A Randomized, Double Blind, Active Control Study of the Safety and Efficacy of PRX-102 Compared to Agalsidase Beta on Renal Function in Patients With Fabry Disease Previously Treated With Agalsidase Beta
Phase: PHASE3
Conditions: Fabry Disease
Sponsor: Protalix

Protocol Number PB-102-F20 
 
 
 
Protalix Ltd. 
EudraCT- 2016-000378-38 
 
July 14, 2017 
______________________________________________________________________________ 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Title:  A Randomized, Double blind, Active Control Study of the 
Safety and Efficacy of PRX-102 compared to Agalsidase Beta on Renal 
Function in Patients with Fabry Disease Previously Treated With Agalsidase 
Beta 
 
Protocol Number: PB-102-F20 
 
Investigational Product: 
Pegunigalsidase alfa (PRX-102) a recombinant human alpha 
galactosidase-A 
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: 
3 
Version 1, January 26, 2016 
Version 2, April 5, 2016 
Version 3, May 26, 2016 
Version 4, September 29, 2016 
Version 5, July 14, 2017 
 
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. 

Protocol Number PB-102-F20 
 
 
 
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EudraCT- 2016-000378-38 
 
July 14, 2017 
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1 
SYNOPSIS 
TITLE:  A Randomized, Double blind, Active Control Study of the Safety and Efficacy 
of PRX-102 compared to Agalsidase Beta on Renal Function in Patients with Fabry 
Disease Previously Treated With Agalsidase Beta 
INVESTIGATIONAL PRODUCT:  Pegunigalsidase alfa (PRX-102), recombinant 
human alpha galactosidase-A 
 
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:  3 
 
INVESTIGATIONAL SITES/LOCATIONS:  Multicenter 
 
OBJECTIVES:  To evaluate the safety and efficacy of PRX-102 compared to 
agalsidase beta in Fabry disease patients with impaired renal function 
 
STUDY DESIGN:  This is a randomized, double blind, active control study of PRX-102 
in Fabry disease patients with impaired renal function.  Patients treated for 
approximately 1 year with agalsidase beta and on a stable dose for at least 6 months will 
be screened and then randomized to continue treatment with 1 mg/kg agalsidase beta or 
to treatment with 1 mg/kg of PRX-102.  The identity of the enzyme will be blinded to 
the patient and the investigator.  Patients will receive intravenous infusions every two 
weeks.   
No more than 50% of the patients enrolled will be female 
Patients will be randomized in a 2:1 ratio of PRX-102 to agalsidase beta.  
Randomization will be stratified by urine protein to creatinine ratio (UPCR) of < or ≥ 1 
g/g  (1 mg/mg or 1000 mg/g) by spot urine sample. 
At the time of randomization, premedication, if used for the agalsidase beta infusions 
before study entry will be continued and gradually tapered at the investigator’s discretion 
during the first 3 months of the study.  The first infusions of blinded agalsidase beta or 
PRX-102 will be administered under controlled conditions at the investigation site.  The 
patient can receive their infusions as part of a home setup once the investigator and 
Sponsor Medical Director agree that it is safe to do so. 
An interim analysis will be conducted at 12 months and the final analysis at 24 months 
of treatment. 
 
NUMBER OF SUBJECTS (PLANNED):  78 (PRX-102 n=52 and agalsidase beta 

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n=26) with an assumption of a 15% dropout 
 
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION:   
Key inclusion criteria: 
Eligible subjects must fulfill the following inclusion criteria: 
 
1. Symptomatic adult Fabry disease patients, age 18-60 years 
2. Males: Plasma and/or leucocyte alpha galactosidase activity (by activity 
assay) less than 30% mean normal levels and one or more of the 
characteristic features of Fabry disease 
i. neuropathic pain 
ii. cornea verticillata 
iii. clustered angiokeratoma 
3. Females:  
a. historical genetic test results consistent with Fabry pathogenic mutation 
and one or more of the described characteristic features of Fabry disease: 
i. 
neuropathic pain, 
ii. 
cornea verticillata, 
iii. 
clustered angiokeratoma 
b. or in the case of novel mutations a first degree male family member with 
Fabry disease with the same mutation, and one or more of the 
characteristic features of Fabry disease  
i. 
neuropathic pain, 
ii. 
cornea verticillata, 
iii. 
clustered angiokeratoma 
4. Screening eGFR by CKD-EPI equation 40 to 120 mL/min/1.73 m2  
5. Linear negative slope of eGFR of ≥ 2 mL/min/1.73 m2 based on at least 3 
serum creatinine values over approximately 1 year (range of 9 to 18 months, 
including the value obtained at the screening visit) 
6. Treatment with a dose of 1 mg/kg agalsidase beta per infusion every 2 weeks 
for at least one year and at least 80% of 13 (10.4) mg/kg total dose over the 
last 6 months 
7. Female patients and male patients whose co-partners are of child-bearing 
potential agree to use a medically accepted method of contraception, not 
including the rhythm method. 
Key exclusion criteria: 
The presence of any of the following excludes a subject from study enrollment: 
1. History of anaphylaxis or Type 1 hypersensitivity reaction to agalsidase beta 
2. Known non-pathogenic Fabry mutations  
3. History of renal dialysis or transplantation 
4. History of acute kidney injury in the 12 months prior to screening, including 

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specific kidney diseases (e.g., acute interstitial nephritis, acute glomerular 
and vasculitic renal diseases); non-specific conditions (e.g, ischemia, toxic 
injury); as well as extrarenal pathology (e.g., prerenal azotemia, and acute 
postrenal obstructive nephropathy) 
5. Patient with a screening eGFR value between  91-120 mL/min/1.73 m2, 
having an historical eGFR value  higher than 120 mL/min/1.73 m2 (during  9 
to 18 months before screening) 
6. Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor 
blocker (ARB) therapy initiated or dose changed in the  4 weeks prior to 
screening 
7. Urine protein to creatinine ratio (UPCR) > 0.5 g/g (0.5 mg/mg or 500 mg/g) 
and not treated with an ACE inhibitor or ARB 
8. Cardiovascular event (myocardial infarction, unstable angina) in the 6 month 
period before randomization 
9. Congestive heart failure NYHA Class IV 
10. Cerebrovascular event (stroke, transient ischemic attack) in the 6 month 
period before randomization 
11. Known history of hypersensitivity to Gadolinium contrast agent that is not 
managed by the use of premedication 
12. Female subjects who are pregnant, planning to become pregnant during the 
study, or are breastfeeding 
13. Presence of any medical, emotional, behavioral or psychological condition 
that, in the judgment of the Investigator and/or Medical Director, would 
interfere with the patient’s compliance with the requirements of the study 
 
TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION:  Pegunigalsidase 
alfa (PRX-102) 1 mg/kg or agalsidase beta 1 mg/kg, intravenously over 3 hours, every 2 
weeks.  
After the first 3 months of treatment infusion time may be reduced gradually to 1.5 hours 
pending patient tolerability, PI evaluation, and Medical Monitor/Director approval. 
DURATION OF TREATMENT:  24 months (53 infusions), with the option to be 
enrolled in an open-label extension study upon completion of the study.  Agalsidase beta 
patients are eligible for treatment in the extension study with pegunigalsidase alfa (PRX-
102) 1 mg/kg. 
 
DISCONTINUATION FROM TREATMENT:   
Reasons for permanent discontinuation include the following: 
 The subject experiences two or more Grade 3 toxicities or one or more Grade 4 
toxicity considered by the investigator associated with PRX-102 or agalsidase beta 
treatment (CTCAE v. 4.03, 2010) 
 The subject experiences progressive hypersensitivity or severe hypersensitivity that is 

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not allayed with pre-treatment 
 The subject requests to discontinue treatment 
 The Investigator feels that it is not in the best interest of the subject to continue 
treatment and/or if the investigator believes that the subject can no longer be 
compliant with the requirements of the study 
 
EFFICACY ENDPOINTS: 
The primary efficacy parameter is the comparison of the mean annualized change (slope) 
in estimated glomerular filtration rate (eGFRCKD-EPI) between treatment groups.  
Secondary efficacy endpoints: 
 Left Ventricular Mass Index (g/m2) by MRI  
 Plasma Lyso-Gb3 
 Plasma Gb3 
 Urine Lyso-Gb3 
 Protein/Creatinine ratio spot urine test 
 Frequency of pain medication use 
 Exercise tolerance (Stress Test) 
 Short Form Brief Pain Inventory (BPI) 
 Mainz Severity Score Index (MSSI) 
 Quality of life EQ-5D-5L 
 
Pharmacokinetics (PK):  
For 30 subjects in the study, blood samples will be taken for PK analysis on Day 1 and at 
6, 12 and 24 months of treatment. The following PK parameters will be derived from the 
plasma concentration versus time profiles to determine the pharmacokinetics of the study 
drug: Cmax, Tmax, AUC0-t, t1/2, and AUC0-∞. Blood samples will be drawn at the following 
time points: pre-infusion (baseline); 0.5 and 1 hour after the beginning of the infusion; at 
the end of the infusion, at 0.5±0.05, 1±0.25, 2±0.25, 4±0.25, 8±0.25, 24 ±0.5, 48±3, and 
96±3) hours post-infusion and at 14±3 days post-infusion. 
SAFETY ENDPOINTS:  
Changes from baseline in: 
 Clinical laboratory tests 
 Physical examination 
 Assessment of the injection site 
 ECG 
 Treatment-emergent adverse events 
 Ability to taper off infusion pre-medication throughout the first 3 months of the 
study 
 Requirement for use of pre-medication overall to manage infusion reactions 

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 Treatment-emergent anti-PRX-102 antibodies 
 Treatment-emergent anti-agalsidase beta antibodies 
 
STATISTICAL ANALYSIS: 
Sample Size Rational 
This orphan indication allows for a small number of patients, given the rarity of the 
disease and the difficulties in allocating patients for clinical trials. With a total of at least 
66 patients at 24 months, randomized 2:1 to PRX-102:agalsidase beta, there is 80% 
power to detect a change of 1.1 mL/min/1.73 m2/year using a two-sample t-test 
(alpha=0.049, 2-sided test) to evaluate the primary outcome of an annualized eGFR 
slope after 24 months. This calculation is based on the assumption that the standard 
deviation for the annualized eGFR slope is 1.5 mL/min/1.73 m2/year in each treatment 
group.  For this analysis the null hypothesis is that the difference in annualized eGFR 
slope between the treatment groups is 0 versus an alternative hypothesis that the 
difference in annualized slopes between treatment groups is not 0. A 30% improvement 
in the slope of eGFR would be considered a clinically relevant improvement.  Based on 
previous research, the annualized eGFR slope in patients treated with agalsidase beta is -
3.0 mL/min/1.73 m2/year, and under the null hypothesis that is the slope assumed for 
both groups.  Thus, a 1.1 mL/min/1.73 m2/year reduction in the rate of decline in renal 
function (improvement) is anticipated to be equal to an annualized eGFR slope with 
PRX-102 of -1.9 mL/min/1.73 m2/year. This sample size calculation was made using a 
group sequential testing procedure that used the O’Brien Fleming spending function to 
determine test boundaries.  There is one interim analysis (see below) scheduled at the 
halfway (1 year) time point and will have a nominal superiority alpha level of 0.003 
whereas the final analysis at 2 years will have a nominal alpha of 0.049.  Since it is 
anticipated that some patients may not be available for any follow-up (i.e., not have 24 
months of follow up), 78 patients will be enrolled, with 52 randomized to PRX-102 and 
26 randomized to agalsidase beta.  With a potential 15% total dropout rate this would 
result in 44 PRX-102 and 22 agalsidase beta patients at 24 months.  These power/sample 
size calculations were performed using PASS-13 Group Sequential Tests for Two Means 
procedure (Hintze, J. (2014). PASS 13. NCSS, LLC. Kaysville, Utah, USA. 
www.ncss.com).  
 
