A Multicenter, Safety and Efficacy Study of Taliglucerase Alfa in Subjects With Type 3 Gaucher Disease
Phase: PHASE4
Conditions: Gaucher Disease, Type 3
Sponsor: Ari Zimran

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Study Title: 
A Multicenter, Safety and Efficacy Study of Taliglucerase Alfa in Subjects With Type 3 Gaucher 
Disease 
 
 
NCT Number: 
NCT04002830 
 
 
Protocol Date: 
10 December 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CLINICAL STUDY PROTOCOL 
 
Protocol Title:  A Multicenter, Safety and Efficacy Study of 
Taliglucerase Alfa in Subjects with Type 3 Gaucher Disease 
 
 
 
Study Product: 
Taliglucerase alfa (plant cell expressed 
recombinant human glucocerebrosidase) 
Indication: 
Type 3 Gaucher Disease 
Phase: 
3B 
Version and Date: 
Version: 5.0   Date: December 10 2021 
Name and Affiliation of 
Principal Investigators 
A list of the Principal Investigators is 
maintained in the trial master file 
Name and Address of Sponsor 
 Prof. Ari Zimran, MD 
Shaare Zedek Medical Center 
Jerusalem 
Israel 
Good Clinical Compliance (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 the Sponsor. It is understood that information 
in this document shall not be disclosed to any third party, in any form, without prior written consent of the Sponsor. 

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1. 
SYNOPSIS 
TITLE:  A Multicenter, Safety and Efficacy Study of Taliglucerase Alfa in Subjects with 
Type 3 Gaucher Disease  
INVESTIGATIONAL PRODUCT:  Taliglucerase alfa (plant cell expressed recombinant 
human glucocerebrosidase) 
INDICATION:  Gaucher Disease (GD) 
PHASE OF DEVELOPMENT:  3B 
INVESTIGATIONAL SITES/LOCATIONS:  Multicenter, (Israel, India, and Turkey) 
INTERNAL PFIZER STUDY NUMBER:  WI224302 
OBJECTIVES:  To assess the safety and efficacy of taliglucerase alfa in untreated subjects 
(any age) with symptoms and clinical manifestations of Type 3 GD. 
STUDY DESIGN:  This is a multicenter study to assess the safety and efficacy of 
taliglucerase alfa (60 units/kg) in previously untreated subjects of any age with Type 3 GD.  
Subjects will receive an infusion of taliglucerase alfa every 2 weeks for 12 months.  Subjects 
who tolerate the infusions well, and who are treated in centers where home therapy is the SOC 
will be allowed to switch from site to home treatment at the discretion of the PI but after no 
less than 3 uneventful infusions at the site.  
NUMBER OF SUBJECTS (PLANNED): up to 15 
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: 
Key inclusion criteria 
Eligible subjects must fulfill the following inclusion criteria: 
1. Male or female of any age; however, if female: 
• must be using contraception if of childbearing potential or must be surgically sterile 
• must not be lactating 
2. Diagnosis of Type 3 GD by enzyme and sequence analysis; and confirmed by the 
Medical Monitor. 
3. Splenomegaly at least 5 x multiples of normal (MN). 
4. Treatment-naïve. 

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Key exclusion criteria 
Eligible subjects may not have any of the following exclusion criteria: 
1. Type 2 GD. 
2. Presence of myoclonic seizures. 
3. At least one allele of: 
• N370S (N409S in recent nomenclature) 
• R496H (R535H in recent nomenclature) 
 
4. Presence of calcification in heart valves or arteries in echocardiography. 
5. Presence of untreated iron, folic acid, vitamin B12 deficiency and/or hypothyroidism.  
(Resolved anemia is not an exclusion criterion.) 
6. Presence of human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), and/or hepatitis C infections. 
7. Splenectomy and bone marrow transplantation. 
8. Presence of any medical, emotional, behavioural, or psychological condition that in the 
judgment of the Investigator would interfere with the subject’s compliance with the 
requirements of the study. 
9. Any other disorder that may interfere with the results of the efficacy endpoints. 
10. Pregnancy or breastfeeding. 
11. Currently taking another investigational drug for any condition or any therapeutic drug 
for Gaucher disease. 
12. The subject and/or subject’s parent(s) or legal guardian(s) are unable to understand the 
nature, scope, and possible consequences of the study. 
13. Medical history of any food/drugs allergy. 
TEST PRODUCT(S), DOSE AND MODE OF ADMINISTRATION:  Taliglucerase alfa, 
60 units/kg, intravenously, every 2 weeks 
DURATION OF TREATMENT:  12 months 
DISCONTINUATION FROM THE STUDY:   
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 taliglucerase alfa treatment 
• A subject who experiences progressive hypersensitivity or severe hypersensitivity will 
be treated appropriately and may be withdrawn from the study, at the discretion of the 
treating Investigator and/or Medical Monitor 

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• The subject, or subject’s parent or guardian, requests to discontinue treatment 
• Investigator feels that it is not in the best interest of the subject to continue treatment 
and/or the Investigator believes that the subject can no longer be compliant with the 
requirements of the study 
• Deteriorating clinical condition, for which the Investigator decides additional 
treatments would be needed 
EFFICACY VARIABLES: 
Primary efficacy variable is: 
• Percent change in spleen volume (expressed in MN) from baseline to Month 12 
Secondary efficacy variables are: 
• Percent change in liver volume (expressed in MN) from baseline to Month 12 
• Percent change in hemoglobin from baseline to Months 3, 6, 9, and 12 
• Percent change in platelet count from baseline to Months 3, 6, 9, and 12 
• Percent change in Lyso-Gb1 from baseline to Months 3, 6, 9, and 12 
• Percent change in Chitotriosidase from baseline to Months 3, 6, 9, and 12 
Other efficacy variables are: 
• Change in height SDS (standard deviation score) from baseline to Months 3, 6, 9, and 
12 
• Change in weight SDS from baseline to Months 3, 6, 9, and 12 
• Change in Tanner Stage from baseline to Month 12 
• Change in bone age (by X-ray of left hand and wrist) from baseline to Month 12 
• Change in bone mineral density (DEXA) from baseline to Month 12 
Exploratory endpoints: 
• Change in mSST from screening, Month 6 and 12. 
SAFETY ENDPOINTS: 
• Adverse events 
• Clinical laboratory tests 
• Vital signs 
• Physical examinations 
IMMUNOGENICITY: 
• Anti-taliglucerase alfa antibodies 

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STATISTICAL ANALYSIS: 
A sample size of 9 subjects is chosen to evaluate the efficacy and safety of taliglucerase alfa in 
subjects with this orphan disease in which recruitment in clinical trials is difficult. This sample 
size of 9 evaluable subjects will provide a power of 80.9% to detect a responder rate of 0.91 
for reduction in spleen volume from baseline to Month 12, with an actual significant level of 
0.04. Up to 15 subjects will be enrolled in order to yield at least 9 subject who will complete 
the study. 
The primary endpoint is the percent change in spleen volume (expressed in MN) from baseline 
to Month 12.  The Wilcoxon signed rank test at 2-sided significance level of 0.05 will be 
performed to analyse this primary efficacy endpoint.  The Wilcox signed rank test will be 
applied for the secondary efficacy endpoints: percent change from baseline to Month 12 in 
liver volume MN, hemoglobin, platelet count, chitotriosidase and Lyso-Gb1 separately.  
The other efficacy endpoints will be primarily summarized using descriptive statistics by visit. 
For example, change in growth and development assessment from baseline to each visit will 
be summarized using descriptive statistics by visit.  Descriptive statistics will also be reported 
for change in Tanner Stage, bone assessment (bone age, bone mineral density and Z-score) and 
modified severity score (mSST) from screening to Month 12. 
The immunogenicity status will be tabulated by frequency and percentage.  Safety data will be 
descriptively summarized. 
 

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DOCUMENT APPROVAL 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
applicable regulatory requirements. 
 
 
 
PRINCIPAL INVESTIGATOR 
 
 
Signature: _______________________________ Date: ______________________ 
 
Name (print): _Ari Zimran___________________ 
 
 

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TABLE OF CONTENTS 
1. 
SYNOPSIS ...............................................................................................................................3 
2. 
ABBREVIATIONS ................................................................................................................11 
3. 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY REQUIREMENTS ........12 
3.1 
Institutional Review Board (IRB) ......................................................................................12 
3.2 
Ethical Conduct of the Study .............................................................................................12 
3.3 
Subject Information and Consent.......................................................................................12 
4. 
INTRODUCTION ..................................................................................................................13 
4.1 
Gaucher Disease (GD) .......................................................................................................13 
4.2 
Taliglucerase Alfa ..............................................................................................................13 
4.3 
Overview of Clinical Data .................................................................................................13 
4.3.1 
Study PB-06-001 in Adult GD Patients ......................................................................13 
4.3.2 
Study PB-06-002 in Adult and Pediatric GD Patients Previously Treated with 
Imiglucerase ................................................................................................................14 
4.3.3 
Study PB-06-005 in Pediatric Patients with Type 1 GD or Type 3 GD .....................15 
4.3.4 
Long-term Studies in Adult GD Patients ....................................................................15 
4.3.4.1 
Extension Study PB-06-003 ...................................................................................15 
4.3.4.2 
Extension Study PB-06-007 ...................................................................................16 
4.3.5 
Long-Term Extension Study in Pediatric GD Patients ...............................................16 
4.4 
Rationale for Study ............................................................................................................16 
5. 
STUDY OBJECTIVES ..........................................................................................................17 
6. 
INVESTIGATIONAL PLAN .................................................................................................17 
6.1 
Overall Study Design and Plan – Description ...................................................................17 
6.2 
Discussion of Study Design and Choice of Control Group(s) ...........................................17 
6.3 
Selection of Study Population ............................................................................................18 
6.3.1 
Inclusion Criteria ........................................................................................................18 
6.3.2 
Exclusion Criteria .......................................................................................................18 
6.3.3 
Removal of Subjects from Study ................................................................................19 
6.3.4 
Replacement Policy ....................................................................................................19 
7. 
STUDY PRODUCT ...............................................................................................................19 
7.1 
Study Medication Supply ...................................................................................................19 
7.2 
Description of Study Product .............................................................................................19 
7.3 
Description of Comparator Product ...................................................................................20 
7.4 
Study Drug Administration ................................................................................................20 
7.5 
Packaging and Labeling .....................................................................................................20 
7.6 
Conditions for Storage and Use .........................................................................................20 
7.7 
Method of Assigning Subjects to Treatment Groups .........................................................20 
7.8 
Dispensing, Compliance, and Accountability ....................................................................20 
7.9 
Prior and Concomitant Therapy .........................................................................................20 
8. 
EFFICACY AND SAFETY ASSESSMENTS ......................................................................21 
8.1 
Efficacy Variables ..............................................................................................................21 
8.2 
Safety Variables .................................................................................................................22 
8.2.1 
Adverse Events ...........................................................................................................22 

