that are judged to be of special interest because of their clinical importance. 
10.4.2 
Clinical Laboratory 
Clinical Laboratory examination will be performed prior to treatment 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. 
10.5 
Interim Analysis 
An interim analysis may be performed after all subjects have completed months 12, 24, 36 
and/or 48 months.  In these analyses, descriptive statistics methods will be used to summarize 
available efficacy and safety parameters. 
 
 

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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Source Data and Records 
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 patient 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.  
11.2 
Reporting of Results 
The Case Report Form (CRF) is an integral part of the study and subsequent reports.  The CRF 
must be used to capture all study data recorded in the patient’s medical record.  The CRF must 
be kept current to reflect patient status during the course of the study.  Only a patient screening 
and treatment number and patient initials will be used to identify the patient.  In countries in 
which subject initials is confidential information, pseudo initials will be used. 
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 
CRF. 
Protalix Ltd. or their designee will monitor completed Case Report Forms (CRFs).  A case report 
form will be provided for each screened patient. 
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 CRF completion and correction will be explained to the investigator.  
The management module of Target e*CRF includes edit check and query systems that 

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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 CRF, 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 patient 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 case report form 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. 
11.3 
Confidentiality of Subject Data 
The investigator will ensure that the confidentiality of the subjects' data will be preserved. In the 
CRF or any other documents submitted to the sponsor, the subjects will not be identified by their 
names, but by an identification system, which consists of their initials and number in the study. 
In countries in which subject initials is confidential information, pseudo initials will be used. The 
investigator will maintain documents not meant for submission to the sponsor, e.g., the 
confidential subject identification code and the signed informed consent forms, in strict 
confidence. 

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12 REPORTING AND PUBLICATION 
12.1 
Confidentiality of Study Data 
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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13 Appendices 
13.1 
Appendix 1.  Vial Label 
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: PRX-102 
20 mg/vial for intravenous injection only as directed 
10mL in each vial 
Batch number: ___________ Expiry:  MM-YYYY 
Protocol #: PB-102-F03 
Caution: New Drug-Limited by Federal (or United States) 
law to investigational use. 
Subject/patient number: ____________  
Visit number: ____________ 
Sponsor: Protalix Ltd, 2 Snunit St., Carmiel, Israel, 
Tel: +972-4-9889488 
 
Protocol #: PB-102-F03 
Study drug name: 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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13.2 
Appendix 2.  Infusion Rate Algorithm 
The infusion rate (IR) may be adjusted according to individual subject symptoms and signs.  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 symptoms and signs 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 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 
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 (example, 
antihistamine for urticaria). 
The specific algorithm for infusion rates to be followed:  

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* For patients with a good tolerability the time of infusion will be decreased by 30 minutes every 
third infusion, up to a minimum infusion time of 1.5 hours. 
Infusion rate can be adjusted according to patient tolerability as described above; continuation of 
the rate of infusion should be agreed between the PI and the Medical Director 
 
 

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13.3 
Appendix 3.  PRX-102 Evaluation and Treatment Algorithm 
During and after infusion of PRX-102, 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. 
In the case of progressive or severe hypersensitivity, treat appropriately and withdraw the patient 
from the study. 

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Treat as follows: 
Urticaria or edema of the face, neck, or soft tissues 
 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 give 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 PRX-102 infusions may be considered at the discretion of the 
investigator and Medical Director for patients experiencing early clinical signs of 
hypersensitivity or rash/urticaria that responds promptly to oral antihistamine administration (see 
also Appendix 2 for adjustment of infusion rate).  The premedication will be administered 
according to the following steps as needed to prevent progressive hypersensitivity: 

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1. Antihistamine (H1 blocker: diphenhydramine, hydroxyzine, cetrizine, loratadine, 
desloratidine) 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. 
 
3. H1 blocker plus H2 blocker plus prednisone up to 50 mg administered 12 hours and 2 
hours before the start of the infusion. 
 
All infusions of patients in Treatment Group III (2mg/kg) will be given with premedication: H1 
(diphenhydramine, hydroxyzine, cetrizine, loratadine, desloratidine) blocker plus H2 blocker 
(ranitidine, cimetidine, famotidine) at standard doses 12 ±2 hours and 2 ±0.5 hours before the 
start of the infusion. 

