Phase III, Open-label, Switch Over Trial of the Efficacy and Safety of Agalsidase Beta Biosidus (AGA BETA BS) in Fabry Disease Patients Previously Stabilized With Fabrazyme®
Phase: PHASE3
Conditions: Fabry Disease
Sponsor: Bio Sidus SA

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Protocol BIO-AGA-Fase III-001, Version 6.0
 
 
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TITLE PAGE 
Protocol Title: 
Phase III, Open-label, Switch Over Trial of the Efficacy and Safety of Agalsidase Beta 
Biosidus (AGA BETA BS) in Fabry Disease Patients Previously Stabilized with Fabrazyme®. 
Protocol Number: BIO-AGA-Fase III-001 
Amendment Number: 5 
Compound: Recombinant human α-galactosidase A (agalsidase beta) 
Brief Title: Switch over study of biosimilar AGA for Fabry Disease (SMILE) 
Study Phase: III 
Sponsor Name: Biosidus S.A.U. 
Legal Registered Address: Biosidus, Constitución 4234 (1254), Buenos Aires 
Regulatory Agency Identifier Number(s): Not applicable 
Version: April 22, 2024 
Sponsor Signatory 
 
 
Viridiana Berstein, MD 
Manager of Clinical Investigation 
 
Date 
 

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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................... 1 
TABLE OF CONTENTS ........................................................................................................ 2 
LIST OF TABLES ................................................................................................................... 6 
LIST OF FIGURES ................................................................................................................. 6 
1.0 
PROTOCOL SUMMARY .......................................................................................... 7 
1.1 
Synopsis ............................................................................................................ 7 
1.2 
Schema ............................................................................................................ 11 
1.3 
Schedule of Activities .................................................................................... 12 
2.0 
INTRODUCTION ..................................................................................................... 16 
2.1 
Study Rationale .............................................................................................. 16 
2.2 
Background .................................................................................................... 17 
2.3 
Benefit/Risk Assessment................................................................................ 18 
2.3.1 
Risk Assessment................................................................................ 19 
2.3.2 
Benefit Assessment ........................................................................... 19 
2.3.3 
Overall Benefit Risk Conclusion ...................................................... 20 
3.0 
OBJECTIVES AND ENDPOINTS .......................................................................... 21 
4.0 
STUDY DESIGN ....................................................................................................... 23 
4.1 
Overall Design ................................................................................................ 23 
4.2 
Scientific Rationale for Study Design .......................................................... 24 
4.3 
Justification for Dose ..................................................................................... 26 
4.4 
End of Study Definition ................................................................................. 26 
4.5 
Study Stopping Criteria ................................................................................ 26 
4.5.1 
Stopping Criteria for Individual Participants .................................... 26 
4.5.2 
Criteria for Stopping the Study ......................................................... 26 
5.0 
STUDY POPULATION ............................................................................................ 28 
5.1 
Inclusion Criteria ........................................................................................... 28 
5.2 
Exclusion Criteria .......................................................................................... 29 
5.3 
Lifestyle Considerations ................................................................................ 30 
5.4 
Screen Failures ............................................................................................... 30 
6.0 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .................... 31 
6.1 
Study Intervention(s) Administered ............................................................ 31 