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8.2.1.1 
Adverse Events (AE) and Serious Adverse Events (SAE) ....................................22 
8.2.1.2 
Procedures for Assessing, Recording, and Reporting Adverse Events and Serious 
Adverse Events ......................................................................................................23 
8.2.2 
Clinical Laboratory .....................................................................................................24 
8.2.3 
Vital Signs ..................................................................................................................25 
8.2.4 
Physical Examination .................................................................................................25 
8.3 
Immunogenicity .................................................................................................................25 
9. 
STUDY PROCEDURES AND FLOW CHART ...................................................................25 
9.1 
Study Flow Chart ...............................................................................................................26 
9.2 
Study Visits ........................................................................................................................28 
9.2.1 
Screening (Visit 0, Day -25 ± 10) ...............................................................................28 
9.2.2 
Visit 1 (Baseline, Day 1) ............................................................................................28 
9.2.3 
Visits 2 – 5 (Weeks 2, 4, 6, and 8 ± 3 Days) ..............................................................29 
9.2.4 
Visit 6 (Week 10 ± 3 Days) ........................................................................................30 
9.2.5 
Visit 7 (Month 3 [Week 12] ± 7 Days) .......................................................................30 
9.2.6 
Visits 8 – 13 (Weeks 14, 16, 18, 20, 22, and 24 ± 3 Days) ........................................30 
9.2.7 
Visit 14 (Month 6 [Week 26] ± 7 Days) .....................................................................31 
9.2.8 
Visits 15 – 19 (Weeks 28, 30, 32, 34, and 36 ± 3 Days) ............................................31 
9.2.9 
Visit 20 (Month 9 [Week 38] ± 7 Days) .....................................................................32 
9.2.10 
Visits 21 – 26 (Weeks 40, 42, 44, 46, 48, and 50 ± 3 Days) ......................................32 
9.2.11 
Visit 27 (Month 12 [Week 52] ± 7 Days) ...................................................................32 
9.2.12 
Early Termination Visit ..............................................................................................33 
10. STATISTICAL METHODS PLANNED AND SAMPLE SIZE ...........................................33 
10.1 Determination of Sample Size ...........................................................................................33 
10.2 Analysis Populations ..........................................................................................................34 
10.3 Analysis..............................................................................................................................34 
10.3.1 
Demographics .............................................................................................................34 
10.3.2 
Medical History ..........................................................................................................34 
10.3.3 
Medications .................................................................................................................34 
10.3.4 
Efficacy Analysis ........................................................................................................34 
10.3.5 
Safety Analysis ...........................................................................................................35 
10.3.5.1 Adverse Events ......................................................................................................35 
10.3.5.2 Clinical Laboratory ................................................................................................35 
10.3.5.3 Vital Signs ..............................................................................................................36 
10.3.5.4 Physical Examinations ...........................................................................................36 
10.3.6 
Immunogenicity ..........................................................................................................36 
11. QUALITY CONTROL AND QUALITY ASSURANCE .....................................................36 
11.1 Source Data Records ..........................................................................................................36 
11.2 Reporting of Results ..........................................................................................................36 
11.3 Confidentiality of Subject Data .........................................................................................37 
12. REPORTING AND PUBLICATION .....................................................................................37 
12.1 Confidentiality of Subject Data .........................................................................................37 
12.2 Publication Policy ..............................................................................................................37 
13. REFERENCES .......................................................................................................................38 

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14. APPENDICES ........................................................................................................................40 
14.1 Appendix 1:  ELELYSO® Prescribing Information (US) ..................................................40 
14.2 Appendix 2:  Infusion Rate Algorithm ..............................................................................44 
14.3 Appendix 3:  Taliglucerase Alfa Hypersensitivity Evaluation and Treatment Algorithm 46 
14.4 Appendix 4:  Magnetic Resonance Imaging (MRI) ...........................................................49 
14.4.1 
Subject and Sites .........................................................................................................49 
14.4.2 
MRI Data ....................................................................................................................49 
14.4.3 
MRI Evaluation Parameters ........................................................................................49 
14.4.4 
Sites and Image Data Management ............................ Error! Bookmark not defined. 
14.4.4.1 Standardization of Image Acquisition, Initial Site Qualification...........................49 
14.4.4.2 Subject Sedation.....................................................................................................49 
14.4.4.3 Quality Control of Image Data and Site Quality Assurance During the Course of 
the Study ................................................................................................................49 
14.4.5 
Image Processing and Centralized Analysis ............... Error! Bookmark not defined. 
14.4.5.1 Spleen and Liver Segmentation ............................. Error! Bookmark not defined. 
14.4.5.2 Centralized Image Review by Independent ReadersError! Bookmark not defined. 
14.4.6 
Data and Report Transfers to Sponsor ........................ Error! Bookmark not defined. 
14.4.7 
Direct Access to Study Data ....................................... Error! Bookmark not defined. 
14.4.8 
Unevaluable MRI ........................................................ Error! Bookmark not defined. 
14.5 Appendix 5:  WHO Common Toxicity Criteria ................................................................51 
 
LIST OF TABLES 
Table 1: 
Study Flow Chart ........................................................................................................26 
 
 
 

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2. 
ABBREVIATIONS 
 
Abbreviation or 
Specialist Term 
 
Definition/Description 
AE(s) 
Adverse Event(s) 
β-GCD 
β-Glucocerebrosidase 
CCL18 
Pulmonary and activation-regulated chemokine 
CDC 
Centers for Disease Control and Prevention 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DEXA 
Dual-emission X-ray Absorptiometry 
EC 
Ethics Committee 
ERT 
Enzyme Replacement Therapy 
GBA 
Glucoside Beta Acid 
GCP 
Good Clinical Practice 
GD 
Gaucher Disease 
HBsAg 
Hepatitis B Surface Antigen 
HCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
hGCD 
Human Glucocerebrosidase 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
IR 
Infusion Rate 
IRB 
Institutional Review Board 
IV 
Intravenous 
Lyso-Gb1 
Lyso-glucosylsphingosine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MN 
Multiples of Normal 
MRI 
Magnetic Resonance Imaging 
mSST 
Modified severity scoring tool 
PK 
Pharmacokinetic 
SAE(s) 
Serious Adverse Event(s) 

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Abbreviation or 
Specialist Term 
 
Definition/Description 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
Taliglucerase alfa 
Plant Cell Expressed Recombinant Human Glucocerebrosidase 
TEAE 
Treatment-emergent Adverse Event 
T4 
Free Thyroxine 
TSH 
Thyroid Stimulating Hormone 
WHO 
World Health Organization 
 
3. 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY 
REQUIREMENTS 
3.1 
Institutional Review Board (IRB) 
An Institutional Review Board (IRB) or Ethics Committee (EC) will review the study protocol 
and any amendments. The IRB or EC will also review the informed consent form, 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. 
3.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their origins in 
the Declaration of Helsinki, in compliance with the approved protocol, GCP and applicable 
regulatory requirements. 
3.3 
Subject Information and Consent 
The Investigator will obtain a freely given written consent or assent from each subject or parent 
or guardian 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 form must be signed and dated by the subject or parent or guardian 
before the subject 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 or parent or guardian will receive a copy of the subject information and the signed 
informed consent. 
The subject or parent or guardian will be informed if information becomes available that may be 
relevant to his/her willingness to continue participation in the study. 

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Each subject or parent or guardian 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. 
4. 
INTRODUCTION 
4.1 
Gaucher Disease (GD) 
Gaucher disease is a rare genetic disorder of lipid metabolism 
is the most common inherited 
lysosomal storage disorder, thought to affect around 10,000 people globally [1,2].  The disease 
affects persons of all ages and both sexes and is the result of mutations that affect the GBA gene 
that encodes β-glucocerebrosidase (β-GCD) [3, 4].  The defect results in a deficiency in β-GCD, 
which consequently leads to the build-up of glucocerebroside in macrophages, mostly in the 
spleen, liver, lungs, and bone marrow [5].   
Gaucher disease is classified into 3 major phenotypic subcategories based on the absence 
(Type 1) or presence and severity (Types 2 and 3) of primary central nervous system 
involvement [6].  Gaucher disease Type 3, the population under study in this current protocol, 
affects approximately 5% of documented GD cases [6].  Type 3 GD is associated with 
progressive neurodegenerative disease, with symptom onset usually between infancy and 
adolescence [7].  Manifestations of Type 3 GD vary among patients, ranging from visceral and 
bone disease, cytopenia, hearing impairment, supranuclear gaze palsy, developmental delay, and 
cardiac calcification to myoclonic encephalopathy with seizures and eventual death [8, 9].  
Overall life expectancy is usually dramatically shortened, although there are some documented 
patients now alive in their sixth decade [10]. 
4.2 
Taliglucerase Alfa 
Taliglucerase alfa, a hydrolytic lysosomal glucocerebroside-specific enzyme for intravenous 
infusion, is a recombinant active form of the lysosomal enzyme, β-GCD.  In contrast to other 
β-GCD products for GD therapy, which are produced in mammalian cell culture [11, 12] 
taliglucerase alfa is produced using transgenic [13] carrot plant root cells [14] grown in 
suspension culture with a modified gene sequence encoding human β-GCD [13].  Taliglucerase 
alfa is a glycosylated protein with mannose-terminated oligosaccharide chains that are 
specifically recognized by endocytic carbohydrate receptors on macrophages [14], enabling 
uptake into Gaucher cells [13]. 
Taliglucerase alfa is currently an approved therapy in the United States and many other countries 
for adults and children with a confirmed diagnosis of Type 1 GD [14], and is also approved for 
use in Type 3 GD in a small number of countries. 
4.3 
Overview of Clinical Data 
4.3.1 
Study PB-06-001 in Adult GD Patients 
Study PB-06-001 was a Phase 3, multicenter (11 centers worldwide), double-blind trial in which 
32 adult patients with Type 1 GD randomly received either 30 units/kg or 60 units/kg of 
taliglucerase alfa intravenously every 2 weeks for 38 weeks (20 infusions).  At the end of the 
study, eligible patients were offered enrollment in an open-label extension study (PB-06-003). 