In addition to the primary efficacy comparison described above, a series of secondary 
efficacy analyses will be performed to compare groups on the secondary outcomes of 
interest. These analyses will be described in the statistical analysis plan (SAP).  
 
Interim Analysis 
An interim analysis for non-inferiority will be performed for purposes of submitting a 
marketing application to the European Medicines Agency.  Consistent with the 
power/sample size calculation provided for the Primary 24-month Superiority 

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calculation described above, the following 12-month interim analysis to test for Non-
inferiority will be performed.  Specifically, with a total of at least 66 patients included, 
there is 80% power to detect whether the difference in mean annualized change in eGFR 
in PRX-102 is non-inferior to the rate in agalsidase beta using a 1-sided (0.025) two 
sample t-test. For this test the non-inferior margin is 3.0 mL/min/1.73 m2/year and the 
true difference between groups is assumed to be 1.1 mL/min/1.73 m2/year with standard 
deviations of the slopes being 1.5 in both groups.  With the proposed sample size, non-
inferiority margin and expected differences in slope, the standard deviation could be as 
large as 3.4 and still maintain adequate power (greater than 80%) for non-inferiority. 
  

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July 14, 2017 
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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 
                                                          July 14, 2017 
___________________________________________ 
 
_______________________ 
Signature 
 
 
 
 
 
 
 
Date 
 
 
 
PRINCIPAL INVESTIGATOR 
 
___________________________________________ 
 
_______________________ 
Signature 
 
 
 
 
 
 
 
Date 
Print Name:  ________________________________ 
 

Protocol Number PB-102-F20 
 
 
 
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EudraCT- 2016-000378-38 
 
July 14, 2017 
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TABLE OF CONTENTS 
1 
SYNOPSIS .................................................................................................................................. 2 
2 
LIST OF ABBREVIATIONS .................................................................................................... 12 
3 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY REQUIREMENTS ........... 13 
 
Institutional Review Board (IRB) ................................................................................... 13 
3.1
 
Ethical Conduct of the Study ........................................................................................... 13 
3.2
 
Subject Information and Consent .................................................................................... 13 
3.3
4 
INTRODUCTION ..................................................................................................................... 14 
5 
STUDY OBJECTIVES.............................................................................................................. 18 
6 
INVESTIGATIONAL PLAN .................................................................................................... 19 
 
Overall Study Design and Plan – Description ................................................................. 19 
6.1
 
Discussion of Study Design ............................................................................................. 19 
6.2
6.2.1 
Inclusion Criteria ................................................................................................. 20 
6.2.2 
Exclusion Criteria................................................................................................ 20 
6.2.3 
Re-screening of Subjects ..................................................................................... 21 
6.2.4 
Removal of Subjects from Therapy or Assessment ............................................ 21 
7 
STUDY PRODUCT .................................................................................................................. 23 
 
Study Medication Supply ................................................................................................ 23 
7.1
 
Description and Formulation of Study Product ............................................................... 23 
7.2
 
Description and Formulation of Comparator Product ..................................................... 23 
7.3
 
Study drug dosage and preparation ................................................................................. 23 
7.4
 
Study Drug Administration ............................................................................................. 24 
7.5
 
Packaging and Labeling .................................................................................................. 24 
7.6
 
Conditions for Storage and Use ....................................................................................... 24 
7.7
 
Dispensing, Compliance and Accountability .................................................................. 24 
7.8
 
Prior and Concomitant Therapy ...................................................................................... 24 
7.9
 Method of Assigning Subjects to Treatment Groups ...................................................... 25 
7.10
 Unblinding Procedure ...................................................................................................... 25 
7.11
8 
EFFICACY AND SAFETY ASSESSMENTS .......................................................................... 26 
 
Efficacy Variable(s)......................................................................................................... 26 
8.1
 
Pharmacokinetic Variables .............................................................................................. 26 
8.2
 
Safety Variables............................................................................................................... 26 
8.3
8.3.1 
Clinical Laboratory ............................................................................................. 27 
8.3.2 
Adverse Events.................................................................................................... 27 
9 
STUDY PROCEDURES AND FLOW CHART ....................................................................... 30 
 
Study Flow Chart ............................................................................................................. 30 
9.1
 
Study Visits ..................................................................................................................... 33 
9.2
9.2.1 
Screening (Visit S, Day -30 ± 10 Days) .............................................................. 33 
9.2.2 
Visit 1 (Baseline, Day 1 ± 7 Days)...................................................................... 33 
9.2.3 
Visits 2 through 52(±3 days, if not listed below) ................................................ 34 
9.2.4 
All Odd Numbered Visits (3 through 53) ............................................................ 35 
9.2.5 
Visits 2, 15, 28, and 2 weeks after Visit 53 ( 3 Days) ....................................... 35 
9.2.6 
Visits 2, 3, 5, 9, 11 ( 3 Days) ............................................................................ 35 
9.2.7 
Visit 4 (±3 days) .................................................................................................. 35 
9.2.8 
Visits 7, 20 ( 3 Days) ........................................................................................ 35 

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9.2.9 
Visit 14 ( 3 Days) .............................................................................................. 36 
9.2.10 Visit 27 (Week 52  3 Days, Month 12) ............................................................. 36 
9.2.11 Visits 33 and 47 (± 3 Days) ................................................................................. 36 
9.2.12 Visit 40 (± 3 Days) .............................................................................................. 37 
9.2.13 Visit 53 (Week 104 ± 3 Days, Month 24) ........................................................... 37 
9.2.14 Premature Withdrawal Visit ................................................................................ 38 
10 STATISTICAL METHODS PLANNED AND SAMPLE SIZE .............................................. 39 
 Determination of Sample Size ......................................................................................... 39 
10.1
 Subject Populations ......................................................................................................... 39 
10.2
10.2.1 Intent-to-Treat (ITT) Population ......................................................................... 39 
10.2.2 Per Protocol (PP) Population .............................................................................. 39 
10.2.3 Safety Population ................................................................................................ 39 
 Analysis ........................................................................................................................... 40 
10.3
10.3.1 Primary Efficacy Analysis .................................................................................. 40 
10.3.2 Secondary Efficacy Analyses .............................................................................. 41 
10.3.3 Other Analyses .................................................................................................... 41 
 Safety Analysis ................................................................................................................ 41 
10.4
10.4.1 Adverse Events.................................................................................................... 41 
10.4.2 Clinical Laboratory ............................................................................................. 42 
 Interim Analysis .............................................................................................................. 42 
10.5
 Missing Data .................................................................................................................... 42 
10.6
11 QUALITY CONTROL AND QUALITY ASSURANCE ......................................................... 43 
 Source Data and Records ................................................................................................. 43 
11.1
 Reporting of Results ........................................................................................................ 43 
11.2
 Confidentiality of Subject Data ....................................................................................... 44 
11.3
12 REPORTING AND PUBLICATION ........................................................................................ 45 
 Confidentiality of Study Data .......................................................................................... 45 
12.1
13 References .................................................................................................................................. 46 
14 Appendices ................................................................................................................................ 50 
 Appendix 1.  Vial Label .................................................................................................. 50 
14.1
 Appendix 2.  Infusion Rate Algorithm ............................................................................ 51 
14.2
 Appendix 3.  PRX-102 Evaluation and Treatment Algorithm ........................................ 54 
14.3
 Appendix 4.  Cardiac MRI .............................................................................................. 57 
14.4
14.4.1 Patients and sites ................................................................................................. 57 
14.4.2 Magnetic Resonance Imaging (MRI) data .......................................................... 57 
14.4.3 MRI evaluation parameters ................................................................................. 58 
14.4.4 Sites and image data management ...................................................................... 58 
14.4.5 Image processing and centralized analysis .......................................................... 58 
14.4.6 Data and report transfers to Sponsor ................................................................... 59 
14.4.7 Direct access to Study data ................................................................................. 59 
14.4.8 Unevaluable MRI: ............................................................................................... 60 
 Appendix 5.  The Mainz Severity Score Index (MSSI)................................................... 61 
14.5
 Appendix 6.  National Kidney Foundation Guidelines for Chronic Kidney Disease ...... 64 
14.6
14.6.1 Estimation of GFR: ............................................................................................. 64 
14.6.2 CKD-EPI Equation: ............................................................................................ 64 
 Appendix 7.  Brief Pain Inventory- BPI (Short Form) .................................................... 65 
14.7
 Appendix 8. Premedication Discontinuation Guide ........................................................ 68 
14.8

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 Appendix 9. EQ-5D-5L ................................................................................................... 69 
14.9

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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 
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 
Pharmacokinetic(s) 
PP 
Per Protocol 
PT 
Prothrombin time 
PTT 
Partial Thromboplastin time 
SAE 
Serious adverse event 
TIA 
Transient ischaemic attack 
t1/2 
Time at which the concentration is half of the maximum value (Cmax) 
Tmax 
Time at which the concentration is the maximum value (Cmax) 

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3 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY 
REQUIREMENTS 
 
Institutional Review Board (IRB) 
3.1
An Institutional Review Board (IRB) or Ethics Committee (EC) will review the study protocol 
and any amendments.  The IRB or EC will also review the informed consent forms, their updates 
(if any), and any written materials given to the subjects. A list of all IRBs and ECs and contact 
information will be included in the study report. 
 