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13.4 
Appendix 4.  Cardiac MRI 
13.4.1 
Patients and Sites 
Up to eighteen (18) patients will be enrolled in this trial in several sites worldwide. 
13.4.2 
Magnetic Resonance Imaging (MRI) Data 
Each patient enrolled in this trial had a cardiac MRI at baseline of Protocol PB-102-F01 for 
screening and as a reference for further MRI evaluations in protocol PB-102-F02 and in this 
protocl (12 and 24 Months of this study, respectively). A set of ECG gated cine and delayed 
contrast enhanced MRI sequences (SSFP resp. Inversion recovery Gradient echo) will be 
acquired. A Gadolinium based contrast agent will be used during image acquisition of the 
delayed contrast enhanced scan. 
The sequences will be defined based on the equipment and ability to provide sufficient image 
quality and contrast for myocardium and fibrosis detection and quantification in Fabry’s disease 
patients.  
13.4.3 
MRI Evaluation Parameters 
The following MRI parameters will be evaluated during this trial: 
 Number and location of left ventricular segments with fibrosis 
 Percentage and mass of cardiac fibrosis (in grams) 
 Left ventricular myocardial mass (in grams) 
 
13.4.4 
Sites and Image Data Management 
All image management activities will be centralized and conducted by an independent imaging 
Contract Research Organization (imaging CRO) with operational capabilities in Europe and the 
United States in compliance with all regulatory requirements. An overview of the main activities 
performed by the imaging CRO is provided in the next sections. 
13.4.4.1 Standardization of Image Acquisition, Initial Site Qualification 
In general, this trial will use the same imaging procedures already established and validated in 
Protocol PB-102-F01 and in protocol PB-102-F02. 
The image acquisition procedure will be standardized by the imaging CRO among 
allparticipating sites. The same image acquisition and management procedure will be used by all 
sites. This procedure will be defined by the imaging CRO and approved by the Sponsor. All 
images will be anonymized by the sites (in order to remove any patient-related nominative 
information) and provided in digital format (DICOM). Only digital images will be centrally 
processed by the imaging CRO. 

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13.4.4.2 Subject Sedation 
Patients may require sedation in order to obtain the high quality images required.  Sites may use 
standard sedation protocols approved by the institution.   
13.4.4.3 Quality Control of Image Data and Site Quality Assurance During the Course of 
the Trial 
The image data will be collected and quality controlled by the imaging CRO for checking the 
technical adequacy, the compliance of data acquisition with the study imaging protocol, the 
anonymization of the images and the diagnostic quality of the images (their appropriateness for 
centralized evaluations). If any quality-related issue is detected by the imaging CRO, specific 
queries will be sent to the sites to implement appropriate corrective (including potential repeat 
scans if needed) and preventive actions. 
13.4.5 
Image Processing and Centralized Analysis 
13.4.5.1 Cardiac MRI Assessment 
Analysis of the cine short-axis and delayed contrast enhanced images of the left ventricle will be 
performed with dedicated MRI quantification software.   
Myocardial contours will be detected semi-automatically and manually edited and quality 
controlled by an expert technician at the imaging CRO.  
The left ventricular contours will be submitted for final approval to an independent and blinded 
reader. 
Based on approved contours, the left ventricular mass and % and mass of the fibrotic area are 
calculated automatically by the software algorithm. 
13.4.5.2 Centralized and Blinded Image Review by Independent Readers 
The MRI data will be centrally evaluated in a fully blinded manner by an independent reader. 
The reading sessions will be organized at the imaging CRO site. The same image evaluation 
procedure will be used for all patients’ MRI scans in this trial. 
Expertise of independent readers, training sessions 
The reader will be a Cardiologist with a significant experience in cardiac MRI. The reader will 
be trained prior to start of centralized image review sessions.  

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Conduct of centralized image review sessions 
The reader will be fully blinded with regard to Treatment Groups, patient’s ID and site number. 
The images will have been pre-analyzed by experienced image analysis technologists from the 
imaging CRO. 
The image review sessions by the cardiologist will include: 
Efficacy Image Review 
MRI efficacy analysis results at 12 and 24 Months of this study (total treatment of 2 and 3 years). 
Reference for these evaluations will be the cardiac MRI prformed at baseline And in study PB-
102-F02. 
13.4.6 
Data and Report Transfers to Sponsor 
 Efficacy image Review sessions will be exported to the Sponsor using a predefined, 
standardized and secure data transfer procedure. 
 The final Study database will be submitted to the Sponsor in digital format. 
 