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6.2 
Preparation, Handling, Storage, Administration and 
Accountability ................................................................................................ 31 
6.2.1 
Packaging and Labeling .................................................................... 31 
6.2.2 
Storage and Accountability ............................................................... 32 
6.2.3 
Reconstitution and Administration ................................................... 32 
6.3 
Measures to Minimize Bias: Randomization and Blinding ....................... 33 
6.4 
Study Intervention Compliance ................................................................... 33 
6.5 
Dose Modification .......................................................................................... 33 
6.6 
Continued Access to Study Intervention After the End of the 
Study ............................................................................................................... 34 
6.7 
Treatment of Overdose ................................................................................. 34 
6.8 
Concomitant Therapy ................................................................................... 34 
6.8.1 
Prohibited and Allowed Concomitant Medications .......................... 35 
6.8.2 
Rescue Medicine ............................................................................... 36 
7.0 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ................................... 37 
7.1 
Discontinuation of Study Intervention ........................................................ 37 
7.1.1 
Temporary Discontinuation .............................................................. 37 
7.2 
Participant Discontinuation/Withdrawal from the Study ......................... 38 
7.3 
Lost to Follow-up ........................................................................................... 38 
8.0 
STUDY ASSESSMENTS AND PROCEDURES .................................................... 40 
8.1 
General Assessments ..................................................................................... 40 
8.1.1 
Inclusion and Exclusion Criteria ....................................................... 40 
8.1.2 
Assignment of an Identification Number .......................................... 41 
8.1.3 
Demographics ................................................................................... 41 
8.1.4 
Medical History ................................................................................. 41 
8.1.5 
Phone Calls or Text Messages .......................................................... 41 
8.2 
Efficacy Assessments ..................................................................................... 41 
8.2.1 
Serum Lyso-Gb3 Marker .................................................................. 42 
8.2.2 
Brief Pain Inventory-Short Form ...................................................... 42 
8.2.3 
36-Item Short Form Health Survey ................................................... 42 
8.3 
Safety Assessments ........................................................................................ 43 
8.3.1 
Physical Examinations ...................................................................... 43 
8.3.2 
Vital Signs ......................................................................................... 43 
8.3.3 
Electrocardiograms ........................................................................... 44 
8.3.4 
Echocardiograms ............................................................................... 44 
8.3.5 
Clinical Safety Laboratory Tests ....................................................... 45 
8.3.6 
Antialgasidase Antibodies ................................................................. 45 
8.3.7 
Pregnancy Testing ............................................................................. 46 
8.4 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting ........................................................................................................ 46 
8.4.1 
Time Period and Frequency for Collecting Adverse Events 
and Serious Adverse Event Information ........................................... 46 
8.4.2 
Method of Detecting AEs and SAEs ................................................. 47 

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8.4.3 
Follow-up of AEs and SAEs ............................................................. 47 
8.4.4 
Regulatory Reporting Requirements for SAEs ................................. 47 
8.4.5 
Pregnancy .......................................................................................... 48 
8.4.6 
Infusion-associated Reactions ........................................................... 49 
8.4.7 
Adverse Events of Special Interest ................................................... 49 
8.5 
Pharmacokinetics .......................................................................................... 49 
8.6 
Pharmacodynamics ....................................................................................... 49 
8.7 
Genetics .......................................................................................................... 49 
8.8 
Biomarkers ..................................................................................................... 49 
8.9 
Immunogenicity Assessments ....................................................................... 49 
8.10 
Health Economics .......................................................................................... 49 
9.0 
STATISTICAL CONSIDERATIONS ..................................................................... 50 
9.1 
Statistical Hypotheses .................................................................................... 50 
9.1.1 
Multiplicity Adjustment .................................................................... 50 
9.2 
Analysis Sets ................................................................................................... 50 
9.2.1 
General Considerations ..................................................................... 50 
9.2.2 
Primary Endpoint(s) Analysis ........................................................... 51 
9.2.3 
Secondary Endpoint(s) Analysis ....................................................... 52 
9.2.4 
Pharmacokinetic/Pharmacodynamic Analyses ................................. 53 
9.2.5 
Safety Analyses ................................................................................. 53 
9.2.6 
Other Analyses .................................................................................. 53 
9.3 
Interim Analysis ............................................................................................. 53 
9.3.1 
Sample Size Reevaluation ................................................................. 53 
9.4 
Sample Size Determination ........................................................................... 54 
10.0 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................. 55 
10.1 
Appendix 1: Contraceptive and Barrier Guidance and 
Collection of Pregnancy Information .......................................................... 55 
10.1.1 
Definitions ......................................................................................... 55 
10.1.2 
Contraception Guidance .................................................................... 55 
10.2 
Appendix 2: Reconstitution and Dose Preparation for 
Fabrazyme or AGA BETA BS ..................................................................... 59 
10.3 
Appendix 3: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................... 61 
10.3.1 
Regulatory and Ethical Considerations ............................................. 61 
10.3.2 
Adequate Resources .......................................................................... 61 
10.3.3 
Financial Disclosure .......................................................................... 62 
10.3.4 
Insurance ........................................................................................... 62 
10.3.5 
Informed Consent Process................................................................. 62 
10.3.6 
Data Protection .................................................................................. 63 
10.3.7 
Committees Structure ........................................................................ 63 
10.3.8 
Dissemination of Clinical Study Data ............................................... 63 
10.3.9 
Data Quality Assurance ..................................................................... 63 
10.3.10 Source Documents ............................................................................ 64 