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The primary efficacy analysis demonstrated that taliglucerase alfa treatment significantly 
reduced spleen volume from screening to Month 9 (taliglucerase alfa 30 units/kg, 26.91%, 
p<0.0001; taliglucerase alfa 60 units/kg, 38.01%, p<0.0001) and Month 6 (taliglucerase alfa 
30 units/kg, 22.21%, p<0.0001; taliglucerase alfa 60 units/kg, 29.94%, p<0.0001). 
The secondary efficacy analysis demonstrated that taliglucerase alfa treatment significantly 
increased hemoglobin level from baseline to Month 9 (taliglucerase alfa 30 units/kg, 1.6 g/dL, 
p<0.0001; taliglucerase alfa 60 units/kg, 2.2 g/dL, p<0.0001).  A significant reduction in liver 
volume from screening was also observed in both taliglucerase alfa dose groups at the end of the 
study (taliglucerase alfa 30 units/kg, 10.48%, p=0.0041; taliglucerase alfa 60 units/kg, 11.11%, 
p<0.0001).  In addition, a significant increase in platelet count from baseline was observed in the 
60 units/kg dose group at Month 9 (41,494/mm3, p=0.0031) and an increase in platelet count at 
Month 9 was also observed for the taliglucerase alfa 30 units/kg dose group (11,427/mm3, 
p=0.0460).  Improvements were also observed at the Month 6 visit.   
Overall, 23 patients experienced 137 adverse events (AEs) (12 in the 30 units/kg had 65 AEs and 
11 in the 60 units/kg had 72 AEs).  Eight patients (3 in the 30 units/kg group and 5 in the 
60 units/kg group) experienced 28 events that were considered by the respective investigators to 
be treatment-related.  Of the treatment-related events, none were seen in more than one patient in 
each group.  All AEs were mild or moderate in intensity and the majority of the events resolved 
by the end of the study.  No deaths or serious adverse events (SAEs) occurred during the study.  
Two patients (1 per dose group) discontinued from the study due to a hypersensitivity reaction. 
Pharmacokinetic (PK) analyses showed no tendency for accumulation or change in PK 
parameters with repeated doses of taliglucerase alfa. 
4.3.2 
Study PB-06-002 in Adult and Pediatric GD Patients Previously Treated with 
Imiglucerase 
Study PB-06-002 was a Phase 3, multicenter (11 centers worldwide), open-label study that 
assessed the safety and efficacy of taliglucerase alfa in adult (n=25) and pediatric (n=5) patients 
with Type 1 GD who were switched from treatment with Cerezyme® (imiglucerase) (note: 1 
pediatric patient was subsequently diagnosed with Type 3 GD).  The initial dose of taliglucerase 
alfa was equivalent to the patient’s imiglucerase dose, with subsequent dosage increases allowed 
up to a maximum of 60 units/kg.  Taliglucerase alfa was administered intravenously every 
2 weeks for 9 months.  At the end of the study, eligible patients were offered enrollment in open-
label extension studies (PB-06-003 for adults, PB-06-006 for pediatric patients). 
At the end of 9 months of treatment, all patients main disease parameters remained clinically 
stable.  Mean platelet counts and hemoglobin values were within expected parameters in both 
adult and pediatric patients, and there was also a mean reduction in spleen and liver volumes. 
There was no evidence of increased safety concerns in patients after switching from imiglucerase 
to taliglucerase alfa. 
Comparison between Type 1 GD and Type 3 GD Pediatric Patients 
Pediatric patients showed improvement in the systemic symptoms of Gaucher disease, regardless 
of disease variant.  The absolute mean reductions observed in spleen volume and liver volume in 
the single pediatric patient with Type 3 GD were qualitatively similar, yet quantitatively greater 

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than the change observed in the 4 pediatric patients with Type 1 GD: spleen volume -1.9 MN 
(-9.5%) vs. -0.5 (-23.7%) MN; liver volume 0.1 MN (-6.3%) vs. 0 MN (-3.5%). 
4.3.3 
Study PB-06-005 in Pediatric Patients with Type 1 GD or Type 3 GD 
Study PB-06-005 was a multicenter (11 centers in Israel, Paraguay, and South Africa), double-
blind trial in which 11 untreated pediatric patients (2 to <18 years of age) with a diagnosis of 
Type 1 or Type 3 GD (excluding acute neuropathic GD) were randomized to receive 30 units/kg 
(n=6) or 60 units/kg (n=5) of taliglucerase alfa intravenously every 2 weeks for 12 months.  At 
the end of the study (Month 12) both treatment doses demonstrated the therapeutic efficacy of 
taliglucerase alfa in this pediatric population.  Patients had an increase from baseline in median 
hemoglobin level, decrease in chitotriosidase and CCL18 levels, mean reduction in spleen and 
liver volumes, and mean increase in platelet count, height and weight, and bone age.  
Additionally, the Child Health Questionnaire scores showed that the quality of life of both the 
children and their parents/guardians improved after 12 months of taliglucerase alfa treatment.  
The efficacy results and the observed safety profile in these pediatric patients are consistent with 
previous data of taliglucerase alfa from clinical trials conducted in adult patients.  No new safety 
signals were observed in this study. 
Comparison between Type 1 GD and Type 3 GD in Pediatric Patients 
The 9 patients with Type 1 GD receiving either 30 units/kg or 60 units/kg of taliglucerase alfa 
had improvements in hemoglobin concentration of +2.1 g/dL (20.8%) and 1.6 g/dL (15.8%), 
respectively, from baseline to Month 12, whereas the 2 patients with Type 3 GD had no 
meaningful change in hemoglobin.  The changes from baseline to Month 12 in liver volume, 
spleen volume, and platelet count in the patients with Type 3 GD were qualitatively similar, but 
quantitatively less than the changes observed in patients with Type 1 GD. 
4.3.4 
Long-term Studies in Adult GD Patients 
4.3.4.1 
Extension Study PB-06-003 
This study extended treatment for adult patients who were treatment-naïve (n=26) or previously 
treated with imiglucerase (n=18) and had completed studies PB-06-001 PB-06-002, respectively.  
Thirty-seven patients completed this long-term extension study. 
Long-term data from treatment-naïve adult patients with Type 1 GD who were treated for a total 
of 36 months (9 months in PB-06-001 and 27 months in extension study PB-06-003) support a 
conclusion of continued improvement with both doses of taliglucerase alfa.  After 36 months, 
reductions in spleen volume of 50.1% and 64.6% were observed in the 30 units/kg and 
60 units/kg dose groups, respectively. 
Patients from study PB-06-002 who were switched from imiglucerase to taliglucerase alfa 
maintained stability across efficacy measures, with a reduction in spleen volume of 19.8% after 
36 months of treatment. 
Overall, long-term treatment with taliglucerase alfa was well tolerated and there was no evidence 
of increased safety concerns in patients switched from imiglucerase to taliglucerase alfa. 

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4.3.4.2 
Extension Study PB-06-007 
This study extended treatment for 17 treatment-naïve adult patients (8 at 30 units/kg and 9 at 
60 units/kg) who completed studies PB-06-001 and PB-06-003.  Patients demonstrated 
tolerability and efficacy as determined by organ volume size, hematologic parameters, and 
biomarker measurements.  Taligulcerase alfa was well tolerated during administration for up to 
60 months. 
4.3.5 
Long-Term Extension Study in Pediatric GD Patients 
Study PB-06-006 extended treatment for pediatric patients who were previously treated with 
imiglucerase (n=10) or were treatment-naïve (n=5) and had completed studies PB-06-002 or 
PB-06-005, respectively.  Eleven patients completed this long-term extension study. 
After a total of 36 months of treatment with taliglucerase alfa, treatment-naïve patients showed 
improvements from baseline in organ volumes, hematologic parameters, and biomarkers.  
Patients receiving 60 units/kg of taliglucerase alfa showed greater improvement in most of these 
parameters compared with patients receiving 30 units/kg.  In patients previously treated with 
imiglucerase, disease parameters (spleen volume, liver volume, platelet counts, and hemoglobin 
levels) remained stable through 33 months of treatment. 
Overall, taliglucerase alfa was well tolerated and there was no evidence of increased safety 
concerns in pediatric patients with up to 36 months of treatment. 
Type 3 GD Pediatric Patients 
Two patients with Type 3 GD continued into the PB-06-006 extension study: 1 treatment-naïve 
patient and the 1 previously treated with imiglucerase. 
At 36 months, the treatment-naïve patient showed improvement in hemoglobin (4.9%) and 
platelet count (5.5%), both less than changes observed in patients with Type 1 GD.  For the 
Type 3 GD patient previously treated with imiglucerase, changes in spleen volume and platelet 
count were greater than changes observed in patients with Type 1 GD, whereas changes in liver 
volume and hemoglobin were less in the Type 3 GD patient than in Type 1 GD patients. 
4.4 
Rationale for Study 
Patients with Type 3 GD exhibit both visceral and neurologic manifestations.  In addition to the 
progressive neurologic involvement, somatic disease manifestations, especially splenomegaly 
and resulting cytopenia, contribute to significant mortality and morbidity [15].  The effects of 
enzyme replacement therapy (ERT) on patients with Type 1 GD have been clearly documented 
and have a beneficial effect on visceral and hematologic disease parameters [16].  It is known 
that recombinant enzyme does not pass the blood-brain barrier and has no effect on neurologic 
involvement [17].  Probably due to the rarity of Type 3 GD, information on the somatic effects 
of ERT is largely limited to case reports or single-center series [18].  There are also few reviews 
of cohorts but the clinical subtype, age, genotype, ERT dosage, accompanying therapies, and 
treatment response vary widely among patients in these cohorts [19].  This prospective study 
aims to objectively evaluate the hematologic and visceral effects of ERT with taliglucerase alfa 
on a rather clinically and genetically homogenous group of treatment-naïve patients with Type 3 
GD.  For the purposes of this study, subjects receiving no Gaucher-specific medications for at 