Ethical Conduct of the Study 
3.2
This study will be conducted in accordance with the ethical principles that have their origins in 
the Declaration of Helsinki, in compliance with the approved protocol, GCP and applicable 
regulatory requirements. 
 
Subject Information and Consent 
3.3
The investigator will obtain a freely given written consent from each subject after an appropriate 
explanation of the aims, methods, anticipated benefits, potential hazards, and any other aspects 
of the study that are relevant to the subject's decision to participate. The consent forms must be 
signed and dated by the subject before he/she is exposed to any protocol-specific procedure. 
The investigator will explain that the subjects are completely free to refuse to enter the study or 
to withdraw from it at any time, without any consequences for their further care and without the 
need to justify. 
The subject will receive a copy of the subject information and the signed informed consent 
forms.  
The subject will be informed if information becomes available that may be relevant to his/her 
willingness to continue participation in the study. 
Each subject will be informed that a monitor or a health authority inspector, in accordance with 
applicable regulatory requirements, may review the portions of their source records and source 
data related to the study. Data protection and confidentiality will be handled in compliance with 
local laws. 

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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 FOS—the Fabry Outcome 
Survey, showed no significant differences between men and women for most clinical features 

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evaluated. Overall, both sexes responded to enzyme replacement treatment in a similar way 
(Hughes et al. 2011). 
Most men and some women with Fabry disease exhibit deterioration of renal function 
(Schiffmann et al., 2009; Wanner et al., 2010; Ortiz et al., 2008), and many eventually develop 
end-stage renal disease (ESRD) (Ortiz et al., 2010; Mignani et al., 2010). Although progression 
to ESRD is much less common in women, the median age at which patients reached ESRD (38 
years) was the same in both genders (Ortiz et al., 2010; Mignani et al., 2010). Studies of 
untreated patients with Fabry disease have identified proteinuria as a major risk factor for renal 
disease progression (Schiffmann et al., 2009; Wanner et al., 2010). 
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 & 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). 
In clinical studies, agalsidase beta provided long-term stabilization of renal function in patients 
with mild renal involvement (serum creatinine <2.2 mg/dL) (Germain et al., 2007) and delayed 
time to renal, cardiovascular and cerebrovascular events in patients with more advanced Fabry 
disease (Banikazemi et al., 2007). Agalsidase beta treatment did not stabilize renal function in 
patients with severe renal involvement (i.e., proteinuria > 1 g/24 h or estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.73m2) at the time treatment was started (Germain et al., 
2007: Banikazemi et al., 2007). 
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 

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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 & Banikazemi et al. 2001; Eng & 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 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 
homo dimer with active enzyme over longer period, extended circulation residence time and 
enhanced bioavailability of the enzyme relative to the commercial drug. Therefore, PRX-102 
provides continuous presence of enzyme over the 2 week dosing interval.  
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 thus, reinforce the homodimeric structure, which is crucial for 
the enzymatic activity of this enzyme. 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. 
PRX-102 has been studied in Fabry disease patients in a Phase 1/2 study PB-102-F01 for 12 
weeks and continued in extension studies for long-term treatment.  The extension studies are 
ongoing.  The results of the study are summarized in the Investigator’s Brochure.  At the time of 
database freeze on 31Jul2015, six (6) patients in the 0.2 mg/kg treatment group completed 12 
months of treatment, six (6) in the 1.0 mg/kg treatment group completed 6 months of treatment 
and four (4) in the 2.0 mg/kg completed 3 months of treatment. 
The interim efficacy analysis results demonstrated that all patients exhibited stable cardiac and 
renal function with favorable trends after receiving six months of PRX-102.  Gb3 inclusions in 
kidney peritubular capillaries were substantially reduced after 6 months of treatment with both 

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0.2 and 1.0 mg/kg doses.  A mean reduction was observed in the total score of the Mainz 
Severity Score Index (MSSI) for the severity of Fabry disease in general, neurological, 
cardiovascular and renal systems; a stable or favorable trend was observed in the severity and 
frequency of abdominal pain, and frequency of diarrhea in Gastrointestinal Symptoms 
Assessment (GSA); and the reduction in pain severity score and pain interference score with the 
Brief Pain Inventory (BPI) scale indicates an improvement in general activity, walking, working, 
sleeping, enjoyment of life and other people. 
PRX-102 has enhanced pharmacokinetic properties including a half-life (T½) of approximately 
70 hours, and AUC of approximately 400,000 ng/mL*hour for the 1.0 mg/kg dose after one day 
of treatment (Day 1), which are believed to be the result of the covalent cross-linking to make 
PRX-102 enzyme a more stable homo-dimer.  
The most commonly experienced AEs were fatigue in 6 patients, and nausea and vomiting each 
in 5 patients.  The most commonly experienced AEs that were considered possibly related to the 
treatment were nausea in 3 patients, chest discomfort and fatigue each in 2 patients. 
Two patients each experienced an SAE.  One patient experienced a Grade 3 hypersensitivity 
related serious adverse event of bronchospasm.  The second patient experienced renal hematoma 
following kidney biopsy and was not considered related to the treatment. 
Currently, the safety results of the one completed and two ongoing studies showed that PRX-102 
is well tolerated with a favorable safety profile, the majority of adverse events being mild and 
moderate in severity and a low rate of treatment induced antibody formation. 
In view of the data it is concluded that dosing of PRX-102 at 1.0 mg/kg every 2 weeks offers the 
optimal treatment regimen for attenuating disease progression. 

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5 
STUDY OBJECTIVES 
The objective of this study is to evaluate the safety and efficacy of PRX-102 compared to 
agalsidase beta in adult Fabry disease patients with impaired renal function. 

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6 
INVESTIGATIONAL PLAN 
 
Overall Study Design and Plan – Description 
6.1
The study will be a randomized, double blind, active-control study of the efficacy and safety of 
PRX-102 compared to agalsidase beta in adult Fabry disease patients with impaired renal 
function under treatment already with agalsidase beta for at least a year.  Patient age will be 18 to 
60 years.  The estimated glomerular filtration rate (eGFR) using the CKD-EPI equation will be 
40 to 120 mL/min/1.73 m2 and evidence of renal disease progression of at least 2 mL/min/1.73 
m2/year.  
Patients will receive intravenous infusions of PRX-102 1 mg/kg or agalsidase beta 1 mg/kg every 
two weeks.  Infusion duration will initially be 3 hours, but may be decreased gradually after 
establishment of tolerability by agreement of the investigator and Protalix Medical Director. 
Efficacy will be determined by the slope of eGFR over the course of the study.  Two analyses of 
efficacy will be performed – at 12 and 24 months of treatment.  For regulatory purposes, 
demonstration of non-inferiority of PRX-102 compared to agalsidase beta at 12 months for 
submission of MAA to the European Medicines Agency and superiority at 24 months for FDA 
BLA submission will be considered trial success. 
At the end of the study patients may be offered to continue to an extension open label study; 
patients on the agalsidase beta arm will be offered to move to PRX-102 1 mg/kg every 2 weeks.  
 
Discussion of Study Design  
6.2
Agalsidase beta has shown limited success in preventing the progression of renal function 
deterioration.  Based on the differences in PRX-102 pharmacokinetics compared to agalsidase 
beta, there is the potential that PRX-102 will be demonstrated to be clinically superior to 
agalsidase beta when administered every 2 weeks.  Therefore, a head-to-head comparison of the 
two products in Fabry disease patients who are at risk of renal deterioration is the appropriate 
study design to demonstrate whether it is superior or non-inferior.  Demonstration of non-
inferiority will be a successful study, particularly if there is a better safety profile. 
PRX-102 and agalsidase beta are different products and immunogenicity and hypersensitivity 
may be different between the products.  Pre-medication to prevent adverse reactions during 
infusion is administered in some patients receiving agalsidase beta.  Because the requirements 
for pre-medication may be different between the two products and to maintain blinding, pre-
medication will be tapered off, as tolerated, over the initial 3 months of infusions under careful 
observation.  Pre-medication to prevent infusion reactions can be maintained or re-introduced as 
required. 
Males and females with phenotypically classic Fabry disease will be included in the study to 
maximize the homogeneity of the patient population. 
No more than 50% of the patients enrolled will be female. 
Selection of Study Population 

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6.2.1 
Inclusion Criteria 
The subjects must fulfil the following inclusion criteria: 
1. Symptomatic adult Fabry disease patients, age 18-60 years 
2. Males:  
plasma and/or leucocyte alpha galactosidase activity (by activity assay) less than 30% 
mean normal levels and one or more of the characteristic features of Fabry disease 
i. 
neuropathic pain 
ii. 
cornea verticillata 
iii. 
clustered angiokeratoma 
3. Females:  
a. historical genetic test results consistent with Fabry pathogenic mutation One or 
more of the described characteristic features of Fabry disease: 
i. 
neuropathic pain, 
ii. 
cornea verticillata, 
iii. 
clustered angiokeratoma 
b. or in the case of novel mutations a first degree male family member with Fabry 
disease with the same mutation, and one or more of the characteristic features of 
Fabry disease  
i. neuropathic pain, 
ii. cornea verticillata, 
iii. clustered angiokeratoma 
4. Screening eGFR by CKD-EPI equation 40 to 120 mL/min/1.73 m2  
5. Linear negative slope of eGFR of ≥ 2 mL/min/1.73 m2/year based on at least 3 serum 
creatinine values over approximately one year (range of 9 to 18 months including the 
value obtained at the screening visit)  
6. Treatment with a dose of 1 mg/kg agalsidase beta per infusion every 2 weeks for at 
least one year and at least 80% of 13 (10.4) mg/kg total dose over the last 6 months 
7. Female patients and male patients whose co-partners are of child-bearing potential 
agree to use a medically accepted method of contraception, not including the rhythm 
method. 
6.2.2 
Exclusion Criteria 
The presence of any of the following excludes a subject from study enrollment: 
1. History of anaphylaxis or Type 1 hypersensitivity reaction to agalsidase beta 
2. Known non-pathogenic Fabry mutations (polymorphism) 
3. History of renal dialysis or transplantation 
4. History of acute kidney injury in the 12 months prior to screening, including specific 
kidney diseases (e.g., acute interstitial nephritis, acute glomerular and vasculitic renal 
diseases); non-specific conditions (e.g., ischemia, toxic injury); as well as extrarenal 
pathology (e.g., prerenal azotemia, and acute postrenal obstructive nephropathy) 