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10.3.11 Study and Site Start and Closure ....................................................... 65 
10.3.12 Publication Policy ............................................................................. 66 
10.4 
Appendix 4: Clinical Laboratory Tests ....................................................... 67 
10.5 
Appendix 5: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting for Study 
Intervention .................................................................................................... 70 
10.5.1 
Definition of Adverse Event ............................................................. 70 
10.5.2 
Definition of Serious Adverse Event ................................................ 71 
10.5.3 
Recording and Follow-Up of Adverse Event and/or 
Serious Adverse Event ...................................................................... 72 
10.5.4 
Reporting of SAEs ............................................................................ 73 
10.6 
Appendix 6: Abbreviations and Definitions ................................................ 75 
11.0 
REFERENCES .......................................................................................................... 77 
Signature of Investigator........................................................................................... 79 
 

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LIST OF TABLES 
Table 1 
Schedule of Activities ....................................................................................... 12 
Table 2 
Schedule of Activities in the Event of Discontinuation ................................... 15 
Table 3 
Study Objectives and Corresponding Endpoints .............................................. 21 
Table 4 
Study Intervention(s) Administered ................................................................. 31 
Table 5 
Noninvestigational Antihistaminic Pretreatment ............................................. 35 
Table 6 
Efficacy Analyses ............................................................................................. 52 
Table 7 
Highly Effective Contraceptive Methods ......................................................... 56 
Table 8 
Minimum Total Volume According to the Participant's Weight ...................... 60 
Table 9 
Protocol-required Safety Laboratory Tests – Local Laboratory ....................... 68 
Table 10 
Protocol-required Safety Laboratory Tests – Central Laboratory .................... 69 
 
LIST OF FIGURES 
Figure 1 
Study Schema .................................................................................................. 11 
 

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1.0 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: 
Phase III, Open-label, Switch Over Trial of the Efficacy and Safety of Agalsidase Beta 
Biosidus (AGA BETA BS) in Fabry Disease Patients Previously Stabilized with Fabrazyme®. 
Rationale: 
Biosidus’ Agalsidase Beta is being developed as a proposed biosimilar product to Fabrazyme, 
a recombinant human α-galactosidase A used for enzyme replacement therapy in patients with 
Fabry disease (FD). AGA BETA BS already have shown biosimilarity with Fabrazyme in 
7 nonclinical studies involving pharmacodynamics (PD), pharmacokinetics (PK) and toxicit, 
and in a phase I clinical study.  
The latter was a comparative study of pharmacokinetics and pharmacodynamics between 
AGA BETA BS and Fabrazyme® in healthy volunteers carried out between 2021 and 2022 in 
the Province of Buenos Aires. It was a sequential, open-label, randomized, parallel two-arm 
study. Each participant received a single dose of 1 mg/kg body weight of the drug assigned at 
randomization, at a 1:1 ratio. Participants were followed for 35 days after infusion for safety 
assessment. Pharmacokinetics, pharmacodynamics and safety results are detailed below: 
(1)From the average values obtained for pharmacokinetics parameters (Cmax, AUC0-12h 
and AUC0-∞), the biosimilarity between formulations was analyzed by calculating the ratio 
of Test/Reference formulations and its 90% confidence interval. All three parameters were 
found to be within the accepted biosimilarity range of 0.80 - 1.25. (2) The average enzyme 
activity at the end of infusion (5h) for the Biosidus Agalsidase product was 78.38 ± 20.89 
mU/ml and for Fabrazyme® 80.81 ± 28.60 mU/ml. These results showed an enzyme activity 
ratio at 5h Test/Referent of 0.97. No significant differences were found between the two 
treatment groups (p= 0.8210). (3) Regarding the safety profile, AGA BETA BS showed a 
similar behavior to the reference agalsidase, both in the number of adverse events and in the 
category and degree of severity. There were no serious adverse events.  All adverse events 
were classified as mild by the principal investigator. Those classified as "possible" in terms of 
causality relationship with the investigational drug were expected and were described in the 
investigator's brochure and the reference product package insert. No neutralizing anti-
agalsidase antibodies were detected in any volunteer, neither in the pre-dose samples, nor at 
12h post start of infusion nor at 35 days post administration.  
 