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least 12 months will be considered “untreated”.  The results of this study are expected to provide 
a more objective view of the degree of response of this patient type, and potentially create new 
areas of research. 
5. 
STUDY OBJECTIVES 
The efficacy objectives of this study are to assess the efficacy of taliglucerase alfa in subjects 
with Type 3 GD, as measured by percent change from baseline in spleen and liver volume 
evaluated by magnetic resonance imaging (MRI), hemoglobin, platelet count, and Lyso-
Glucosylsphingosine (Lyso-Gb1); bone mineral density evaluated by dual-emission X-ray 
absorptiometry (DEXA) in all children 9 years of age and above, and evaluation of modified 
severity. 
For children, change from baseline in growth and development (height, weight, sexual 
development by Tanner classification, and bone age by X-ray of left hand and wrist) will be 
measured,   
The safety of taliglucerase alfa will be assessed by adverse events, clinical laboratory tests, vital 
signs, and physical examinations.  Anti-taliglucerase alfa antibodies will also be assessed. 
6. 
INVESTIGATIONAL PLAN 
6.1 
Overall Study Design and Plan – Description 
This is a multicenter study to assess the efficacy and safety of taliglucerase alfa (60 units/kg) in 
previously untreated subjects of any age with Type 3 GD.  For the purposes of this study, 
subjects receiving no Gaucher-specific medications for at least 12 months will be considered 
“untreated”. Subjects will receive an IV infusion of taliglucerase alfa every 2 weeks for 
12 months. Subjects who are treated in centers where home therapy is the SOC will be allowed 
to switch from site to home treatment at the discretion of the PI but after no less than 3 
uneventful infusions at the site. At the end of the 12-month treatment period, eligible subjects 
will be offered enrollment in an open-label extension study if taliglucerase alfa is not 
commercially available. 
6.2 
Discussion of Study Design and Choice of Control Group(s) 
Type 3 GD is a very rare genetic orphan disease.  This study will not have a placebo control 
group because it would be unethical to deny patients the possibility to improve their 
symptomology with an ERT that has been proved efficacious and safe, not only for Type 1 GD 
in many countries but also for Type 3 GD in a small number of countries.  Thus, all subjects will 
receive the investigational product in this study. 
The parameters chosen as endpoints for this study are the most relevant parameters to GD and 
allow a significant and relevant evaluation of improvement as a result of treatment for 
12 months.  Improvement in the clinical manifestations of the disease leads to the achievement of 
the therapeutic goals of GD treatment in the medical community, which are improved fatigue 
and decreased risk for morbidities. 

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6.3 
Selection of Study Population 
6.3.1 
Inclusion Criteria 
For inclusion into the trial, subjects are required to fulfill all of the following criteria: 
1. Male or female of any age; however, if female: 
• must be using contraception if of childbearing potential or must be surgically sterile 
• must not be lactating 
2. Diagnosis of Type 3 GD by enzyme and sequence analysis; and confirmed by the 
Medical Monitor. 
3. Splenomegaly at least 5 x multiples of normal (MN). 
4. Treatment-naïve. 
6.3.2 
Exclusion Criteria 
Any of the following is regarded as a criterion for exclusion from the trial: 
1. Type 2 GD. 
2. Presence of myoclonic seizures. 
3. At least one allele of: 
• N370S (N409S in recent nomenclature) 
• R496H (R535H in recent nomenclature) 
 
4. Presence of calcification in heart valves or arteries in echocardiography. 
5. Presence of untreated iron, folic acid, vitamin B12 deficiency and/or hypothyroidism.  
(Resolved anemia is not an exclusion criterion.) 
6. Presence of human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), 
and/or hepatitis C virus (HCV) infections. 
7. Splenectomy and bone marrow transplantation. 
8. Presence of any medical, emotional, behavioural, or psychological condition that in the 
judgment of the Investigator would interfere with the subject’s compliance with the 
requirements of the study. 
9. Any other disorder that may interfere with the results of the efficacy endpoints. 
10. Pregnancy or breastfeeding. 
11. Currently taking another investigational drug for any condition or any therapeutic drug 
for Gaucher disease. 
12. The subject and/or subject’s parent(s) or legal guardian(s) are unable to understand the 
nature, scope, and possible consequences of the study. 
13. Any medical history of food/drugs allergy. 

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6.3.3 
Removal of Subjects from Study 
Reasons for permanent discontinuation include the following: 
1. The subject experiences two or more Grade 3 toxicities or one or more Grade 4 toxicity 
considered by the Investigator associated with taliglucerase alfa treatment (see Section 
8.2.1: Adverse Events; and Appendix 14.5: WHO Common Toxicity Criteria) 
2. The subject experiences progressive hypersensitivity or severe hypersensitivity will be 
treated appropriately and may be withdrawn from the study, at the discretion of the 
treating Investigator and/or Medical Monitor (see Appendix 14.2: Infusion Rate 
Algorithm; and Appendix 14.3: Taliglucerase Alfa Hypersensitivity Evaluation and 
Treatment Algorithm) 
3. The subject, or subject’s parent or guardian, requests to discontinue treatment 
4. Investigator feels that it is not in the best interest of the subject to continue treatment 
and/or the Investigator believes that the subject can no longer be compliant with the 
requirements of the study 
5. Deteriorating clinical condition, which the Investigator decides additional treatments 
would be needed 
For any discontinuation, the Investigator will obtain all required details and document the date 
and the main reason for the premature discontinuation.  If the reason for discontinuation is an 
adverse event, the specific event or the main laboratory abnormality will be recorded in the case 
report form (CRF).  The Investigator will make thorough efforts to document the outcome.  The 
Investigator will attempt to continue to follow the subject for the full duration of the study or at 
least for 30 days following discontinuation. If circumstances prevent the subject from completing 
all visits, every attempt will be made to complete all procedures listed in Section 9.2.11 for 
Visit 27. 
6.3.4 
Replacement Policy 
Withdrawn subjects will not be replaced. 
7. 
STUDY PRODUCT 
7.1 
Study Medication Supply 
Reconstitution of each taliglucerase alfa vial (212 units) with sterile water for injection (5.1 mL) 
yields a final volume of 5.3 mL human taliglucerase alfa (40 U/mL), which provides a 
withdrawal volume of 5.0 mL (200 units).  The solution must be mixed gently until clear. 
7.2 
Description of Study Product 
Human taliglucerase alfa is a purified recombinant, plant cell-expressed glucocerebrosidase, 
which is described in detail in the taliglucerase alfa Prescribing Information (Appendix 14.1). 
Each 200 unit vial contains the following lyophilized ingredients: 
• 212 units of taliglucerase alfa 

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• 195 mg mannitol 
• 35 mg sodium citrate 
• 0.53 mg polysorbate 80, NF 
7.3 
Description of Comparator Product 
Not applicable. 
7.4 
Study Drug Administration 
Taliglucerase alfa will be administered over 1 to 2 hours (the total volume to be prepared and 
infused is 100-120 mL + 20 mL saline flushing of the system) for initial infusions in all subjects.  
Tolerability will be determined by vital signs taken 30 minutes after starting the infusion and 
symptoms during the infusion and for one hour after the infusion in the clinic and also by 
telephone contact the day after the first infusion.  If this initial rate of infusion is well tolerated, 
the infusion rate may be increased up to 2.0 mL/min (120 mL/hr) to deliver the volume of 
reconstituted enzyme plus 20 mL saline flush over 1 to 2 hours for all subsequent dose 
administrations (see Appendix 14.2: Infusion Rate Algorithm). 
7.5 
Packaging and Labeling 
Lyophilized drug powder is stored in 13.5 mL borosilicate glass (Type 1) bottles (Forma Vitrum 
AG, Hungary).  Lyophilization stoppers (Helvoet Pharma, Belgium) composed of two-leg 
brombutyl rubber are sealed with aluminum Snap Caps and polypropylene discs (Helvoet 
Pharma, Belgium). 
7.6 
Conditions for Storage and Use 
The study product is to be stored at 2°C to 8°C (36°F to 46°F) before reconstitution. 
7.7 
Method of Assigning Subjects to Treatment Groups 
Not applicable. 
7.8 
Dispensing, Compliance, and Accountability 
The Sponsor 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 study monitor or designee.  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.  This record is in addition to any drug accountability information recorded on the CRF.  
These records will be readily available for inspection by a monitor or Sponsor audits and are 
open to regulatory authority inspection at any time. 
7.9 
Prior and Concomitant Therapy 
Medications having the potential to interfere with the evaluation of efficacy are excluded 
throughout the trial. 

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The following medications are strictly prohibited during the study: 
• Zavesca® (miglustat) 
• Ceredase® (algucerase) 
• Cerezyme® (imiglucerase) 
• Vpriv® (velaglucerase alfa) 
• Cerdelga® (eliglustat) 
The following medications are allowed and expected during the study: 
• Treatments for hypersensitivity, anaphylaxis, or anaphylactoid reactions, 
e.g., epinephrine, norepinephrine, glucagon, albuterol 
• Treatments for anemia, e.g., iron, folic acid, vitamin B12 
• Treatments for bone disease, e.g., bisphosphonates 
• Analgesics, e.g., nonsteroidal anti-inflammatory drugs (note: aspirin may be 
contraindicated due to its effects on platelets and risk for bleeding) 
8. 
EFFICACY AND SAFETY ASSESSMENTS 
8.1 
Efficacy Variables 
Spleen and liver volumes will be measured by MRI using a standardized protocol (see 
Appendix 14.4).  Hemoglobin and platelet counts will be measured locally by standard 
laboratory procedures, and biomarkers will be analyzed at a central laboratory 
Primary efficacy variable is: 
• Percent change in spleen volume (expressed in MN) from baseline to Month 12 
Secondary efficacy variables are: 
• Percent change in liver volume (expressed in MN) from baseline to Month 12 
• Percent change in hemoglobin from baseline to Months 3, 6, 9, and 12 
• Percent change in platelet count from baseline to Months 3, 6, 9, and 12 
• Percent change in Lyso-Gb1 from baseline to Months 3, 6, 9, and 12 
• Percent change in Chitotriosidase from baseline to Months 3, 6, 9, and 12 
 
Other efficacy variables are: 
• Change in height SDS from baseline to Months 3, 6, 9, and 12 
• Change in weight SDS from baseline to Months 3, 6, 9, and 12 
• Change in Tanner Stage from baseline to Month 12 
• Change in bone age (by X-ray of left hand and wrist) from baseline to Month 12 

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• Change in bone mineral density (DEXA) from baseline to Month 12 
• Change in mSST from screening Month 6 and 12 
8.2 
Safety Variables 
8.2.1 
Adverse Events 
8.2.1.1 
Adverse Events (AE) and Serious Adverse Events (SAE) 
An adverse event 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.  Adverse events will be collected from the start of treatment until 30 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 (TEAE) is any adverse event occurring after start of study 
medication and within the time of residual drug effect, 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 to be recorded.  One diagnosis/symptom should be entered per record. 
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. 
An overdose or medication error is not an adverse event unless it is temporally associated with 
an unfavorable or unintended sign or symptom. 
Each adverse event 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 

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• 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 on 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?” 
8.2.1.2 
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) that 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. 
Adverse events will be coded to one of the following intensity categories below: 
Severity 
Definition 
Mild 
Awareness of signs or symptoms, but no disruption of usual activity 
Moderate 
Event sufficient to affect usual activity (disturbing) 
Severe 
Event causes inability to work or perform usual activities (unacceptable) 
 

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Adverse events will be coded into one of the following causality categories as defined below: 
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. 
 