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5. Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker 
(ARB) therapy initiated or dose changed in the 4 weeks prior to screening 
6. Patient with a screening eGFR value of 91-120 mL/min/1.73 m2, having an historical 
eGFR value  higher than 120 mL/min/1.73 m2 (during  9 to 18 months before 
screening) 
7. Urine protein to creatinine ratio (UPCR) > 0.5 g/g (0.5 mg/mg or 500 mg/g) and not 
treated with an ACE inhibitor or ARB 
8. Cardiovascular event (myocardial infarction, unstable angina) in the 6 month period 
before randomization 
9. Congestive heart failure NYHA Class IV 
10. Cerebrovascular event (stroke, transient ischemic attack) in the 6 month period before 
randomization 
11. Known history of hypersensitivity to Gadolinium contrast agent that is not managed 
by the use of premedication 
12. Female subjects who are pregnant, planning to become pregnant during the study, or 
are breastfeeding 
13. Presence of any medical, emotional, behavioral or psychological condition that, in the 
judgment of the Investigator and/or Medical Director, would interfere with the 
patient’s compliance with the requirements of the study 
6.2.3 
Re-screening of Subjects 
A subject that fails screening based on Inclusion Criteria #4 and/or #5 (eGFR range and/or slope) 
may be re-tested for serum creatinine with cystatin C within a period of 2 months pending the 
approval of the Protalix Medical Director.  In those occasions, the patient will maintain same 
screening number with no need to perform additional evaluations.  
6.2.4 
Removal of Subjects from Therapy or Assessment 
Reasons for permanent discontinuation include the following: 
 The subject experiences two or more Grade 3 toxicities or one or more Grade 4 toxicity 
considered by the investigator associated with PRX-102 or agalsidase beta treatment (CTCAE 
v. 4.03, 2010) 
 The subject experiences progressive hypersensitivity or severe hypersensitivity that is not 
allayed with pre-treatment 
 The subject requests to discontinue treatment 
 The Investigator feels that it is not in the best interest of the subject to continue treatment 
and/or if the investigator believes that the subject can no longer be compliant with the 
requirements of the study 
For any discontinuation, the Investigator will obtain all the required details and document the 
date and the main reason for the premature termination.  If the reason for discontinuation is an 
adverse event, the specific event or the main laboratory abnormality will be recorded in the 
eCRF.  The Investigator will make thorough efforts to document the outcome.  The Investigator 
will attempt to continue to follow the subject for the full duration of the study or at least for 90 

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days following discontinuation.  If circumstances prevent the subject from completing all visits, 
every attempt will be made to complete all procedures listed in Section 9 for Visit 53.   

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7 
STUDY PRODUCT 
 
Study Medication Supply 
7.1
Protalix will provide PRX-102 and agalsidase beta to the sites as needed  
 
Description and Formulation of Study Product  
7.2
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 10.5 ml of the following contents in liquid form: 
20 mg PRX-102 (2mg/ml) 
0.7% NaCl  
25-30 mM Sodium Citrate (pH 5.7 - 6.3). 
 
 
Description and Formulation of Comparator Product 
7.3
Fabrazyme is supplied as a sterile, nonpyrogenic, white to off-white, lyophilized cake or powder 
for reconstitution with Sterile Water for Injection, USP to yield a concentration of 5 mg/ml; and 
then further diluted with 0.9% Sodium Chloride Injection, USP for intravenous infusion. Single 
use vials are available in 35 mg and 5 mg dosages. 
 
Study drug dosage and preparation 
7.4
Two treatment groups will be evaluated in this study: 
1. PRX-102 1 mg/kg; the individual dose for each patient will be prepared according to the 
patient’s weight. 
2. Agalsidase beta will be administered at 1 mg/kg dose according to the patient’s weight.  
In both treatment groups the drug dosage will be adjusted to patient weight obtained at Visits 14, 
27, and 40 if the weight changes by 25% from the previous adjustment 
Each dose will be prepared by an un-blinded pharmacist or nurse at each site.  
The required amount of either enzyme will be adjusted with normal saline (0.9% NaCl) to a final 
volume of:  
150 mL/infusion, for patients weighting up to 70 Kg 
250 mL/infusion, for patients weighting between 70 Kg-100Kg 
500 ml/infusion for patients weighting above 100 Kg 
The infusion volume will be recalculated, only if dosage adjustment was performed.  
 

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Study Drug Administration 
7.5
Study drug and agalsidase beta will be administered by intravenous infusion over 3 hours (0.83, 
1.39 or 2.78 mL/min for 150, 250 and 500 mL volumes, respectively).  After 3 months of 
infusions, if the patient is tolerating the infusions well, the infusion time may be reduced 
gradually to 1.5 hours based on investigator evaluation and Protalix Medical Director approval. 
At any time the infusion rate may be adjusted according to individual subject’s signs and 
symptoms (see Appendix 2).  
 
Packaging and Labeling  
7.6
The study drug product is packed in vials containing 20 mg PRX-102 (2mg/ml), 0.7% NaCl and 
25-30 mM Sodium Citrate (pH 5.7 - 6.3). 
It is presented as a liquid 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). 
Agalsidase beta is packed in vials containing: Lyophilized powder for reconstitution with Sterile 
Water for Injection, USP to yield 5 mg/mL. Available as 35 mg or 5 mg single-use vials. 
The template labels are in Appendix 1. 
 
Conditions for Storage and Use 
7.7
The products are stored at 2-8°C (36-46°F). 
 
Dispensing, Compliance and Accountability 
7.8
Protalix will provide drug accountability forms to assist the pharmacist in maintaining current 
and accurate inventory records covering receipt, dispensing, and the return of investigational 
drug supplies.  When a shipment is received, the pharmacist will verify the quantities received 
and return the acknowledgment to the Protalix’s CTM (Clinical Trial Material) coordinator. The 
drug will not be used without Protalix’s approval in writing.  The pharmacist investigational drug 
accountability record includes the identification of the person to whom the drug is dispensed, the 
quantity and the date of dispensing and any returned or unused drug, as well as full record of 
CTM 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. 
 
Prior and Concomitant Therapy 
7.9
Medications having the potential to interfere with the evaluation of efficacy are excluded 
throughout the trial. 
The following medications are strictly prohibited during the study: 

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 Replagal® (agalsidase-alpha) 
 Any other investigational or approved drug for treating Fabry disease 
The use of pre-medication to prevent infusion reactions associated with agalsidase beta initiated 
before entry to the study and recorded in the eCRF will be continued, but subjects will be titrated 
down over the course of the first three months of the study.  The rate of down titration/removal 
of the pre-medication will be at the investigator’s discretion and recurrence of infusion reactions.  
Re-institution of pre-medication to manage infusion reactions will be allowed see also Appendix 
8. 
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) 
at a stable dose for 4 weeks prior to entry into the study are allowed, but once a subject is 
randomized in the study, initiation of ACEI or ARB therapy is permitted only after discussion 
and approval of the Protalix Medical Director. 
 
Method of Assigning Subjects to Treatment Groups 
7.10
This is double blind, active control study and all subjects will be randomly assigned to treatment 
with PRX-102 1 mg/kg or agalsidase beta infused every two weeks over 3 hours. 
A fixed block randomization list, stratified at Baseline by urine protein to creatinine ratio 
(UPCR) (< or ≥ 1 g/g, 1mg/mg or 1000 mg/g), will be generated with a 2:1 randomization (PRX-
102:agalsidase beta) and incorporated into the Target e*CRF system.  Once patient eligibility has 
been confirmed by the Protalix Medical Director, the system will generate a subject 
randomization id number.  The investigative staff and patient will be blinded to the treatment 
assignment.  The pharmacist preparing the study drug will be given unblinded access to the 
e*CRF system and will record information regarding the prepared dose for each patient. 
A unique screening number (formatted as xxSF20yyy [x: site number, S: screening, F: constant 
mark for Fabry: protocol number (20), y: sequential subject number at the site]) will be assigned 
to each screened subject.  Once a subject is eligible for treatment, including successful 
completion of screening but prior to visit 1, a subject randomization id number will be generated 
that will include the site and subject number (formatted as xx-F20yyy [x: site number, F: 
constant for Fabry, protocol number (20), y: treatment number]). 
 
Unblinding Procedure 
7.11
Identification of the assigned treatment group will be allowed under two circumstances: (1) 
emergency unblinding at the request of the Investigator for a patient with a serious adverse 
reaction where knowledge of the treatment group will be needed to determine the most 
appropriate management of the patient, and (2) unblinding for determining whether an 
unexpected and associated serious adverse event is a reportable event.  In either circumstance, 
the study Safety Monitor will request the treatment from an unblinded statistician at Target 
Health.  The treatment assignment will be communicated on a need to know basis only. 
 

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8 
EFFICACY AND SAFETY ASSESSMENTS 
 
Efficacy Variable(s) 
8.1
The primary efficacy parameter is the comparison of the mean annualized change (slope) in 
estimated glomerular filtration rate (eGFRCKD-EPI) between treatment groups. 
 
Secondary efficacy variables are as follows:  
 
1. Left Ventricular Mass Index (g/m2) by MRI  
2. Plasma Lyso-Gb3 
3. Plasma Gb3 
4. Urine Lyso-Gb3 
5. Protein/Creatinine ratio spot urine test 
6. Frequency of pain medication use 
7. Exercise tolerance (Stress Test) 
8. Short Form Brief Pain Inventory (BPI) 
9. Mainz Severity Score Index (MSSI) 
10. Quality of life EQ-5D-5L 
 
 
Pharmacokinetic Variables 
8.2
For 30 subjects in the study, blood samples will be taken for PK analysis on Day 1 and at 6 
months, 12 months and 24 months of treatment. The following PK parameters will be derived 
from the plasma concentration versus time profiles to determine the pharmacokinetics of the 
study drug: Cmax, Tmax, AUC0-t, t1/2, and AUC0-∞. Blood samples will be drawn at the 
following time points: pre-infusion (baseline); 0.5 and 1 hour after the beginning of the infusion; 
at the end of the infusion, at 0.5±0.05, 1±0.25, 2±0.25, 4±0.25, 8±0.25, 24±0.5, 48±3, and 96±3 
hours post-infusion and at 14±3 days post-infusion.  
 