In line with the ANMAT Provision 7729/2011, it is proposed to carry out this clinical trial to 
evaluate the similarity of AGA BETA BS, in terms of safety and efficacy, with the innovator 
product. Using the same reference product as in previous studies. This is a comparative study, 
under the same conditions as the authorized use of the innovator product (IV infusion every 
two weeks, at a dose of 1 mg/kg of body mass), in the indication approved for the innovator 
product (Fabry disease) adapted to the recommendations accepted in other regulatory agencies 
for low prevalence diseases.   
 

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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
• 
The primary objective of the study is to evaluate 
the equivalence in efficacy between AGA BETA 
BS and Fabrazyme after 6 months of treatment in 
participants with Fabry disease previously 
stabilized with Fabrazyme, by measuring disease 
biomarker. 
• 
Mean serum Lyso-Gb3 marker ratio after 
26 weeks of treatment, defined as plasma level of 
the marker Lyso-Gb3 after 26 weeks (6 months) 
divided by plasma level of the marker Lyso-Gb3 
at baseline.  
Secondary 
 
• 
To evaluate the difference in efficacy between 
AGA BETA BS and Fabrazyme after 1 year of 
treatment in participants with Fabry disease 
previously stabilized with Fabrazyme, by 
measuring disease biomarker. 
• 
Mean serum Lyso-Gb3 marker ratio after 
54 weeks of treatment, defined as plasma level of 
the marker Lyso-Gb3 after 54 weeks (12 months) 
divided by plasma level of the marker Lyso-Gb3 
at baseline.  
• 
To compare the pain severity before and after the 
treatment with AGA BETA BS in participants 
with Fabry disease previously stabilized with 
Fabrazyme, as measured by the BPI-short form. 
• 
Change from baseline in pain severity as 
assessed by BPI-short form pain severity items 
scores after 26 and 54 weeks of treatment.  
• 
To compare the impact of pain on daily functions 
before and after the treatment with AGA BETA 
BS in participants with Fabry disease previously 
stabilized with Fabrazyme, as measured by the 
BPI-short form. 
• 
Change from baseline in pain interference as 
assessed by BPI-short form pain interference 
items scores after 26 and 54 weeks of treatment. 
• 
To compare the participants’ perception of their 
own health before and after the treatment with 
AGA BETA BS in participants with Fabry 
disease previously stabilized with Fabrazyme, as 
measured by the SF-36. 
• 
Change from baseline in SF-36 scores after 26 
and 54 weeks of treatment. 
Safety  
 
• 
To characterize the safety of AGA BETA BS 
treatment in participants with Fabry disease 
previously stabilized with Fabrazyme. 
• 
Evaluation of general health based on the 
analysis of laboratory values for hematology and 
clinical chemistry from blood samples collected 
at baseline and after 14, 26, and 54 weeks of 
treatment. 
• 
Evaluation of renal function based on the 
analysis of laboratory values for BUN, eGFR, 
urine albumin-creatinine ratio, electrolytes, and 
phosphate, from blood and urine samples 
collected at baseline and after 14, 26, and 
54 weeks of treatment. 
• 
Evaluation of cardiac function based on the 
analysis of electrocardiogram and bidimensional 
echocardiogram exams performed at baseline 
and after 26 and 54 weeks of treatment. 