Adverse events with the causality assessed as unrelated or unlikely are categorized as not related 
to study medication. 
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).  The Investigator must complete the eCRF SAE Report according to the Serious Adverse 
Event Report Form Instructions. 
8.2.2 
Clinical Laboratory 
The following laboratory tests will be analyzed locally by standard laboratory procedures: 
• Hematology: complete blood count, total white blood cell count, differential count 
(neutrophils, lymphocytes, monocytes, eosinophils and basophils), red blood cells 
(hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and 
mean corpuscular hemoglobin concentration), platelets and reticulocytes. 
• Biochemistry: sodium, potassium, glucose, blood urea nitrogen, creatinine, calcium, 
phosphate (inorganic), uric acid, total protein, albumin, bilirubin (total), alkaline 
phosphatase, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, 
and lactate dehydrogenase, iron, activated AST (GOT), activated ALT(GPT), LDH, 
cholesterol,HDL cholesterol, C-reactive protein, TIBC. 
• Endocrynology: Ferritin, Vitamin D. 
• Urinalysis:  presence of glucose, ketones, protein, and leukocytes 
 
 

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8.2.3 
Vital Signs 
Vital signs measurements will include systolic/diastolic blood pressure, pulse rate, temperature, 
and respiratory rate. 
8.2.4 
Physical Examination 
Physical examination will include assessment of standard body systems. 
8.3 
Immunogenicity 
Anti-taliglucerase alfa antibodies, including neutralizing antibodies in subjects having a positive 
antibody response, will be assessed using a validated analytical method by a central laboratory. 
 
9. 
STUDY PROCEDURES AND FLOW CHART 

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9.1 
Study Flow Chart 
Table 1: 
Study Flow Chart 
Activity 
Visit 0 
Screening 
Visit 1 
Baseline 
Visits 
2-5 
 
Visit 6 
Visit 7 
Month 3 
Visits  
8-13 
Visit 14 
Month 6 
Visits  
15-19 
Visit 20 
Month 9 
Visits  
21-26 
Visit 27 
Month 12 
Day 
-50 ±10 
Day 1 
Weeks 2, 
4, 6, 8, 
(±3 days) 
Week 10 
(±3 days) 
Week 12  
(±7 days) 
Weeks 14, 
16, 18, 20, 
22, 24 
(±3 days) 
Week 26 
(±7 days) 
Weeks 28, 
30, 32,  
34, 36 
(±3 days) 
Week 38 
(±7 days) 
Weeks 40, 
42, 44, 46, 
48, 50 
(±3 days) 
Week 52d 
(±7 days) 
Sign informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Current/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/height 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Physical examination 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Neurologic assessment 
X 
 
 
 
 
 
X 
 
 
 
X 
Hematology 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Biochemistryf,g 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Serology (HIV, HBsAg, HCV) 
X 
 
 
 
 
 
 
 
 
 
 
TSH, free T4, transferrin, B12 and 
folic acid 
X 
 
 
 
 
 
 
 
 
 
 
Beta HCG (post-menarcheal girls) 
X 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-taliglucerase alfa antibodies 
 
X 
 
 
 
 
X 
 
 
 
X 
Organ volumes (MRI) 
X 
 
 
 
 
 
 
 
 
 
X 
Ultrasound (liver and spleen) 
X 
 
 
 
 
 
X 
 
 
 
X 
Echocardiography 
X 
 
 
 
 
 
 
 
 
 
 
Tanner Stage 
 
X 
 
 
 
 
 
 
  
 
X 
X-ray of left hand and wrist 
 
X 
 
 
 
 
 
 
 
 
X 
DEXA 
 
X 
 
 
 
 
 
 
 
 
X 
mSST 
X 
 
 
 
 
 
X 
 
 
 
X 
Molecular analysise 
X 
 
 
 
 
 
 
 
 
 
 
Lyso-Gb1 biomarker 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Chitotriosidase 
 
X 
 
 
X 
 
X 
 
X 
 
X 
IV infusion of taliglucerase alfa 
 
Xa 
Xb 
X 
Xc 
X 
Xc 
X 
Xc 
X 
Xc 
Observe subject clinically 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
Evaluate injection site 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DEXA = dual-emission X-ray absorptiometry; HBsAg = hepatitis B surface antigen; HCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human immunodeficiency 
virus, IV = intravenous; MRI = magnetic resonance imaging; T4 = thyroxine; TSH = thyroid stimulating hormone 

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a A follow-up telephone call with the subject and/or parent or guardian will be held the day after the infusion. 
b Subjects who tolerate the infusions will be eligible for transfer to home or infusion center treatment after this visit at the discretion of the Investigator and Medical Monitor. 
c Taliglucerase alfa infusion must be done at the subject’s selected medical center. 
d All Month 12 (Week 52) procedures/assessments are to be done for any subject who withdraws or is discontinued from the study before completion. 
e Molecular  analysis will be done localy (if not done before), and a confirmation from Central Laboratory (Centogene) will be done using the CentoCard. 
f HDL, Phosphate inorganic and cholesterol assessments, which are taken at screening, should not be repeated at baseline, if done within a period of 1 month. 
g  ALT and AST assessments are enough if activated ALT and activated AST are done on site (or the way around). 
h Vital signs to be done once on screening visit, from baseline till visit 27; to be done only pre and post infusion, and as needed  if an AE occurs during infusion.  

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9.2 
Study Visits 
9.2.1 
Screening (Visit 0, Day -50 ± 10) 
The following procedures will be performed: 
1. Obtain written informed consent from the subject and/or parent or guardian 
2. Assign screening number 
3. Record demographic data 
4. Medical history 
5. Current medications 
6. Physical examination, including body weight and height 
7. Neurologic assessment 
8. mSST evaluation 
9. Molecular Analysis; Done locally (if not done before), and a confirmation from Central 
Laboratory (Centogene) will be done using the CentoCard) 
10. Vital signs (systolic/diastolic blood pressure, pulse rate, temperature, and respiration rate) 
11. MRI for spleen and liver volume 
12. Ultrasound for spleen and liver volume. 
 
13. Clinical laboratory tests: 
• Hematology 
• Biochemistry 
• Urinalysis 
• Thyroid stimulating hormone (TSH) 
• Free thyroxine (free T4) 
• Transferrin 
• Folic acid 
• Vitamin B12 
• Blood pregnancy test (beta-HCG) for females of childbearing potential 
• Serology for HIV, HBsAg, HCV 
14. Review all inclusion and exclusion criteria and determine subject’s eligibility 
15. Request for subject and/or parent or guardian approval 
9.2.2 
Visit 1 (Baseline, Day 1) 
The following procedures will be performed: 

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1. Concomitant medications 
2. Physical examination including body weight and height 
3. Clinical laboratory tests: 
• Hematology 
• Biochemistry; 
- 
 (HDL, Phosphate inorganic and cholesterol assessments, which are taken at 
screening, should not be repeated at baseline, if done within a period of 1 
month). 
- 
ALT and AST assessments are enough if activated ALT and activated AST 
are done on site (or the way around). 
• Urinalysis 
• Anti-taliglucerase alfa antibody test 
• Biomarkers: Lyso-Gb1 and Chitotriosidase 
4. Left hand and wrist X-ray for bone age 
5. Tanner Stage 
6. DEXA 
7. Taliglucerase alfa infusion 
8. Adverse event evaluation 
The following procedures will be performed after taliglucerase alfa dosing: 
1. Observe the subject clinically for a minimum of 1 hour post-dosing. 
2. Evaluate vital signs pre and post infusion, and as needed  if an AE occurs during infusion. 
Evaluate the injection site. 
3. A follow up telephone call with the subject and/or parent or guardian will be held the day 
after the infusion. 
The subject and/or parent or guardian will be reminded of the date of the next visit. 
9.2.3 
Visits 2 – 5 (Weeks 2, 4, 6, and 8 ± 3 Days) 
Subjects will receive their taliglucerase alfa infusion at their selected medical center.  The 
following procedures will be performed post-dosing: 
1. Observe the subject clinically for a minimum of 1 hour post-dosing. 
2. Evaluate vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
3. Evaluate the injection site. 
Adverse events and concomitant medications will be recorded at each visit. 

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Subjects will only receive transfusions at the medical center where they will be followed up and 
treated.  The procedures to be followed will depend on local standards of care and procedures 
established at the medical center Minimally, safety data (vital signs, adverse events, concomitant 
medications) will be recorded at each bi-weekly treatment with taliglucerase alfa administered at 
the medical center. 
The subject and/or parent or guardian will be reminded of the date of the next visit. 
9.2.4 
Visit 6 (Week 10 ± 3 Days) 
Subjects will receive their taliglucerase alfa infusion at their selected medical center.  The 
following procedures will be performed post-dosing: 
1. Adverse event evaluation. 
2. Concomitant medications. 
3. Vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
The subject and/or parent or guardian will be reminded of the date of the next infusion/visit. 
9.2.5 
Visit 7 (Month 3 [Week 12] ± 7 Days) 
All subjects will receive their taliglucerase alfa infusion at their selected medical center and have 
the following evaluations: 
1. Adverse event evaluation. 
2. Concomitant medications. 
3. Physical examination including body weight and height. 
4. Clinical laboratory tests: 
• Hematology 
• Biochemistry 
• Urinalysis 
• Biomarkers: Lyso-Gb1 and Chitotriosidase 
The following procedures will be performed post-dosing: 
1. Observe subjects clinically for 1 hour post-dosing 
2. Evaluate vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
3. Evaluate the injection site. 
The subject and/or parent or guardian will be reminded of the date of the next visit. 
9.2.6 
Visits 8 – 13 (Weeks 14, 16, 18, 20, 22, and 24 ± 3 Days) 
Subjects will receive their Taliglucerase alfa infusion at their selected medical center. The 
following procedures will be performed post-dosing: 
4. Adverse event evaluation. 