 
Safety Variables 
8.3
 Safety will be assessed by the frequency, severity, and duration of treatment-emergent AEs 
(adverse events), including clinically significant laboratory abnormalities, ECG changes from 
baseline, physical examination findings and assessment of the injection site after 
administration of the study drug 
 Anti-Drug (i.e. PRX-102 or agalsidase beta) IgG antibodies will be assessed before dosing at: 
baseline, 2 and 4 weeks after the first infusion, and then every month for the first 6 months 
and every 3 month until the end of study through the last infusion. If a patient continues 
treatment in an extension study, the anti-Drug antibodies will be assessed as part of that 
study. For patients who end treatment with PRX-102 or agalsidase beta, anti-PRX-102 
antibodies will be assessed 1 and 3 months after last infusion 
 Anti-Drug IgE antibodies and tryptase will be assessed in events of hypersensitivity reaction 
following Sponsor request 
 Ability to taper off infusion pre-medication at the start of the study 
 Requirement for use of pre-medication overall to manage infusion reactions 

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8.3.1 
Clinical Laboratory 
 Hematology: total white blood cell count hemoglobin, and platelets.  
 Coagulation profile: prothrombin time  (PT) and partial thromboplastin time (PTT)  
 Biochemistry: sodium, potassium, glucose, blood urea nitrogen, creatinine, cystatin C, 
calcium, phosphate (inorganic), uric acid, total protein, albumin, bilirubin (total), alkaline 
phosphatase, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, 
lactate dehydrogenase, and creatine phosphokinase 
 Vitamin D   
 Urinalysis: dipstick for presence of blood, glucose, ketones, and protein 
8.3.2 
Adverse Events 
8.3.2.1 
Adverse Events (AE) and Serious Adverse Events (SAE) 
An adverse event (AE) is any untoward medical occurrence in a subject 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 (90 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. 
However, if deemed necessary by the Investigator, a procedure can be captured along with the 
reason for conducting the procedure. 

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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 subject’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 subject using concise medical terminology.  In addition, each 
trial subject will be questioned about adverse events.  The question asked will be “Since you 
began taking the study medication, have you had any health problems?” 
8.3.2.2 
Procedures for Assessing, Recording, and Reporting Adverse Events and Serious 
Adverse Events 
Throughout the duration of the study, the Investigator will closely monitor each subject 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 subject, and whether or not thought to 
be drug-related, will be reported and followed until resolution or until they become stable. 
The description of the 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 subject 
died, and if treatment was required. 
Events will be recorded as one of the following severity and causality categories below: 

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Severity 
Definition 
Mild (Grade 1) 
Awareness of signs or symptoms, but no disruption of usual activity 
Moderate (Grade 2) 
Discomfort sufficient to interfere, but not prevent, daily activity 
Severe (Grade 3) 
Unable to carry out usual activity 
Very severe (Grade 4)  Incapacitating, requires hospitalization, results in death 
 
Category 
Definition 
Unrelated 
Clearly and incontrovertibly due only to extraneous causes, and does not 
meet criteria listed under possible or probable. 
Unlikely 
Does not follow a reasonable temporal sequence from administration. May 
have been produced by the subject’s clinical state or by environmental 
factors or other therapies administered. 
Possible 
Follows a reasonable temporal sequence from administration, but may have 
been also produced by the subject’s clinical state, environmental factors or 
other therapies administered. 
Probable 
Clear-cut temporal association with administration with improvement on 
cessation of investigational medicinal product or reduction in dose. 
Reappears upon rechallenge. Follows a known pattern of response to the 
investigational medicinal product. 
Definitely 
There is evidence of exposure to the test product, for example, reliable 
history or acceptable compliance assessment; the temporal sequence of the 
AE onset relative to the drug is reasonable; the AE is most likely to be 
explained by the drug treatment than by another cause; the challenge is 
positive; re-challenge (if feasible) is positive; the AE shows a pattern 
consistent with previous knowledge of the drug treatment. 
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 (972-54-
2228472) or Safety Monitor (1-212-681-2100) to notify the Sponsor of the event. 
8.3.2.3 
Acute Kidney Injury 
Episodes of Acute Kidney Injury (AKI) will be considered adverse events.  AKI will be defined 
by a 1.5 fold or greater increase in serum creatinine from the immediately previous laboratory 
value and assessment by the investigator.  The Protalix Medical Director will work with the 
investigator to ensure that such changes in renal function are thoroughly evaluated.  See Section 
10.6 Missing Data for further description of how episodes of AKI will be handled in data 
analysis for efficacy. 

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9 
STUDY PROCEDURES AND FLOW CHART 
 
Study Flow Chart 
9.1
Activity 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number 
S4 
1 
2 
through 
52 
All odd 
numbered 
visits 
2, 15, 
28 and 
2 
weeks 
after 
Visit 
53 
4 
2, 3, 5, 
9, 11 
7, 20 
14 
27 
33, 47 
40 
53 
Sign IC 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Assign screening number 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & Specific FD 
history  
x 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
x 
x 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Body weight 
x 
x 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Body height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
Current medications 
 
Pain medications  
 
Pre-medication Use 
x  
x  
x  
 
 
 
 
 
 
 
 
 
 
Alpha-galactosidase activity 
in plasma 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha-galactosidase activity 
in leucocytes 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Urine protein/creatinine 
ratio (UPCR) 
x 
x 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Hematology 
x 
x 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
PT and PTT 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry   
x 
x 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Serum creatinine and 
Cystatin C 
x 
x 
 
x 
 
 
 
 
 
 
 
 
 
Vitamin D 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy (beta 
x 
 
 
 
 
 
 
 
 
 
 
 
 

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Activity 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Number 
S4 
1 
2 
through 
52 
All odd 
numbered 
visits 
2, 15, 
28 and 
2 
weeks 
after 
Visit 
53 
4 
2, 3, 5, 
9, 11 
7, 20 
14 
27 
33, 47 
40 
53 
HCG) for females, 
Urinalysis - dipstick 
x 
x 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
HbsAg, HCV & HIV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Short Form Brief Pain 
Inventory (BPI) 
x 
x 
 
 
 
 
 
 
x 
x 
 
x 
x 
Anti-Drug Antibodies 
(IgG)2 
x 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
Electrocardiography (ECG) 
x 
x 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Chest X-ray1 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life 
 
x 
 
 
 
 
 
 
x 
x 
 
x 
x 
Mainz Severity Score Index 
(MSSI) 
 
x 
 
 
 
 
 
 
x 
x 
 
x 
x 
Request for randomization 
approval 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Echocardiography 
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
Cardiac function assessment 
(stress test) 
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
Cardiac MRI 
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
Brain MRI 
 
X 
 
 
 
 
 
 
 
x 
 
 
x 
Adverse events assessments 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
Mutation analysis 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Plasma samples for PK3 
 
x 
 
 
x  
 
 
 
x 
x 
 
 
x 
Urine lyso Gb3 
concentration 
 
x 
 
 
 
x 
 
x 
x 
x 
 
x 
x 
Plasma Gb3 concentration2 
 
x 
 
 
 
x 
 
x 
x 
x 
 
x 
x 
Plasma Lyso Gb3 
concentration2 
 
x 
 
 
 
x 
 
x 
x 
x 
 
x 
x 
Study Drug IV infusion 
 
x 
x 
 
 
 
 
 
 
 
 
 
x 
 

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1will be performed only for patients who have not had the test during last 3 months before screening 
2will be performed pre-infusion 
3only for 30 enrolled subjects. Time points : pre-infusion (baseline); 0.5 and 1 hour after the beginning of the infusion; at the end of the infusion, at 0.5±0.05, 1±0.25, 
2±0.25, 4±0.25, 8±0.25, 24±0.5, 48±3, and 96±3 hours post-infusion and at 14±3 days post-infusion 
4Re-screening may be performed with Medical Director approval for patients failing to fulfill Inclusion criteria #2 and/or #3 within 2 months of initial screening visit 
 

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Study Visits 
9.2
9.2.1 
Screening (Visit S, Day -30 ± 10 Days) 
1. Obtain written informed consent from the subject  
2. Assign screening number 
3. Review inclusion/exclusion criteria 
4. Demographics 
5. General medical history and specific Fabry disease history 
6. Physical examination, including weight and height 
7. Vital signs, including blood pressure, pulse, temperature and respiration rate 
8. Current medications,  
 Review pain medications 
 Review pre-medication use 
 Review general other medications including ACEI and ARBs 
9. Laboratory tests  
 Hematology  
 PT and PTT 
 Biochemistry 
 Serum creatinine and cystatin C (pre-infusion) 
 Vitamin D 
 Serum pregnancy test (beta HCG) for females   
 Urinalysis 
 Spot urine for UPCR 
 Plasma and leucocyte alpha-galactosidase activity (pre agalsidase beta infusion or at 
least 3 days post agalsidase beta infusion) 
 Anti-PRX-102 and anti-agalsidase beta antibodies 
 Serology for HBsAg, HCV and HIV 
10. Short Form Brief Pain Inventory (BPI) (Appendix 7) 
11. ECG 
12. Chest X-ray (if not performed in the last 3 months) 
 
Re-screening 
A subject that fails screening based on Inclusion Criteria 4 and/or 5 (eGFR range and/or slope) 
may be re-screened for serum creatinine and cystatin C within 2 months with the approval of the 
Protalix Medical Director. 
 