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Objectives 
Endpoints 
• 
Evaluation of immunogenicity based on the 
analysis of anti-AGA levels from blood samples 
collected at baseline and after 14, 26, and 
54 weeks of treatment. 
• 
Analysis of data obtained from clinical and 
physical assessments, and from reported adverse 
events and IARs throughout the clinical trial. 
 
Abbreviations: AGA BETA BS=Agalsidase Beta Biosidus; Anti-AGA=anti-agalsidase antibodies; BPI=Brief 
Pain Inventory; BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; 
IARs=infusion-associated reactions; Lyso-Gb3=globotriaosylsphingosine; SF-36=36-Item Short Form Health 
Survey. 
Overall Design: 
BIO-AGA-Fase III-001 is a Phase III, prospective, multicenter, open-label, single-group, 
baseline-controlled, switch over clinical trial to evaluate the efficacy and safety of 
AGA BETA BS in patients with FD already treated and previously stabilized with 
Fabrazyme®. 
The study will be conducted in 2 parts: a 5-week Lead-in period (period 1) and 54-week 
treatment period (period 2). During period 1 all participants will receive 2 intravenous (IV) 
infusions of Fabrazyme®, provided by Biosidus. After that, in period 2 all participants will 
switch treatment to AGA BETA BS. 
The design of this study is based on that used for the only biosimilar approved in an ICH 
member country (Japan). In both, a "patient's own historical control" is used as a control, in 
which the efficacy of AGA BETA BS is measured by comparing the value of the surrogate 
marker (Lyso-Gb3) at baseline - after at least 6 months of treatment with Fabrazyme® - 
compared to the value at 6 and 12 months of treatment with AGA BETA BS. This will be a 
paired comparison that maximizes the ability to detect variations in treatment efficacy.  
 
According to the FDA, in its document: "Rare Diseases: Common Issues in Drug 
Development Guidance for Industry 2019 Feb.", a historical control, is acceptable in two 
situations: (1) diseases where the course of the disease can be objectively verified and 
measured, and (2) in cases where concurrent controls are impractical.   
 
We consider that this study is framed in both situations for the following reasons::  
 
- 
Since FD is a low prevalence disease and considered rare (orphan), two-arm clinical 
trials are more complex, as it is very difficult to achieve a sufficient sample size (n).  
- 
Lyso-Gb3 is a verifiable and objective marker of disease course, widely accepted as a 
short-term follow-up parameter.17  
- 
Lyso-Gb3 also meets FDA surrogate marker criteria (1992 FDA's Accelerated 
Approval regulations).    
- 
This single arm design has already been used and approved by the regulatory agency 
in Japan16, where a formulation of agalsidase beta was shown to be biosimilar to the 
original formulation (also using a biomarker as an efficacy criterion). This biosimilar 

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was approved by the regulatory agency at the end of the study, and is currently 
commercialized.  
- 
This design has also been used in the comparative study of agalsidase beta conducted 
in South Korea that led to the approval and commercialization of FABAGAL®18.  
 