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5. Concomitant medications. 
6. Vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
The subject and/or parent or guardian will be reminded of the date of the next infusion/visit. 
9.2.7 
Visit 14 (Month 6 [Week 26] ± 7 Days) 
All subjects are required to return to their selected medical center to receive their taliglucerase 
alfa infusion and have the following evaluations: 
1. Adverse event evaluation 
2. Concomitant medications 
3. Physical examination including body weight and height 
4. Neurologic assessment 
5. Ultrasound for spleen and liver volume. 
6. mSST evaluation. 
7. Clinical laboratory tests: 
• Hematology 
• Biochemistry 
• Urinalysis 
• Biomarkers: Lyso-Gb1 and Chitotriosidase 
• Anti-taliglucerase alfa antibody test 
The following procedures will be performed post-dosing: 
1. Observe the subject clinically for 1 hour post-dosing 
2. Evaluate vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
3. Evaluate the injection site. 
The subject and/or parent or guardian will be reminded of the date of the next visit. 
9.2.8 
Visits 15 – 19 (Weeks 28, 30, 32, 34, and 36 ± 3 Days) 
Subjects will receive their taliglucerase alfa infusion at their selected medical center.  The 
following procedures will be performed post-dosing: 
1. Adverse event evaluation. 
2. Concomitant medications. 
3. Vital signs pre and post infusion, and as needed beforehence 
The subject and/or parent or guardian will be reminded of the date of the next infusion/visit. 

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9.2.9 
Visit 20 (Month 9 [Week 38] ± 7 Days) 
All subjects are required to return to their selected medical center to receive their taliglucerase 
alfa infusion and have the following evaluations: 
1. Adverse event evaluation. 
2. Concomitant medications. 
3. Physical examination including body weight and height. 
4. Clinical laboratory tests: 
• Hematology 
• Biochemistry 
• Urinalysis 
• Biomarkers: Lyso-Gb1 and Chitotriosidase 
The following procedures will be performed post-dosing: 
1. Observe the subject clinically for 1 hour post-dosing. 
2. Evaluate vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
3. Evaluate the injection site. 
The subject and/or parent or guardian will be reminded of the date of the next infusion/visit. 
9.2.10 
Visits 21 – 26 (Weeks 40, 42, 44, 46, 48, and 50 ± 3 Days) 
Subjects will receive their aliglucerase alfa infusion at their selected medical center. The 
following procedures will be performed post-dosing: 
1. Adverse event evaluation. 
2. Concomitant medications. 
3. Vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
The subject and/or parent or guardian will be reminded of the date of their next infusion/visit. 
9.2.11 
Visit 27 (Month 12 [Week 52] ± 7 Days) 
All subjects are required to return to their selected medical center to receive their taliglucerase 
alfa infusion and have the following evaluations: 
1. Physical examination including body weight and height. 
2. Neurologic assessment. 
3. MRI for spleen and liver volume. 
4. Ultrasound for spleen and liver volume. 
 
5. Clinical laboratory tests 

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• Hematology 
• Biochemistry 
• Urinalysis 
• Biomarkers: Lyso-Gb1 and Chitotriosidase 
• Anti-taliglucerase antibody test 
6. Left hand and wrist X-ray for bone age 
7. Tanner Stage 
8. DEXA  
9. mSST evaluation 
10. Adverse event evaluation 
11. Concomitant medications 
The following procedures will be performed post-dosing: 
1. Observe the subject clinically for 1 hour post-dosing. 
2. Evaluate vital signs pre and post infusion, and as needed  if an AE occurs during infusion 
3. Evaluate the injection site. 
9.2.12 
Early Termination Visit 
If the subject withdraws or is discontinued from the study before completion, the reason for 
discontinuation must be documented in the subject’s CRF.  Whenever a subject is discontinued, 
the procedures/assessments listed in Section 9.2.11 should be conducted, unless advised 
otherwise by the Medical Monitor. 
10. STATISTICAL METHODS PLANNED AND SAMPLE SIZE 
Detailed methodology for the summary and statistical analysis of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be prepared and finalized 
prior to database lock.  
10.1 Determination of Sample Size 
It is assumed that the Type 3 GD patients and Type 1 GD patients will have similar efficacy 
response to taliglucerase alfa 60 units/kg.  Given the fact that Type 3 GD usually develops at 
younger age and 60 units/kg is the recommended dose, data from the 5 treatment-naïve pediatric 
patients (Type 1 GD) treated with taliglucerase alfa 60 units/kg in Study PB-06-005 are used to 
calculate sample size.  Since the available data are limited and the data distribution is unknown, a 
responder rate is calculated from the percent change from baseline in spleen volume MN in these 
5 patients as a reference.  A subject is considered a responder if the subject has a reduction from 
baseline in spleen volume MN greater than 20%. 

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The sample size and power calculation are then estimated using the exact computation from a 
2-sided sign test for the null hypothesis that the responder rate is equal to 0.5 for this single-
group design.  This null hypothesis is corresponding to a median reduction of 20% in spleen 
volume at Month 12.  A sample size of 9 evaluable subjects will provide a power of 80.9% to 
detect a responder rate of 0.91 with an actual significant level of 0.04.  An actual significant level 
of 0.05 is not available when the data are discrete and the sample size is small.  
10.2 Analysis Populations 
Full analysis population is defined as all subjects who receive at least one complete dose (or 
partial dose if adverse events prevent complete infusion dose) of study medication. 
Per protocol population is defined as subjects who have the primary efficacy data collected at 
Month 12 and baseline, and receive at least one complete dose (or partial dose if adverse events 
prevent complete infusion dose) of study medication. 
The safety analysis population is equivalent to the full analysis population. 
10.3 Analysis 
10.3.1 
Demographics 
Continuous variables will be summarized with descriptive statistics (number, mean, standard 
deviation, median, minimum, and maximum).  For categorical variables, frequency counts and 
percentages will be presented. 
10.3.2 
Medical History 
Frequency counts will be provided for each body system. 
10.3.3 
Medications 
Data listings of the prior, concomitant medication, and class of medication will be provided. 
10.3.4 
Efficacy Analysis 
Efficacy variables are listed in Section 8.1. 
Analysis for the primary efficacy endpoint 
The primary efficacy evaluation will be the median percent change in spleen volume (expressed 
in MN) from baseline to Month 12 measured by MRI.  For the primary efficacy endpoint, a 
Wilcoxon signed rank test at 2-sided significance level of 0.05 will be applied to test the null 
hypothesis that the median percent change from baseline to Month 12 in spleen volume MN is 
equal to -20%.  The median percent change from baseline and the corresponding p-value will be 
reported. 
Frequency and percentage of the responders who have the reduction greater than 20% in spleen 
volume MN will be provided. The 95% confidence interval for the responder rate will be 
provided using Clopper-Pearson method.  
Analysis for the secondary efficacy endpoints 

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The percent change from baseline (Visit 1 or Screening) to each assessment time point will be 
calculated and summarized by visit with descriptive statistics (number, mean, median, standard 
deviation, minimum, and maximum) for spleen and liver volume (MN), hemoglobin, platelet 
count, chitotriosidase and Lyso-Gb1. 
The Wilcoxon signed rank test will be applied for the secondary efficacy endpoints: percent 
change from baseline to Month 12 in liver volume MN measured by MRI, hemoglobin, platelet 
count, and chitotriosidase and Lyso-Gb1 separately.  Though hemoglobin, platelet counts, 
chitotriosidase and Lyso-Gb1 will be collected at Month 3, 6 and 9 as well, no adjustment will be 
made for multiple comparisons, as the changes from baseline to Month 3, 6 and 9 will be 
descriptively summarized only. 
Analysis for other efficacy variables 
For change in growth and development, the height and weight will be assigned to a SDS-scores 
using the World Health Organization (WHO) Child Growth Standards.  The Centers for Disease 
Control and Prevention (CDC) reference standards will be used for the age categories where the 
WHO reference standards are not available.  Change in growth and development assessment 
from baseline to each visit will be summarized using descriptive statistics by visit. 
Descriptive statistics will also be reported for change in Tanner Stage, bone assessment 
(including bone age, bone mineral density and Z-score for each bone area), and mSST from 
screening to Month 6, Month 12. 
10.3.5 
Safety Analysis 
10.3.5.1 Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) (latest version) will be used to 
classify all adverse events to system organ class and preferred term. All adverse events occurring 
after the initiation of the study treatment (TEAEs) will be reported, including events present at 
baseline that worsened during the study. 
Adverse events will be summarized by overall incidence (the number of subjects reporting at 
least one episode of a specific adverse event), incidence of adverse events by severity within 
system organ class, incidence of adverse events by attribution within system organ class, and 
incidence of adverse events causing discontinuation, 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. 
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. 
10.3.5.2 Clinical Laboratory 
Lab data will be presented for the value and abnormality of each of the clinical laboratory results 
by visit.   

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10.3.5.3 Vital Signs 
Descriptive statistics will be presented for vital signs (systolic/diastolic blood pressure, pulse, 
temperature, and respiratory rate) at baseline (Visit 1) and Month 3, 6, 9 and 12 visits, including 
absolute values, change from baseline and percent change from baseline.   
10.3.5.4 Physical Examinations 
The physical examination data collected at screening and all post-treatment visits will be 
tabulated by frequency count and percentage of normal or abnormal findings for each body 
system. 
10.3.6 
Immunogenicity 
Antibody status (Positive / Negative) determined at baseline (Visit 1), Month 6, and Month 12 
will be tabulated by frequency count and percentage. 
11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Source Data Records 
Source data are all the information in original records and certified copies of original records of 
clinical findings, observations, laboratory reports, data sheets provided by the Sponsor or other 
activities in the study, which are necessary for the reconstruction and evaluation of the study.  
The Investigator will permit study-related monitoring, audit(s), IRB review(s), and regulatory 
inspection(s), with direct access to all the required source records. 
All study records will be retained for a period of time as defined by the regulatory authority for 
the country in which the investigation is conducted.  Generally, this means at least 2 years 
following the date on which the drug is approved by the regulatory authority for marketing for 
the purposes that were the 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 
before disposal of any records related to this study. 
11.2 Reporting of Results 
The 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 number and 
subject initials will be used to identify the subject.  A CRF will be provided for each screened 
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 

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clinical research; and ensure completeness, accuracy, and consistency of the data entered in the 
CRF. 
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. 
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 CRF must be reviewed and signed by the Investigator named in the study 
protocol or by a designated sub-investigator. 
Final monitored and audited eCRFs will be provided by the Sponsor to the sites at the end of the 
study in the format of a PDF file. 
11.3 Confidentiality of Subject Data 
The Investigator will ensure that the confidentiality of the subjects’ data will be preserved.  In 
the CRF or any other documents submitted to the Sponsor, the subjects will not be identified by 
their names, but by an identification system, which consists of their initials and number in the 
study.  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. 
12. REPORTING AND PUBLICATION 
12.1 Confidentiality of Subject Data 
Any information relating to the study product or the study, including any data and results from 
the study, will be the exclusive property of the Sponsor.  The Investigator and any other persons 
involved in the study will protect the confidentiality of this proprietary information belonging to 
the Sponsor. 
12.2 Publication Policy 
The Sponsor agrees to make the report of the multicenter study results available to Investigators 
for preparing a publication of the results in meeting abstract or medical journal form.  The 
Sponsor will have 30 days to review any proposed publication of the data for accuracy and 
proprietary information. 