9.2.2 
Visit 1 (Baseline, Day 1 ± 7 Days) 
1. Review inclusion/exclusion criteria 
2. Request for subject approval from Medical Director of the study 
3. If Medical Director approves subject treatment, subject will be randomized to blinded 
treatment in the e*CRF system 
4. Physical examination, including weight  
5. Vital signs, including blood pressure, pulse, temperature and respiration rate 
6. Current medications 
 Review pain medications 

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 Review pre-medication use. Subjects previously receiving pre-medication for 
prevention of infusion reactions will continue after randomization for the first infusion. 
Pre-medication will be tapered at the investigator’s discretion during the first three 
months of the study. 
7. Laboratory tests 
 Hematology  
 Biochemistry (pre-infusion) 
 Serum creatinine and cystatin C (pre-infusion) 
 Urinalysis 
 Spot urine for UPCR 
 Urine lyso GB3 (pre-infusion) 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Anti-PRX-102 and anti-agalsidase beta antibodies (pre-infusion) 
 Mutation analysis 
 Plasma samples for PK analysis for 30 patients enrolled in the study: pre-infusion at 
baseline, 0.5 and 1 hour after the beginning of the infusion, at the end of the infusion, 
and at 0.5±0.05, 1±0.25, 2±0.25, 4±0.25, 8±0.25, 24±0.5, 48±3, and 96±3 hours post-
infusion and at 14±3 days post-infusion.   
8. ECG 
9. Echocardiogram 
10. Cardiac function assessment (stress test) 
11. Cardiac MRI (Appendix 4) 
12. Brain MRI 
13. Quality of life: EQ-5D-5L 
14. Short Form Brief Pain Inventory (BPI) (Appendix 7) 
15. Mainz Severity Score Index (MSSI) (Appendix 5) 
16. Adverse events 
17. Study drug administration 
 
The following procedures will be performed after the infusion: 
1. Patients will be observed clinically for a minimum of 2 hour after dosing. 
2. Vital signs will be evaluated every 30 minutes for the first hour and every 60 minutes  if 
the patient tolerates the infusion up to the end of observation time The injection site will 
be evaluated. 
3. A follow up telephone call with the patient will be held the day after the first  infusion. 
4. Remind the subject of the date of their next visit. 
 
9.2.3 
Visits 2 through 52(±3 days, if not listed below) 
The activities listed below are included in all visits.  Other activities are listed below for other 
specific visits.  
1. Current medications 
 Review pain medications 

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 Pre-medication use: Patients that were premedicated before the study will be titrated off 
the medication of the first 3 months of the study at the discretion of the investigator. A 
new requirement for pre-medication will be documented for each infusion. 
2. Vital signs, including blood pressure, pulse, temperature and respiration rate 
3. Adverse events 
4. Study drug administration 
 
The following procedures will be performed after the infusion: 
1. Patients will be observed clinically for a minimum of 2 hour after dosing. 
2. Vital signs will be evaluated every 30 minutes for the first hour and then every 60 
minutes  if the patient tolerates the infusion up to the end of observation time  
3. The injection site will be evaluated. 
4. A follow up telephone call with the patient will be held the day after the first  infusion. 
5. Remind the subject of the date of their next visit. 
 
Post dosing clinical observation length time can be shortened to 60 minutes under Investigator 
request and Protalix Medical Director approval based on the tolerability of the infusion. 
 
9.2.4 
All Odd Numbered Visits (3 through 53) 
Serum creatinine and cystatin C (pre-infusion) 
9.2.5 
Visits 2, 15, 28, and 2 weeks after Visit 53 ( 3 Days) 
Plasma samples for PK analysis for 30 enrolled subjects, last sample at 14±3 days post infusion  
9.2.6 
Visits 2, 3, 5, 9, 11 ( 3 Days) 
Anti-PRX-102 and anti-agalsidase beta antibodies 
9.2.7 
Visit 4 (±3 days) 
1. Laboratory tests 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Urine lyso GB3 (pre-infusion) 
9.2.8 
Visits 7, 20 ( 3 Days) 
1. Physical examination with body weight 
2. Laboratory tests 
 Hematology 
 Biochemistry (pre-infusion) 
 Urinalysis 
 Spot urine for UPCR 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Urine lyso GB3 (pre-infusion)  
3. Anti-PRX-102 and anti-agalsidase beta antibodies (pre-infusion)  
4. ECG 

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9.2.9 
Visit 14 ( 3 Days) 
1. Physical examination with body weight 
2. ECG 
3. Laboratory tests 
 Hematology  
 Biochemistry (pre-infusion) 
 Urinalysis  
 Spot urine for UPCR 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Urine lyso GB3 (pre-infusion) 
 Anti-PRX-102 and anti-agalsidase beta antibodies (pre-infusion) 
 Plasma samples for PK analysis for 30 enrolled subjects: pre-infusion, 0.5 and 1 hour 
after the beginning of the infusion, end of infusion, 0.5 (±0.05), 1 (±0.25), 2 (±0.25), 4 
(±0.25), 8 (±0.25), 24 (±0.5), 48 (±3), and 96 (±3) hours post-infusion.   
4. Quality of life: EQ-5D-5L 
5. Short Form Brief Pain Inventory (BPI) (Appendix 7) 
6. Mainz Severity Score Index (MSSI) (Appendix 5) 
9.2.10 
Visit 27 (Week 52  3 Days, Month 12) 
1. Physical examination with body weight 
2. ECG 
3. Laboratory tests 
 Hematology  
 Biochemistry (pre-infusion) 
 Urinalysis  
 Spot urine for UPCR 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Urine lyso GB3 (pre-infusion) 
 Anti-PRX-102 and anti-agalsidase beta antibodies (pre-infusion) 
 Plasma samples for PK analysis for 30 enrolled subjects: pre-infusion, 0.5 and 1 hour 
after the beginning of the infusion, end of infusion, 0.5 (±0.05), 1 (±0.25), 2 (±0.25), 4 
(±0.25), 8 (±0.25), 24 (±0.5), 48 (±3), and 96 (±3) hours post-infusion. 
4. Quality of life: EQ-5D-5L 
5. Short form Brief Pain Inventory (Appendix 7) 
6. Mainz Severity Score Index (MSSI) (Appendix 5) 
7. Echocardiogram 
8. Cardiac function assessment (stress test) 
9. Cardiac MRI (Appendix 4) 
10. Brain MRI 
9.2.11 
Visits 33 and 47 (± 3 Days) 
1. Physical examination with body weight 
2. Laboratory tests 

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 Hematology  
 Biochemistry (pre-infusion) 
 Urinalysis  
 Spot urine for UPCR 
 Anti-PRX-102 and anti-agalsidase beta antibodies (pre-infusion) 
 ECG 
9.2.12 
Visit 40 (± 3 Days) 
1. Physical examination with body weight 
2. ECG 
3. Laboratory tests 
 Hematology  
 Biochemistry (pre-infusion) 
 Urinalysis  
 Spot urine for UPCR 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Urine lyso GB3 (pre-infusion) 
 Anti-PRX-102 and anti-agalsidase beta antibodies (pre-infusion) 
4. Short Form Brief Pain Inventory (BPI) (Appendix 7) 
5. Mainz Severity Score Index (MSSI) (Appendix 5) 
6. Quality of life: EQ-5D-5L 
9.2.13 
Visit 53 (Week 104 ± 3 Days, Month 24) 
1. Physical examination with body weight 
2. Vital signs, including blood pressure, pulse, temperature and respiration rate 
3. Current medications 
 Review pain medications 
 Review pre-medication use. 
4. Laboratory tests 
 Hematology  
 Biochemistry (pre-infusion) 
 Urinalysis  
 Spot urine for UPCR 
 Plasma Gb3 (pre-infusion) 
 Plasma Lyso-Gb3 (pre-infusion) 
 Urine Lyso-Gb3 (pre-infusion) 
 Anti-PRX-102 and anti-agalsidase beta antibodies (pre-infusion) 
 Plasma samples for PK analysis for 30 enrolled subjects: pre-infusion, 0.5 and 1 hour 
after the beginning of the infusion, end of infusion, 0.5 (±0.05), 1 (±0.25), 2 (±0.25), 4 
(±0.25), 8 (±0.25), 24 (±0.5), 48 (±3), and 96 (±3) hours post-infusion. 
5. ECG 
6. Echocardiogram 
7. Cardiac function assessment (stress test) 
8. Cardiac MRI (Appendix 4) 
9. Brain MRI 

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10. Quality of life: EQ-5D-5L 
11. Short Form Brief Pain Inventory (BPI) (Appendix 7) 
12. Mainz Severity Score Index (MSSI) (Appendix 5) 
13. Adverse events 
14. Study drug administration 
 
Subjects who do not continue into an extension study will have follow up anti-PRX-102 and 
anti-agalsidase beta antibody testing performed at 1 and 3 months after Visit 53. 
9.2.14 
Premature Withdrawal Visit 
All attempts should be made to perform all the tests for Visit 53 at the withdrawal visit for 
patients who may discontinue the study before completion. 

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10 STATISTICAL METHODS PLANNED AND SAMPLE SIZE 
 
Determination of Sample Size 
10.1
This orphan indication allows for a small number of patients, given the rarity of the disease and 
the difficulties in allocating patients for clinical trials. With a total of at least 66 patients at 24 
months, randomized 2:1 to PRX-102:agalsidase beta, there is 80% power to detect a change of 
1.1 mL/min/1.73 m2/year using a two-sample t-test (alpha=0.049, 2-sided test) to evaluate the 
primary outcome of an annualized eGFR slope after 24 months. This calculation is based on the 
assumption that the standard deviation for the annualized eGFR slope is 1.5 ml/min/1.73 m2/year 
in each treatment group.  For this analysis the null hypothesis is that the difference in annualized 
eGFR slope between the treatment groups is 0 versus an alternative hypothesis that the difference 
in annualized slopes between treatment groups is not 0. A 30% improvement in the slope of 
eGFR would be considered a clinically relevant improvement.  Based on previous research, the 
annualized eGFR slope in patients treated with agalsidase beta is -3.0 mL/min/1.73 m2/year, and 
under the null hypothesis that is the slope assumed for both groups.  Thus, a 1.1 mL/min/1.73 
m2/year reduction in the rate of decline in renal function (improvement) is anticipated to be equal 
to an annualized eGFR slope with PRX-102 of -1.9 mL/min/1.73 m2/year. This sample size 
calculation was made using a group sequential testing procedure that used the O’Brien Fleming 
spending function to determine test boundaries.  There is one interim analysis (see below) 
scheduled at the halfway (1 year) time point and will have a nominal superiority alpha level of 
0.003 whereas the final analysis at 2 years will have a nominal alpha of 0.049.  Since it is 
anticipated that some patients may not be available for any follow-up (i.e., not have 24 months of 
follow up), 78 patients will be enrolled, with 52 randomized to PRX-102 and 26 randomized to 
agalsidase beta.  With a potential 15% total dropout rate this would result in 44 PRX-102 and 22 
agalsidase beta patients at 24 months.  These power/sample size calculations were performed 
using PASS-13 Group Sequential Tests for Two Means procedure (Hintze, J. (2014). PASS 13. 
NCSS, LLC. Kaysville, Utah, USA. www.ncss.com).  
 