13.4.7 
Direct Access to Study Data 
 A Direct access to Study data will be made possible by the imaging CRO for audit 
purposes.Such Study data include: 
 Information related to interactions between the imaging CRO and the sites (Queries, 
Data Clarification Forms, test data submitted by the sites, etc.) 
 Native MRI data 
 Data processed and generated by the imaging CRO 
 Data generated by the blinded reader 
 Audit trails 
 
13.4.8 
Unevaluable MRI 
Unevaluable MRI data can result from poor quality image, due to patient motion, improper left 
ventricular coverage, technical problems with the image transmission to the imaging CRO, etc. 
The imaging CRO procedures for ensuring quality images are meant to reduce or eliminate such 
poor quality images (Section 13.4.4.3 above). 
If an adequate patient image cannot be obtained for a given time point in the study, the problem 
with the image will be documented at the imaging CRO. In addition, the imaging CRO will 
document all attempted corrective actions with the investigative site imaging centre. 
 

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13.5 
Appendix 5.  The Mainz Severity Score Index (MSSI) 
The MSSI score has been proven to be representative in patients with ‘classic’ Fabry disease and 
is useful for monitoring clinical improvement in patients receiving enzyme replacement therapy. 
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 12 and 24 month visits in this protocol (total treatment of 2 and 3 
years respectively).  
Evaluation of the presence of Cornea Verticillata will be done by the PI or by referral to an 
Ophthalmologist 
13.5.1 
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 
Oedema 
No 
0 
 
Severe 
2 
 
Yes 
1 
Acroparaesthesia 
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 
 
 
Diarrhoea/constipation 
No 
0 
Depression 
No 
0 
 
Yes 
1 
 
Yes 
1 
Haemorrhoids 
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 
 
 
 

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Class III 
3 
 
 
 
 
Class IV 
4 
 
 
 
Maximum Score 
 
18 
Maximum Score
 
20 
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  
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 
 
 
 
Maximun Score 
 
20 
Maximun 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, 
dyspnoea 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 
ischaemic attack. 
 

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13.6 
Appendix 6.  Questionnaire for Evaluation Gastrointestinal Symptoms 
(Dehout et al., 2004) 
Patients will be asked to rate the severity of abdominal pain on a 5-point numerical scale as:  
0 (no pain), representing the absence of any abdominal pain;  
1 (mild pain), representing discomfort;  
2 (moderate pain), representing pain that results in slowing of normal activity;  
3 (severe pain), representing pain that results in cessation of all activity; and  
4 (very severe pain), representing pain requiring medical intervention. 
Patients will be asked to rate the frequency of the occurrence of both abdominal pain and 
diarrhoea as: 
0 (never), representing the absence of the symptom;  
1 (rarely), representing an occurrence rate of less than once a month;  
2 (monthly), representing an occurrence rate of at least once a month;  
3 (weekly), representing an occurrence rate of at least once a week; and  
4 (daily), representing an occurrence rate of at least once a day. 
 
 
 
 
 
 
 
 
 

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13.8 
Appendix 7. IBS SSS 
 

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13.9 
Appendix 8.  Brief Pain Inventory- BPI (Short Form) 
 (www.mdanderson.org/education-and-research/symptom-assessment-tools/BPI User Guide pdf)  

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The short form of the Brief Pain Inventory (BPI) will be performed  Every 3 months in this  
study.
 