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13. REFERENCES 
1. Jmoudiak M, Futerman AH. Gaucher disease: pathological mechanisms and modern 
management. Br J Haematol 2005;129(2):178-188. 
2. Zeller JL, Burke AE, Glass RM. JAMA patient page. Gaucher Disease. JAMA 
2007;298(11):1358. 
3. Amato D, Stachiw T, Clarke JT, Rivard GE. Gaucher disease: variability in phenotype 
among siblings. J Inherit Metab Dis 2004;27(5):659-669. 
4. Sidransky E. Gaucher disease: complexity in a “simple” disorder. Mol Genet Metab 
2004;83(1-2):6-15. 
5. Baris HN, Cohen IJ, Mistry PK. Gaucher disease: the metabolic defect, pathophysiology, 
phenotypes and natural history. Pediatr Endocrinol Rev 2014;12(Suppl 1):72-81. 
6. Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, et al. The Gaucher 
registry: demographics and disease characteristics of 1698 patients with Gaucher disease. 
Arch Intern Med 2000;160(18):2835-2843. 
7. Biegstraaten M, van Schaik IN, Aerts JM, Hollak CE. “Non-neuronopathic” Gaucher disease 
reconsidered. Prevalence of neurological manifestations in a Dutch cohort of type I Gaucher 
disease patients and a systematic review of the literature. J Inherit Metab Dis 
2008;31(3):337-349. 
8. Lim-Melia ER, Kronn DF. Current enzyme replacement therapy for the treatment of 
lysosomal storage diseases. Pediatric Ann 2009;38(8):448-455. 
9. Cox TM. Gaucher disease: clinical profile and therapeutic developments. Biologics 
2010;4:299-313. 
10. Rosenbloom BE, Weinreb NJ. Bone disease in patients with Gaucher disease. Expert Review 
of Endocrinology & Metabolism 2014;9(2):153-162. 
11. Cerezyme (imiglucerase for injection). Prescribing information. Cambridge, MA: Genzyme 
Corporation; 2009. 
12. VPRIV (velaglucerase alfa for injection). Prescribing information. Cambridge, MA: Shire 
Human Genetic Therapies, Inc.; 2010. 
13. Shaaltiel Y, Bartfeld D, Hashmueli S, et al. Production of glucocerebrosidase with terminal 
mannose glycans for enzyme replacement therapy of Gaucher’s disease using a plant cell 
system. Plant Biotechnol J 2007;5:579-590. 
14. Taliglucerase alfa for injection. Prescribing Information. New York, NY: Pfizer, Inc.; 2016. 
15. Lee NC, Chien YH, Wong SL, Sheen JM, Tsai FJ, Peng SF, et al. Outcome of early-treated 
type III Gaucher disease patients. Blood Cells Mol Dis 2014;53(3):105-109. 

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16. Deegan P, Fernandez-Sasso D, Giraldo P, Lau H, Panahloo Z, Zimran A. Blood Cells Mol 
Dis 2016;S1079-9796(16):30213-3. 
17. Zimran A, Elstein D. Management of Gaucher disease: enzyme replacement therapy. Pediatr 
Endocrinol Rev 2014;12(Suppl 1):82-87. 
18. Kraoua I, Sedel F, Caillaud C, Froissart R, Stirnemann J, Chaurand G, et al. A French 
experience of type 3 Gaucher disease: phenotypic diversity and neurological outcome of 
10 patients. Brain Dev 2011;33(2):131–139. 
19. El-Beshlawy A, Tylki-Szymanska A, Vellodi A, Belmatoug N, Grabowski GA, Kolodny EH, 
et al. Long-term hematological, visceral, and growth outcomes in children with Gaucher disease type 
3 treated with imiglucerase in the International Collaborative Gaucher Group Gaucher Registry. 
Mol Genet Metab 2017;120 (1-2):47–56. 
 

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14. APPENDICES 
14.1 Appendix 1:  ELELYSO® Prescribing Information (US) 
 
 
 

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14.2 Appendix 2:  Infusion Rate Algorithm 
The infusion rate (IR) may be adjusted according to individual subject symptoms and signs.  The 
assumptions with respect to adverse experiences to the infusion are: 
1. Most of the subjects will tolerate the infusion without any special symptom or event.  The 
infusion rate may be increased over time to the maximal rate 2.0 mL/minute (or 
120 mL/hour) only after discussion with the Medical Monitor (an infusion duration of 
1 hour). 
2. Subjects presenting symptoms and signs of severe hypersensitivity will be evaluated 
according to the WHO 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 of 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 WHO 
Grade 1 or 2 toxicity 
responding to reduction of 
infusion rate or responding to 
treatment (example, 
antihistamine for urticaria). 
 
The specific algorithm to be followed is below. 
 
 

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Adjust IR 
according to 
protocol 
Adjust IR 
according to 
protocol 
Next infusion at a 
slower IR 
(= 1 treatment) 
<1.3 mL/min 
2.0 to 1.3 mL/min 
2.2 to 1.5 mL/min 
Evaluate 
tolerability and 
decide next IR 
Good 
Tolerability 
Partial 
Tolerability 
Poor 
Tolerability 
Evaluate tolerability of 
the infusion according 
to definitions 

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14.3 Appendix 3:  Taliglucerase Alfa Hypersensitivity Evaluation and 
Treatment Algorithm 
During and after infusion of taliglucerase alfa, the following algorithm will be followed to 
monitor and manage the occurrence of hypersensitivity, anaphylaxis, or anaphylactoid reactions. 
Clinical Signs 
Early 
• Sensations of warmth and itching 
• Feelings of anxiety or panic 
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 

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• Blood samples need to be collected for Tryptase (29-33) and antibodies.  Tryptase 
samples need to be withdrawn at: 
o 1st sample taken 0.25-3 hours after onset of symptoms 
o 2nd sample taken between 3-6 hours 
o 3rd sample taken 24-48 hours to verify the return to baseline 
In the case of progressive or severe hypersensitivity, treat appropriately and withdraw the subject 
from the study.  Treat as detailed below. 
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/minute to maintain 
SBP >90 mmHg 
• Glucagon 1 mg in 1 L 5% dextrose in water given IV at 5-15 μg/minute for refractory 
hypotension 
Bronchospasm 
• Oxygen by face mask at 6-8 L/minute to maintain oxygen saturation at >90% 
• Epinephrine 1:1000 solution, 0.5 mL subcutaneously 
• Albuterol 0.5 mL of 0.5% solution in 2.5 mL of sterile saline every 15 minutes  
up to three doses 
• Inhaled beta-agonists 
• Corticosteroids 
Laryngeal edema 
• Epinephrine 1:1000 solution, 0.5 mL subcutaneously, repeat as needed every  
5 to 10 minutes 
• Corticosteroids 
 

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Premedication 
Premedication for subsequent taliglucerase alfa infusions may be considered at the discretion of 
the Investigator and Medical Monitor for subjects experiencing early clinical signs of 
hypersensitivity or rash/urticaria that responds promptly to oral antihistamine administration (see 
also Appendix 14.2 for adjustment of infusion rate).  The premedication will be applied 
according to the following steps as needed to prevent progressive hypersensitivity: 
• Antihistamine (H1 blocker: diphenhydramine, hydroxyzine, cetrizine, loratadine, 
desloratidine) at a standard dose 12 hours and 2 hours before the start of the infusion 
• H1 blocker plus H2 blocker (ranitidine, cimetidine, famotidine) at standard doses 
12 hours and 2 hours before the start of the infusion 
• 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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14.4 Appendix 4:  Magnetic Resonance Imaging (MRI) 
14.4.1 
Subject and Sites 
Nine subjects will be enrolled in this study by 5 to 10 sites worldwide. 
14.4.2 
MRI Data 
Each subject enrolled in this study will have 2 MRI time points during the course of the trial at 
Baseline and Month 12 (or early termination).  For each time point, the same set of T1 and T2-
weighted MRI sequences will be acquired.  An imaging manual will be shared with sites to 
outline the scanning protocol.  The exact sequence parameters will be defined based on site’s 
equipment and abilities to provide sufficient image quality and contrast for organ (spleen and 
liver) detection and quantification, and full spleen and liver coverage in GD subjects.  No 
contrast agent will be used.   
An MRI of the abdomen containing the entire spleen and liver will be collected at the Screening 
visit (Day -25 ± 10) and Week 52 Visit (± 7 days).  Volumes of liver and spleen will be 
evaluated centrally by an independent radiologist.  All scans should be submitted within 2 days 
of acquisition to allow quality review by the central radiologist. . The MRI site must confirm the 
scan is acceptable prior to sending images for central review.  The inspection by the site will 
include complete anatomic coverage of the liver and spleen.  Scans that are not accepted by the 
central radiologist may result in rescan requests.  The method of evaluation used for each patient 
at baseline should remain consistent for the duration of the study. In instances when the scan 
must be repeated (ie, if upon submission to the central radiologist, quality control issues are 
identified and communicated to the site) the repeated scan must be evaluated.  
14.4.3 
MRI Evaluation Parameters 
The following MRI parameters will be evaluated during this study: 
• Volume of spleen (in cm3) 
• Volume of liver (in cm3) 
14.4.3.1 Standardization of Image Acquisition, Initial Site Qualification 
The image acquisition procedure will be provided to sites in a separate image acquisition 
manual.  The same image acquisition and management procedure will be used by all sites.  All 
images will be anonymized by the sites (in order to remove any subject-related nominative 
information) and provided in digital format (DICOM).  Only digital images will be centrally 
processed by the central radiologist. 
14.4.3.2 Subject Sedation 
Pediatric subjects may require sedation in order to obtain the high quality images required.  Sites 
may use standard sedation protocols approved by the institution. 
14.4.3.3 Quality Control of Image Data and Site Quality Assurance During the Course of 
the Study 
The image data will be collected and quality inspected by the central radiologist for checking the 
technical adequacy, the compliance of data acquisition with the imaging guidelines  and the 

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diagnostic quality of the images (their appropriateness for centralized evaluations).  If any 
quality-related issue is detected by the central reviewer this will be communicated to the site.  