 
Subject Populations 
10.2
10.2.1 
Intent-to-Treat (ITT) Population 
Intent-to-treat (ITT) population includes patients who received at least one complete dose of 
study medication.  
10.2.2 
Per Protocol (PP) Population 
The Per Protocol population includes 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 includes as all patients who received at least one dose (partial or complete) 
of the study medication. 

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Analysis 
10.3
10.3.1 
Primary Efficacy Analysis 
eGFR is calculated from the serum creatinine according to the CKD-EPI formula:  
eGFR (ml/min/1.73 m2) = 141 × min(Scr/κ,1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 
1.018 [if female] * 1.159 [if black] 
Scr = serum creatinine; κ = 0.7 for females and 0.9 for males; α = -0.329 for females and 
-0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the 
maximum of Scr/κ or 1. 
The primary efficacy analysis compares the estimated annualized slope of the glomerular 
filtration rate (eGFR) between the PRX-102 group and the agalsidase beta (Control) group over 2 
years.  A longitudinal mixed model will be used to estimate the eGFR slope in the two groups by 
examining time and group as fixed effects and patient as a random effect in the model.  The time 
by group interaction will be examined to determine if there is evidence that the eGFR slope rates 
are different between groups.   Since the primary comparison is a test of superiority at 24-
months, this interaction is expected to be statistically significant.  If the interaction test is 
significant this would indicate that the eGFR slopes are statistically significantly different and 
depending on the direction of the difference it would indicate that the PRX-102 group is superior 
(or inferior) to the Control group for this measure.  Using this longitudinal mixed model, the 
assumption of whether the change in eGFR is linear over time will be examined.  Specifically, 
residual plots will be estimated from the model to determine whether there is evidence of 
nonlinearity over time.  If there is evidence of non-linearity, transformations of the primary 
outcome will be considered (i.e., log transformation, etc.).  If a transformation is needed, the 
model will be re-fit with the transformation and assessments of linearity will be made again.  If a 
transformation is used and it provides evidence of linearity, slopes will be estimated on the 
transformed scale with corresponding 95% confidence intervals for the difference in slopes 
between groups. 
If there is evidence that the linearity assumption of the mixed model is not met and no adequate 
transformation is identified, then the two groups will be compared using the mixed model with a 
non-linear term added to the model.  This is not anticipated to occur, but if it were needed then a 
polynomial term (i.e., time-squared) could be added to determine if that provides a better fit to 
the observed data.   Once an adequate model is identified that fits the data, then this model will 
be used to derive 1-year (for interim analysis) or 2-year (for final analysis) estimates of the eGFR 
values in each group at those time points.  The differences in these derived values would be 
compared using 95% confidence intervals as described above, and the non-inferiority margin 
described above (1.1 ml/min/1.73 m2/year) at 12 months and the superiority test at 24 months 
will be examined. 
By using a mixed models approach, if there are some patients with missing data and the missing 
data is considered to be missing at random (MAR) then the modelling will handle the missing 
data appropriately without the need for imputation, 

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In addition to this primary comparison, the slope eGFR values will be used for each group to 
estimate the time to a predicted 30% absolute decline in eGFR value.  This comparison will not 
provide a separate p-value since it will be derived from the longitudinal mixed model described 
above, but it will allow estimates of the time to this event (30% drop in eGFR) to be derived and 
reported. 
10.3.2 
Secondary Efficacy Analyses 
Additional secondary endpoint analyses will be detailed in the final Statistical Analysis Plan 
10.3.3 
Other Analyses 
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.  Medications for pain and premedication will be 
specifically listed. 
 
Safety Analysis 
10.4
Safety will be assessed by evaluation of adverse events, clinical laboratory results and anti-drug 
antibodies. 
10.4.1 
Adverse Events 
Adverse events will be coded to system organ class and preferred term using MedDRA version 
9.1 or higher.  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 subjects reporting at 
least one episode of a specific adverse event), incidence of adverse events by severity within 
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 subjects 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.  

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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. 
 
Interim Analysis  
10.5
An interim analysis for non-inferiority will be performed for purposes of submitting a marketing 
application to the European Medicines Agency.  Consistent with the power/ sample size 
calculation provided for the Primary 24-month Superiority calculation described above, the 
following 12 month interim analysis to test for Non-inferiority will be performed.  Specifically, 
with a total of 66 patients included (44 PRX-102 and 22 agalsidase beta) there is 80% to detect 
whether the difference in mean annualized change in estimated glomerular filtration rate 
(eGFRCKD-EPI) in PRX-102 is non-inferior to the rate in agalsidase beta using a one sided (0.025) 
two sample t-test.  For this test the non-inferiority margin is 3.0 mL/min/1.73/m2/year and the 
true difference in slopes is assumed to be 1.1 with standard deviations of the slopes being 1.5 in 
each group.  With the proposed sample size, non-inferiority margin and expected differences in 
slope, the standard deviation could be as large as 3.4 and still maintain adequate power (greater 
than 80%) for non-inferiority. 
 
Missing Data  
10.6
The primary analysis will use a mixed models approach for comparing groups.  This approach 
handles missing data appropriately if the missing data is considered to be missing at random 
(MAR).  This would be the expectation.  Therefore, all patients should be able to provide at least 
some data for the primary efficacy comparisons.  
For secondary efficacy analyses, since measures are being measured at multiple time points, 
mixed models will be used and therefore missing data will be handled by the analytic method if 
the missing data is MAR. 
No imputation will be made for missing values of safety endpoints except for some AE 
parameters as described above. 
Episodes of Acute Kidney Injury (AKI) will be considered missing data for the purposes of the 
primary efficacy analysis.  AKI will be defined by a 1.5 fold increase in serum creatinine from 
the immediately previous laboratory value and assessment by the investigator.  However, prior to 
data base lock and unblinding, cases of AKI will be assessed by two independent nephrology 
experts.  Their evaluation will include whether they agree that AKI occurred in a patient and 
whether serum creatinine values should excluded from the eGFR slope calculations for the 
primary endpoint.  Excluded serum creatinine values will be considered missing data. 
 

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11 QUALITY CONTROL AND QUALITY ASSURANCE 
 
Source Data and Records 
11.1
Source data are all the information in original records and certified copies of original records of 
clinical findings, observations, laboratory reports, data sheets provided by the sponsor or other 
activities in the study, which are necessary for the reconstruction and evaluation of the study. 
The investigator will permit study-related monitoring, audit(s), IRB review(s) and regulatory 
inspection(s), with direct access to all the required source records. 
All study records will be retained for a period of time as defined by the regulatory authority for 
the country in which the investigation is conducted.  Generally, this means at least 2 years 
following the date on which the drug is approved by the regulatory authority for marketing for 
the purposes that were the subject of the investigation.  In other situations (e.g., where the 
investigation is not in support of or as part of an application for a research or marketing permit), 
a period of 2 years following the date on which the entire clinical program is completed, 
terminated or discontinued or the investigational application under which the investigation is 
being conducted is terminated or withdrawn by the regulatory authorities. 
In the event the Investigator retires, relocates or for any other reason withdraws from the 
responsibility for maintaining records for the period of time required, custody of the records may 
be transferred to any other person who will accept responsibility for the records.  Notice of such 
a transfer must be given in writing to the Sponsor.  The Investigator must contact the Sponsor 
prior to disposal of any records related to this study.  
 
Reporting of Results 
11.2
The Case Report Form (CRF) is an integral part of the study and subsequent reports.  The CRF 
must be used to capture all study data recorded in the subject’s medical record.  The CRF must 
be kept current to reflect subject status during the course of the study.  Only a subject screening 
and treatment number will be used to identify the subject.   
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 subject. 
All protocol-required information collected during the study must be entered by the Investigator, 
or designated representative, in the Target e*CRF, an Internet-based electronic data collection 
system.  All details of the CRF completion and correction will be explained to the investigator.  
The management module of Target e*CRF includes edit check and query systems that 
seamlessly integrate with the data entry system.  All modifications to the data in the eCRF are 
tracked by an electronic audit trail (date and identity of the person making the change are 
instantaneously recorded).  Target e*CRF is 21CFR Part 11 compliant. 

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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 subject is seen for an 
examination, treatment, or any other study procedure.  Any outstanding entries must be 
completed immediately after the final examination.  By design, an explanation must be provided 
for all missing data, altered data, and/or out of range data. 
The completed 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. 
 
Confidentiality of Subject Data 
11.3
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 number in the study. The 
investigator will maintain documents not meant for submission to the sponsor, e.g., the 
confidential subject identification code and the signed informed consent forms, in strict 
confidence. 

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12 REPORTING AND PUBLICATION 
 
Confidentiality of Study Data 
12.1
Any information relating to the study product or the study, including any data and results from 
the study, will be the exclusive property of the sponsor. The investigator and any other persons 
involved in the study will protect the confidentiality of this proprietary information belonging to 
Protalix Ltd. 

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13 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. 
Banikazemi M, Bultas J, Waldek S et al. Agalsidase-beta therapy for advanced Fabry disease: a 
randomized trial. Ann Intern Med 2007;146: 77–86. 
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- 
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El Dib, RP, Pastores, GM (2010).  Enzyme replacement therapy for Anderson-Fabry disease.  
Cochrane Database Syst Rev May 12;(5):CD006663. 
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. 
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, Michael O’Callaghan 
M,8  Desnick RJ. A Phase 1/2 clinical trial of enzyme replacement in Fabry disease: 
Pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet 2001;68:711-22. 

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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. 
Garman, SC, Garboczi, DN (2004). The molecular defect leading to Fabry disease: structure of 
human alpha-galactosidase. J Mol Biol 337(2): 319-35. 
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. 
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. 
Ann Intern Med. 2009;150:604-612. 
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.  
Mignani R, Feriozzi S, Schaefer RM et al. Dialysis and transplantation in Fabry disease: 
indications for enzyme replacement therapy. Clin J Am Soc Nephrol 2010; 5: 379–385. 

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Ortiz A, Oliveira JP, Waldek S et al. Nephropathy in males and females with Fabry disease: 
cross-sectional description of patients before treatment with enzyme replacement therapy. 
Nephrol Dial Transplant 2008; 23: 1600–1607.  
Ortiz A, Cianciaruso B, Cizmarik M et al. End-stage renal disease in patients with Fabry disease: 
natural history data from the Fabry Registry. Nephrol Dial Transplant 2010; 25: 769–775.  
National Kidney Foundation (2002).  KDOQI Clinical Practice Guidelines for Chronic Kidney 
Disease: 
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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.  
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. 
Schiffmann R, Warnock DG, Banikazemi M et al. Fabry disease: progression of nephropathy, 
and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy. 
Nephrol Dial Transplant 2009; 24: 2102–2111. 
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). 