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13.10 Appendix 9.  References 
Aerts, JM, Groener, JE, Kuiper, S, Donker-Koopman, WE, Strijland, A, Ottenhoff, R, van Roomen, C, 
Mirzaian, M, Wijburg, FA, Linthorst, GE, Vedder, AC, Rombach, SM, Cox-Brinkman, J, Somerharju, P, 
Boot, RG, Hollak, CE, Brady, RO, Poorthuis, BJ (2008).  Elevated globotriaosylsphingosine is a hallmark 
of Fabry disease.  Proc Natl Acad Sci U S A Feb 26; 105(8):2812-7. 
Barton, NW, Brady, RO, Dambrosia, JM, Di Bisceglie, AM, Doppelt, SH, Hill, SC, Mankin, HJ, Murray, 
GJ, Parker, RI, Argoff, CE (1991). Replacement therapy for inherited enzyme deficiency--macrophage-
targeted glucocerebrosidase for Gaucher's disease. N. Engl. J. Med., 324, 21:1464-70. 
Benichou, B, Goyal, S, Sung, C, Norfleet, AM, O'Brien, F (2009). A retrospective analysis of the 
potential impact of IgG antibodies to agalsidase beta on efficacy during enzyme replacement therapy for 
Fabry disease. Mol. Genet. Metab., 96, 1:4-12. 
Bishop, D. F. and R. J. Desnick (1988). Affinity purification of alpha-galactosidase A from human 
spleen, placenta, and plasma with elimination of pyrogen contamination. Properties of the purified splenic 
enzyme compared to other forms. J Biol Chem 256(3):1307-16. 
Blom, D, Speijer, D, Linthorst, GE, Donker-Koopman, WG, Strijland, A, Aerts, JM (2003). Recombinant 
enzyme therapy for Fabry disease: absence of editing of human alphagalactosidase A mRNA. Am. J. 
Hum. Genet., 72, 1:23-31. 
BPI- Brief Pain Inventory, Short Form. (www.mdanderson.org/education-and-research/symptom-
assessment-tools/BPI User Guide pdf).  
Dehout, F, Roland, D, Treille de Granseigne, S, Guillaume, B, Van Maldergem, L (2004). Relief of 
gastrointestinal symptoms under enzyme replacement therapy in patient with Fabry disease. J. Inherit. 
Metab. Dis., 27:499-505.  
El Dib, RP, Pastores, GM (2011).  Enzyme replacement therapy for Anderson-Fabry disease.  Cochrane 
Database Syst Rev May 12; (5):CD006663. 
Eng, CM, Banikazemi, M, Gordon, RE, Goldman, M, Phelps, R, Kim, L, Gass, A, Winston, J, Dikman, S, 
Fallon, JT, Brodie, S, Stacy, CB, Mehta, D, Parsons, R, Norton, K, O'Callaghan, M, Desnick, RJ (2001).  
A Phase 1/2 Clinical Trial of Enzyme Replacement in Fabry Disease:  Pharmacokinetic, Substrate 
Clearance, and Safety Studies.  Am. J. Hum. Genet., 68:711-722,  
Eng, CM, Guffon, N, Wilcox, WR, Germain, DP, Lee, P, Waldek, S, Caplan, L, Linthorst, GE, Desnick, 
RJ (2001). Safety and efficacy of recombinant human alpha-galactosidase A-- replacement therapy in 
Fabry's disease. N. Engl. J. Med., 345, 1:9-16. 
Garman, SC, Garboczi, DN (2004). The molecular defect leading to Fabry disease: structure of human 
alpha-galactosidase. J Mol Biol 337(2):319-35. 

Protocol Number PB-102-F02 
 
Protalix Ltd. 
 
 
Jan 5, 2016 
_____________________________________________________________________________________ 
 
51 of 53 
Germain, DP, Waldek, S, Banikazemi, M, Bushinsky, DA, Charrow, J, Desnick, RJ, Lee, P, Loew, T, 
Vedder, AC, Abichandani, R, Wilcox, WR, Guffon, N (2007). Sustained, long-term renal stabilization 
after 54 months of agalsidase beta therapy in patients with Fabry disease. J. Am. Soc. Nephrol., 18, 
5:1547-57. 
Hoffmann, B, Mayatepek, E (2009). Fabry disease-often seen, rarely diagnosed. Dtsch Arztebl Int, 106, 
26:440-7. 
Hollak, CE, Aerts, JM, Goudsmit, R, Phoa, SS, Ek, M, van Weely, S, von dem Borne, AE, van Oers, MH 
(1995). Individualised low-dose alglucerase therapy for type 1 Gaucher's disease. Lancet 345(8963): 
1474-8. 
Hollak, CE, Linthorst, GE (2009). Immune response to enzyme replacement therapy in Fabry disease: 
impact on clinical outcome? Mol. Genet. Metab., 96, 1:1-3. 
Hughes, DA, Barba Romero, MA, Hollak, CE, Giugliani, R, Deegan, PB (2011). Response of women 
with Fabry disease to enzyme replacement therapy: comparison with men, using data from FOS--the 
Fabry Outcome Survey. Mol. Genet. Metab., 103, 3:207-14. 
Lidove, O, West, ML, Pintos-Morell, G, Reisin, R, Nicholls, K, Figuera, LE, Parini, R, Carvalho, LR, 
Kampmann, C, Pastores, GM, Mehta, A (2010).  Effects of enzyme replacement therapy in Fabry disease-
-a comprehensive review of the medical literature.  Genet Med Nov;12 (11):668-79. 
Linthorst, GE, Hollak, CE, Donker-Koopman, WE, Strijland, A, Aerts, JM (2004). Enzyme therapy for 
Fabry disease: neutralizing antibodies toward agalsidase alpha and beta. Kidney Int., 66, 4:1589-95. 
Meikle PJ, Hopwood JJ, Clague AE, Carey WF (1999).  Prevalence of lysosomal storage disorders.  
JAMA Jan 20; 281 (3):249-54.   
National Kidney Foundation (2002).  KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: 
Evaluation, Classification, and Stratification.  Available at http://www.kidney.org/professionals/ 
kdoqi/guidelines_ckd/toc.htm. 
Schaefer, RM, Tylki-Szymanska, A, Hilz, MJ (2009). Enzyme replacement therapy for Fabry disease: a 
systematic review of available evidence. Drugs, 69, 16:2179-205. 
Schiffmann, R, Murray, GJ, Treco, D, Daniel, P, Sellos-Moura, M, Myers, M, Quirk, JM, Zirzow, GC, 
Borowski, M, Loveday, K, Anderson, T, Gillespie, F, Oliver, KL, Jeffries, NO, Doo, E, Liang, T, Kreps, 
C, Gunter, K, Frei, K, Crutchfield K, Selden, R F, Brady, RO (2000). Infusion of a-galactosidase A 
reduces tissue globotriaosylceramide storage in patients with Fabry disease. PNAS, 97, 1:365–70. 
Schiffmann, R, Kopp, JB, Austin III, HA. Sabnis, S, Moore, DF, Weibel, T, Balow, JE, Brady, RO (2001) 
Enzyme Replacement Therapy in Fabry Disease: A Randomized Controlled Trial JAMA, 285, 21:2743-9.  