Number of Participants: 
Around 20 participants are planned for the study. Participants will have previous diagnosis of 
FD, will be aged at least 16 years and no more than 60 years, will have received Fabrazyme® 
for at least 6 months, with treatment compliance of at least 80% of the prescribed dose during 
the last 3 months, and with disease status considered clinically stabilized, at the Investigators’ 
discretion.. Male with classic FD phenotype, female with classic FD and men with late onset 
may be included. Participants with chronic kidney disease in stage 3b, 4 or 5, who have 
suffered a clinical cardiovascular or cerebrovascular event in the last 6 months, who have 
acute kidney injury in the last 12 months or who have clinically significant unstable cardiac 
disease will be excluded from the trial. 
Intervention Groups and Duration: 
All participants will receive 2 doses of Fabrazyme® first, administered as an IV infusion at a 
dose of 1.0 mg/kg of body weight with 14 days between doses. After that, all participants will 
receive AGA BETA BS, administered at dose of 1 mg/kg of body weight, infused every 
2 weeks as an IV infusion, for up to 54 weeks (27 infusions). 
1. Non-investigational prophylactic pretreatment with antihistamine will be administered 
at the Investigator’s discretion to avoid infusion-associated reactions during the study, 
except during the first 2 infusions in period 2 in which administration will be 
compulsory. The antihistamine will be loratadine 10 mg, 1 to 2 hours before infusion, 
oral route. Furthermore, patients must remain in observation at the study center for at 
least 1 hour after each infusion during the first four AGA BETA BS infusions. In 
subsequent infusions, the center staff will contact each patient within 24 hours after 
infusion to check their clinical condition. 
Data Monitoring/Other Committee: No 
 

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1.2 
Schema 
Figure 1 
Study Schema 
 
AGA BETA BS=Agalsidase Beta Biosidus; FD=Fabry disease; IV=intravenous. 
 

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1.3 
Schedule of Activities 
Table 1 
Schedule of Activities 
Study Period 
Procedure 
Period 1 - Lead-in 
Period 2 - Treatment 
Screening 
Visit 
Fabrazyme® 
Infusion 
Appointments 
Baseline Visit 
AGA BETA BS 
infusion 
Appointments 
3 months 
Visit 
(After 14 
weeks of 
treatment) 
6 months 
Visit 
(After 26 
weeks of 
treatment) 
Final 
Visit 
(After 54 
weeks of 
treatment) 
Visit day (window) 
Day -42 to 
-35 
Day -28 (±2) 
Day -14 (±2)1 
Day 1 (±2)1 
Every 14 days 
(±2)1 
Day 99 
(±2)1 
Day 183 
(±2)1 
Day 379 
(±2)1 
Informed consent 
● 
 
 
 
 
 
 
Inclusion and exclusion criteria 
● 
●2 
 
 
 
 
 
Demography and height 
● 
 
 
 
 
 
 
Weight 
● 
● 
● 
● 
● 
● 
● 
Full physical examination 
● 
 
 
 
 
 
● 
Medical history (including documented 
confirmed diagnosis of FD) 
● 
 
 
 
 
 
 
Past and current medical conditions 
● 
 
 
 
 
 
 
Urine pregnancy test (WOCBP only)3 
 
Laboratory tests4  
●5 
 
● 
 
●6 
● 
● 
12-lead ECG 
●5 
 
 
 
 
● 
● 
Echocardiogram 
●5 
 
 
 
 
● 
● 
Vital signs7 
● 
● 
● 
● 
● 
● 
● 
SF-36 
 
 
● 
 
 
● 
● 
BPI-short form 
 
 
● 
 
 
● 
● 

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Study Period 
Procedure 
Period 1 - Lead-in 
Period 2 - Treatment 
Screening 
Visit 
Fabrazyme® 
Infusion 
Appointments 
Baseline Visit 
AGA BETA BS 
infusion 
Appointments 
3 months 
Visit 
(After 14 
weeks of 
treatment) 
6 months 
Visit 
(After 26 
weeks of 
treatment) 
Final 
Visit 
(After 54 
weeks of 
treatment) 
Visit day (window) 
Day -42 to 
-35 
Day -28 (±2) 
Day -14 (±2)1 
Day 1 (±2)1 
Every 14 days 
(±2)1 
Day 99 
(±2)1 
Day 183 
(±2)1 
Day 379 
(±2)1 
Phone contact8 
 
● 
● 
● 
● 
● 
● 
Fabrazyme® infusions 
 
● 
 
 
 
 
 