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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. 
Wanner C, Oliveira JP, Ortiz A et al. Prognostic indicators of renal disease progression in adults 
with Fabry disease: natural history data from the Fabry Registry. Clin J Am Soc Nephrol 2010; 
5:2220–2228. 
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. 
 
 

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14 Appendices 
 
Appendix 1.  Vial Label 
14.1
Sample labels for the study drug are illustrated below in Figures 1 and 2. Labels will be adapted 
in accordance with local regulatory and language requirements.  
 
Figure 1. 
Outer Package Label (example) 
 
Figure 2. 
Individual Vials Label (example) 
Study drug name: pegunigalsidase alfa (PRX-102) 
20 mg/vial for intravenous injection only as directed 
10mL in each vial 
Batch number: ___________ Expiry:  MM-YYYY 
Protocol #: PB-102-F20 
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-F20 
Study drug name: pegunigalsidase alfa (PRX-102)  
20 mg/vial; 10mL in each vial 
Qty: N vials_______ 
For intravenous injections only as directed 
Batch number:   
 
 
   Expiry: MM-YYYY 
 
IND No. 110,161 
Directions for use: 
Store at: 2-8°C (36-46°F) 
Caution: New Drug-Limited by Federal (or United States) law to investigational use. 
 
 
  
  
Sponsor: Protalix Ltd, 2 Snunit St., Carmiel, Israel, Tel: +972-4-9889488 

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Appendix 2.  Infusion Rate Algorithm 
14.2
The infusion rate (IR) may be adjusted according to individual subject symptoms and signs.  The 
infusion rate will be adjusted according to Section 7.5 Study Drug Administration under the 
direction of the Investigator and Protalix Medical director.  Pre-medications will be tapered per 
Section 7.9 Prior and Concomitant Therapy under the direction of the Investigator and Protalix 
Medical Director.  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). 
 
 
 

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

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Changes in infusion rates according to the protocol: 
The tolerability of the infusions in these patients will be determined by signs and symptoms 
during the infusion, and observation in the hospital, and by telephone contact the day after the 
infusion. 
For patients with good tolerability after the first 3 months of treatment and the finalization of the 
attempt of premedication discontinuation (in patients who were previously on premedication) the 
time of infusion can be decreased by 30 minutes every third infusion, up to a minimum infusion 
time of 1.5 hours under the agreement between the Investigator and the Medical Director. 
Infusion rate should 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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Appendix 3.  PRX-102 Evaluation and Treatment Algorithm 
14.3
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 
Treat as follows: 

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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 subjects 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: 
1. Antihistamine (H1 blocker: diphenhydramine, hydroxyzine, cetirizine, loratadine, 
desloratidine) at a standard dose 12 hours and 2 hours before the start of the infusion. 
 

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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. 
 
 
 
 

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Appendix 4.  Cardiac MRI 
14.4
14.4.1 
Patients and sites 
Seventy eight patients will be enrolled in this trial in several sites worldwide. 
For each cardiac MRI to be conducted throughout the study, the test will be performed only after 
the Investigator reviews the patient’s kidney function.  
For patients who may present one of the following conditions the performance of the Cardiac 
MRI will be discussed with Protalix Medical Director: 
 GFR < 30 mL/min/1.73m2 based on the last Serum Creatinine value 
or 
 Suspected Acute Kidney Injury 
Gadolinium warnings from USPI: 
 
  
14.4.2 
Magnetic Resonance Imaging (MRI) data 
Each patient enrolled in this trial will have a cardiac MRI at baseline (Visit 1) as a reference for 
further MRI evaluations in the study. 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.  

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14.4.3 
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) 
 
14.4.4 
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. 
14.4.4.1 Standardization of image acquisition, initial site qualification 
The image acquisition procedure will be standardized by the imaging CRO among all 
participating 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. The 
sites will be trained and qualified by the imaging CRO prior to start of patient enrolment. Each 
site will provide test MRI scan(s) during the initial site qualification phase. The source of the test 
scan(s) will be (in order of preference) a patient volunteer, a healthy volunteer, or the screening 
image from the first patient tested at the site. No contrast agent will be used for the test scans 
except when the first image from the first patient is used. 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. 
14.4.4.2 Subject Sedation 
Subjects may require sedation in order to obtain the high quality images required.  Sites may use 
standard sedation protocols approved by the institution.   
14.4.4.3 Quality control of image data and site Quality Assurance  
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. 
14.4.5 
Image processing and centralized analysis 
14.4.5.1 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.   

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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. 
14.4.5.2 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.  
He/she will be provided with a Read Rules document and will be given a training on the use of 
the software.  Test cases representing non-study Fabry patients (as described in section 
14.3.4.4.1) will be used for the training. Main consensus issues (contour detection in apical and 
basal LV slices, trabeculae and papillary muscles, threshold for delayed enhanced areas, etc.) 
will be discussed with the reader and documented. 
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 analysis results at baseline as a reference for further MRI evaluations in the study will be 
evaluated by the reader. 
14.4.6 
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. 
 
14.4.7 
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: 

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o Information related to interactions between the imaging CRO and the sites 
(Queries, Data Clarification Forms, test data submitted by the sites, etc.) 
o Native MRI data 
o Data processed and generated by the imaging CRO 
o Data generated by the blinded reader  
o Audit trails 
 
14.4.8 
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 14.4.4.3 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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Appendix 5.  The Mainz Severity Score Index (MSSI) 
14.5
The MSSI score has been proven representative in patients with ‘classic’ Fabry disease and is 
useful for monitoring clinical improvement in patients receiving enzyme replacement therapy. 
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 only at baseline (visit 1) and every 6 months throughout the study. 
The Mainz Severity Score Index (MSSI): 
 
General Score 
Neurological Score 
Sign/symptom 
Rating 
MSSI 
score 
Sign/symptom 
Rating 
MSSI 
score 
Characteristic 
facial appearance 
No 
0 
Tinnitus 
No 
0 
 
Yes 
1 
 
Mild 
1 
Angiokeratoma 
None 
0 
 
Severe 
2 
 
Some 
1 
Vertigo 
No 
0 
 
Extensive 
2 
 
Mild 
1 
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 
No 
0 
 
 
 

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General Score 
Neurological Score 
Association 
(NYHA) 
classification* 
 
Class I 
1 
 
 
 
 
Class II 
2 
 
 
 
 
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 proteinuria 
0 
 
Thickening of 
wall/septum 
1 
 
Proteinuria 
4 
 
LVH seen on 
ECG 
6 
 
Tubular 
dysfunction/low 
GFR or 
creatinine 
clearance 
8 
 
Cardiomyopathy 
(<15) 
8 
 
End-stage renal 
failure (serum 
creatinine levels 
>3.5 mg/dl) 
12 
 
Severe 
cardiomyopathy 
(>15) 
12 
 
Dialysis 
18 
Valve 
insufficiency 
No 
0 
 
 
 
 
Yes 
1 
 
 
 
ECG abnormalities No 
0 
 
 
 
 
Yes 
2 
 
 
 
Pacemaker 
No 
0 
 
 
 
 
Yes 
4 
 
 
 
Hypertension 
No 
0 
 
 
 
 
Yes 
1 
 
 
 
Maximum Score 
 
20 
Maximum Score 
 
18 
 
* Limitation on physical activity according to NYHA classification is as follows. Class I: none; 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea or anginal pain, 
but echocardiography reveals heart involvement. Class II: slight; comfortable at rest, but 

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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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Appendix 6.  National Kidney Foundation Guidelines for Chronic Kidney Disease 
14.6
Stages of Chronic kidney disease (National Kidney Foundation 2002): 
 Stage 1- Kidney damage with normal or elevated GFR (≥ 90) 
 Stage 2- Kidney damage with mild reduction in GFR (60-89) 
 Stage 3- Kidney damage with moderate reduction in GFR (30-59) 
 Stage 4- Kidney damage with severe reduction in GFR (15-29) 
 Stage 5- Kidney failure (<15 or dialysis) 
 
14.6.1 
Estimation of GFR: 
Estimates of GFR are the best overall indices of the level of kidney function. The level of GFR 
should be estimated from prediction equations that take into account the serum creatinine 
concentration and some or all of the following variables: age, gender, race, and body size. 
Among adults, the CKD-EPI equation provides a clinically useful estimate of GFR (Levey et al., 
2009).  This equation provides estimate of GFR standardized for body surface area. 
14.6.2 
CKD-EPI Equation:  
The CKD-EPI equation performed better than the MDRD (Modification of Diet in Renal Disease 
Study) equation, especially at higher GFR, with less bias and greater accuracy. When looking at 
NHANES (National Health and Nutrition Examination Survey) data, the median estimated GFR 
was 94.5 mL/min per 1.73 m2 vs. 85.0 mL/min per 1.73 m2, and the prevalence of chronic kidney 
disease was 11.5% versus 13.1%. The CKD-EPI equation, expressed as a single equation, is: 
GFR = 141 * min(Scr/κ,1)α * max(Scr/κ,1)-1.209 * 0.993Age * 1.018 [if female] * 1.159 [if 
black/African American] 
Where Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is –0.329 for 
females and –0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the 
maximum of Scr/κ or 1. 
 
 

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Appendix 7.  Brief Pain Inventory- BPI (Short Form) 
14.7
(www.mdanderson.org/education-and-research/symptom-assessment-tools/BPI User Guide pdf)  
 

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Appendix 8. Premedication Discontinuation Guide 
14.8
Patients on agalsidase beta can be included in the study when under premedication to diminish 
the side effects to the drug.  After randomization, patients are assigned in a blinded manner to 
PRX-102 or to continue on agalsidase beta.  To keep the blind in those patients who were under 
premedication first infusion will be given under the regular premedication the patients were 
when on agalsidase beta. 
During the next 3 months (6 infusions), the Investigator will manage a stepwise discontinuation 
of the premedication based on the appropriate tolerability of the patient to the changes.  
Premedication will resume in the case that the patient will present signs and symptoms of non-
tolerability of the infusion. 
All cases of non-tolerabilty and need of premedication will be discussed between the Investigator 
and the Medical Director before reaching infusion 8 and evaluating the reduction of infusion 
rate, see also Appendix 2. 
 

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Appendix 9. EQ-5D-5L 
14.9
 
 

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