Protocol Number PB-102-F02 
 
Protalix Ltd. 
 
 
Jan 5, 2016 
_____________________________________________________________________________________ 
 
52 of 53 
Schiffmann, R, Ries, M, Timmons, M, Flaherty, JT, Brady, RO (2006). Long-term therapy with 
agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting. Nephrol. 
Dial. Transplant., 21, 2:345-54. 
Schiffmann, R (2009). Fabry disease. Pharmacol. Ther., 122, 1:65-77. 
Thurberg, BL, Rennke, H, Colvin, RB, Dikman, S, Gordon, RE, Collins, AB, Desnick, RJ, O'Callaghan, 
M (2002). Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types 
after enzyme replacement therapy. Kidney Int., 62, 6:1933-46. 
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). 
van Breemen, MJ, Rombach, SM, Dekker, N, Poorthuis, BJ, Linthorst, GE, Zwinderman, AH, Breunig, F, 
Wanner, C, Aerts, JM, Hollak, CE. (2011). Reduction of elevated plasma globotriaosylsphingosine in 
patients with classic Fabry disease following enzyme replacement therapy. Biochimica et Biophysica 
Acta 1812:70–76. 
Vedder, AC, Breunig, F, Donker-Koopman, WE, Mills, K, Young, E, Winchester, B, Ten Berge, IJ, 
Groener, JE, Aerts, JM, Wanner, C, Hollak, CE (2008). Treatment of Fabry disease with different dosing 
regimens of agalsidase: effects on antibody formation and GL-3. Mol. Genet. Metab., 94, 3:319-25. 
Veronese, FM, Pasut, G (2005). Pegylation, successful approach to drug delivery. Drug Discov. Today, 
10, 21:1451-8. 
Veronese, FM, Mero, A (2008). The impact of Pegylation on biological therapies. Biodrugs, 22, 5:315-
29. 
Weidemann, F, Niemann, M, Breunig, F, Herrmann, S, Beer, M, Stork, S, Voelker, W, Ertl, G, Wanner, 
C, Strotmann, J (2009). Long-term effects of enzyme replacement therapy on fabry cardiomyopathy: 
evidence for a better outcome with early treatment. Circulation, 119, 4:524-9. 
Whybra, C, Kampmann, C, Krummenauer, F, Ries, M, Mengel, E, Miebach, E, Baehner, F, Kim, K, 
Bajbouj, M, Schwarting, A, Gal, A, Beck, M (2004). 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 65:299–307. 
Wilcox, WR, Banikazemi, M, Guffon, N, Waldek, S, Lee, P, Linthorst, GE, Desnick, RJ, Germain, DP 
(2004). Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am. J. Hum. 
Genet., 75, 1:65-74. 
Wilcox, WR,  Oliveira, JP,  Hopkin RJ, Ortiz A, Banikazemi, M, Feldt-Rasmussen, U, Sims, K, Waldek, 
S, Pastores, GM,  Lee, P, Eng, CM,  Marodi, L,  Stanford KE,  Frank Breunig, F,  Wanner, C,  Warnock, 
DG,  Lemay, RM,  Germain, DP  (2008). Females with Fabry disease frequently have major organ 
involvement: lessons from the Fabry Registry. Mol Genet Metab 93(2):112-28. 

Protocol Number PB-102-F02 
 
Protalix Ltd. 
 
 
Jan 5, 2016 
_____________________________________________________________________________________ 
 
53 of 53 
Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple 
method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther 
1997;11: 395-402.