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14.5 Appendix 5:  WHO Common Toxicity Criteria 
 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hematology 
WBC (x103/L) 
4 
3.0 - 3.9 
2.0 - 2.9 
1.0 - 1.9 
< 1.0 
Hematology 
Platelets (x103/L) 
WNL 
75.0 - normal 
50.0 - 74.9 
25.0 - 49.9 
< 25.0 
Hematology 
Hemoglobin (g/dL) WNL 
10.0 - normal 
8.0 - 9.9 
6.5 - 7.9 
< 6.5 
Hematology 
Granulocytes/ 
Bands 
2 
1.5 - 1.9 
1.0 - 1.4 
0.5 - 0.9 
< 0.5 
Hematology 
Lymphocytes 
(x103/L) 
2 
1.5 - 1.9 
1.0 - 1.4 
0.5 - 0.9 
< 0.5 
Hematology 
Hemorrhage 
none 
mild, no 
gross, 1 - 2 units 
transfusion per episode 
gross, 3 - 4 units 
transfusion per episode 
massive, > 4 units 
transfusion per episode 
Coagulation 
Fibrinogen 
WNL 
0.99 - 0.75 x N 
0.74 - 0.50 x N 
0.49 - 0.25 x N 
< 0.25 x N 
Coagulation 
Prothrombin 
time(Quick) 
WNL 
1.01 - 1.25 x N 
1.26 - 1.50 x N 
1.51 - 2.00 x N 
> 2.00 x N 
Coagulation 
Partial thrombo- 
plastin time 
WNL 
1.01 - 1.66 x N 
1.67 - 2.33 x N 
2.34 - 3.00 x N 
> 3.00 x N 
Metabolic 
Hyperglycemia 
(mg/dL) 
< 116 
116 - 160 
161 - 250 
251 - 500 
> 500 or ketoacidosis 
Metabolic 
Hypoglycemia 
(mg/dL) 
> 64 
55 – 64 
40 - 54 
30 - 39 
< 30 
Metabolic 
Amylase 
WNL 
< 1.5 x N 
1.5 - 2.0 x N 
2.1 - 5.0 N 
> 5.0 x N 
Metabolic 
Hypercalcemia 
(mg/dL) 
< 10.6 
10.6 - 11.5 
11.6 - 12.5 
12.6 - 13.4 
13.5 
Metabolic 
Hypocalcemia 
(mg/dL) 
> 8.4 
8.4 - 7.8 
7.7 - 7.0 
6.9 - 6.1 
6 
Metabolic 
Hypomagnesemia 
(mg/dK) 
> 1.4 
1.4 - 1.2 
1.1 - 0.9 
0.8 - 0.6 
0.5 
 

Protocol Number WI224302 
10Dec2021 
 
Page 52 
 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Gastrointestinal Nausea 
none 
able to eat reasonable intake 
intake significantly 
decreased but can eat 
no significant intake 
----- 
Gastrointestinal Vomiting 
none 
1 episode in 24 hrs 
2 - 5 episodes in 24 hrs 
6 - 10 episodes in 24 hrs 
> 10 episodes in 24 hrs 
or requiring parenteral 
support 
Gastrointestinal Diarrhea 
none 
increase of 2 - 3 stools / day 
over pre-Rx 
increase of 4 - 6 stools / 
day, or nocturnal stools, or 
moderate cramping 
increase of 7 - 9 stools / 
day, or incontinence, or 
severe cramping 
increase of > 10 stools 
/ day or grossly bloody 
diarrhea, or need for 
parenteral support 
Gastrointestinal Stomatitis 
none 
painless ulcers, erythema, or 
mild soreness 
painful erythema, edema, 
or ulcers but can eat solids 
painful erythema, 
edema, or ulcers and 
cannot eat solids 
requires parenteral or 
enteral support for 
alimentation 
Liver 
Bilirubin (N = 17 
µmol/L) 
WNL 
----- 
< 1.5 x N 
1.5 - 3.0 x N 
> 3.0 x N 
Liver 
Transaminase 
(SGOT, SGPT) 
WNL 
2.5 x N 
2.6 - 5.0 x N 
5.1 - 20.0 x N 
> 20.0 x N 
Liver 
Alk phos or 5 
nucleotidase 
WNL 
< 2.5 x N 
2.6 - 5.0 x N 
5.1 - 20.0 x N 
> 20.0 x N 
Liver 
Liver- clinical 
No change 
from baseline ----- 
----- 
precoma 
hepatic coma 
Kidney, bladder Creatinine 
WNL 
< 1.5 x N 
1.5 - 3.0 x N 
3.1 - 6.0 x N 
> 6.0 x N 
Kidney, bladder Proteinuria 
No change 
1 (+) or < 0.3 g% or 3 g/L 
2 - 3 (+) or 0.3 - 1.0 g% or 
3 - 10 g/L 
4 (+) or > 1.0 g% or > 
10g/L 
nephrotic syndrome 
Kidney, bladder Hematuria 
Negative 
microscopic only 
gross, no clots no Rx 
needed 
gross and clots bladder 
irrigation 
requires trans fusion 
or cystectomy 
Kidney, bladder Weight gain/ loss 
< 5.0 % 
5.0 - 9.9 % 
10.0 - 19.9 % 
20.00% 
----- 
Pulmonary 
Pulmonary 
none or no 
change 
asymptomatic, with  
abnormality in PFTs 
dyspnea on significant 
exertion 
dyspnea at normal 
level of activity 
dyspnea at rest 
 
 
 

Protocol Number WI224302 
10Dec2021 
 
Page 53 
 
Category 
Toxicity 
Grade 0 
Grade1 
Grade2 
Grade3 
Grade4 
Cardiac 
Cardiac arrhythmias none 
asymptomatic, transient, 
requiring no therapy 
recurrent or persistent, no 
therapy required 
requires treatment 
requires monitoring; or 
hypotension, or 
ventricular tachycardia 
or fibrillation 
Cardiac 
Cardiac function 
none 
asymptomatic, decline of 
resting ejection fraction by less 
than 20 % of baseline value 
asymptomatic, decline of 
resting ejection fraction by 
more than 20 % of baseline 
value 
mild CHF, responsive to 
therapy 
severe of refractory 
CHF 
Cardiac 
Cardiac ischemia 
none 
non-specific T- wave flattening 
asymptomatic, ST and T 
wave changes suggesting 
ischemia 
angina without evidence 
of infraction 
acute myocardial 
infarction 
Cardiac 
Cardiac-pericardial none 
asymptomatic effusion, no 
intervention required 
pericarditis (rub, chest 
pain, ECG changes) 
symptomatic effusion; 
drainage required 
tamponade; drainage 
urgently required 
Cardiac 
Hypertension 
none or no 
change 
asymptomatic, transient 
increase by greater than 20 mm 
Hg (D) or to > 150 / 100 if 
previously WNL. No treatment 
required. 
recurrent or persistent 
increase by greater than 20 
mm HG (D) or to > 150 / 
100 if previously WNL.  
No treatment required. 
requires therapy 
hypertensive crisis 
Cardiac 
Hypotension 
none or no 
change 
changes requiring no therapy 
(including transient orthostatic 
hypotension) 
requires fluid replacement 
or other therapy but not 
hospitalization 
requires therapy and 
hospitalization; resolves 
within 48 hours of 
stopping the agent 
requires therapy and 
hospitalization for 
> 48 hrs after stopping 
the agent 
Neurologic 
Neuro: sensory 
none or no 
change 
mild paresthesia; loss of deep 
tendon reflexes 
mild or moderate objective 
sensory loss moderate 
paresthesia 
severe objective sensory 
loss or paresthesia that 
interfere with function 
----- 
Neurologic 
Neuro: motor 
none or no 
change 
subjective weakness; no 
objective findings 
mild objective weakness 
without significant 
impairment of function 
objective weakness with 
impairment of function 
paralysis 
 
 
 

Protocol Number WI224302 
10Dec2021 
 
Page 54 
 
 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neurologic 
Neuro: cortical 
none 
mild somnolence or agitation 
moderate somnolence or 
agitation 
severe somnolence,  
(>50% waking 
hours), agitation, 
confusion, 
disorientation or 
hallucinations 
coma, seizures, toxic 
psychosis 
Neurologic 
Neuro: cerebellar 
none 
slight incoordination, 
dysdiadochokinesia 
intention tremor, 
dysmetria, slurred speech, 
nystagmus 
locomotor ataxia 
cerebellar necrosis 
Neurologic 
Neuro: mood 
no change 
mild anxiety or depression 
moderate anxiety or 
depression 
severe anxiety or 
depression 
suicidal ideation 
Neurologic 
Neuro: headache 
none 
mild 
moderate or severe but 
transient 
unrelenting and severe 
----- 
Neurologic 
Neuro: constipation none or no 
change 
mild 
moderate 
severe 
ileus > 96 hrs 
Neurologic 
Neuro: hearing 
none or no 
change 
asymptomatic, hearing loss on 
audiometry only 
tinnitus 
hearing loss interfering 
with function but 
correctable with hearing 
aid 
deafness not 
correctable 
Neurologic 
Neuro: vision 
none or no 
change 
----- 
----- 
symptomatic subtotal 
loss of vision 
blindness 
Pain 
Pain 
none 
mild 
moderate 
severe 
requires narcotics 
Skin 
Skin 
none or no 
change 
scattered macular or papular 
eruption or erythema that is 
asymptomatic 
scattered macular or 
papular eruption or 
erythema with pruritus or 
other associated symptoms 
generalized symptomatic 
macular, papular or 
vesicular eruption 
exfoliative dermatitis 
or ulcerating dermatitis 
Alopecia 
Alopecia 
no loss 
mild hair loss 
pronounced or total hair 
loss 
----- 
----- 
 
 

Protocol Number WI224302 
10Dec2021 
 
Page 55 
 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergy 
Allergy 
none 
transient rash, drug fever 
< 38°C (100.4°F) 
urticaria, drug fever 38°C 
(100.4°F), mild 
bronchospasm 
serum sickness, 
bronchospasm requiring 
parenteral medication 
anaphylaxis 
Local 
Local 
none 
pain 
pain and swelling with 
inflammation or phlebitis 
ulceration 
plastic surgery 
indicated 
Fever of 
unknown origin 
Fever of unknown 
origin 
none 
37.1 - 38.0°C 98.7° - 100.4°F 
38.1 - 40.0°C 100.5 - 
104°F 
> 40.0°C > 104.0°F for 
less than 24hrs 
> 40.0°C (>104°F) for 
more than 24 hrs or 
accompanied by 
hypotension 
Infection 
Infection 
none 
mild 
moderate 
severe 
life-threatening 
Additional 
events 
Asthenia 
analogous to 
Karnofsky 
index (WHO 
grading) 
Additional 
events 
Chills 
Analogous to 
fever 
Additional 
events 
Peripheral edema 
analogous to 
weight gain 
Additional 
events 
Anorexia 
analogous to 
weight loss