AGA BETA BS infusions 
 
 
● 
● 
● 
● 
 
Anti-AGA9 
 
 
● 
 
● 
● 
● 
Lyso-Gb3 (serum)9 
 
 
● 
 
● 
● 
● 
Delivery of the diary to the participant 
● 
 
 
 
 
 
 
Participant diary review10 
 
● 
● 
● 
● 
● 
● 
IARs and AE assessment 
 
 
Concomitant medication review 
 
 
Abbreviations: AE=adverse event; AGA BETA BS= Agalsidase Beta Biosidus; anti-AGA=antiagalsidase antibodies; BPI=Brief Pain Inventory; 
COVID-19=coronavirus disease 2019; ECG=electrocardiogram; FD=Fabry disease; HDL=high-density lipoprotein; IARs=infusion-associated reactions; 
IV=intravenous; LDL=low-density lipoprotein; Lyso-Gb3=globotriaosylsphingosine; SF-36= 36-Item Short Form Survey; WOCBP=women of childbearing 
potential. 
1. Infusions will take place at infusion appointments and at all visits after the Screening visit, except the final visit. If the participant needs to use the +2 days in 
a visit, to comply with the 14 ± 2-day gap between infusions, he or she will not be allowed to use the whole visit window in the next visit. In this trial, the 
participants can use the visit windows if they observe the time between infusions of 14 ±2 days. Patients must remain in observation at the study center for at 
least 1 hour after each infusion during the first four AGA BETA BS infusions. In subsequent infusions, the center staff will contact each patient within 24 
hours after infusion to check their clinical condition. 
2. For participants whose blood and urine samples are collected for laboratory tests at the Screening visit, the inclusion and exclusion criteria must be 
reassessed as soon as the results are available, prior to the first Fabrazyme® infusion. Both Fabrazyme® infusions will be included in the time calculation 
for the assessment of dose stability (participants must be receiving ≥80% of labeled dose/kg for at least last 3 months - inclusion criterion 9). 

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3. Pregnancy test should be done every 4 weeks in WOCBP. If there is no protocol visit scheduled in that period, the urine pregnancy test will be arranged in 
the closest infusion appointment. 
4. Laboratory tests include complete hematology, blood urea nitrogen, electrolytes, phosphate, creatinine (with eGFR calculation), cholesterol (total, LDL and 
HDL), triglycerides, glycemia, bilirubin (total and direct), aspartate and alanine aminotransferases, alkaline phosphatase, total proteins, albumin, gamma 
glutamyl transferase, first morning urine, and urine albumin-creatinine ratio. The blood and urine samples should be collected before the start of the infusion, 
if applicable. 
5. For participants who present results of exams performed in the last 90 days, these exams do not need to be performed again. The results from exams 
performed in this visit must be available during the first Fabrazyme® infusion appointment for confirmation of compliance with inclusion/exclusion criteria. 
6. In this visit the exams urine albumin-creatinine ratio and creatinine will not be performed. 
7. Vital signs include heart rate, respiratory rate, body temperature, and blood pressure. Vital signs will be checked before each infusion and if the investigator 
deems it necessary, hourly during the infusions, if applicable. 
8. Phone calls to the participant must be conducted by the study site personnel 24 to 48 hours before each study appointment or visit to check on symptoms 
compatible with COVID-19 or other infection. To receive the infusions, participants experiencing any infection must wait for clinical recovery, ie, 48 hours 
being afebrile. If clinical recovery is not established when an infusion is scheduled, the dose must be delayed.  
9. Blood sample for this dosage must be collected before the infusion starts. 
10. The diary will be given to the participant for them to record information about AEs and concomitant medications. The participant must be instructed to take 
the diary with them to each medical visit and each infusion appointment for evaluation. 

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Table 2 
Schedule of Activities in the Event of Discontinuation 
Abbreviations: AE=adverse event; anti-AGA=anti-agalsidase; BPI=Brief Pain Inventory; COVID-19=coronavirus disease 2019; ECG=electrocardiogram; 
HDL=high-density lipoprotein; IARs=infusion-associated reactions; LDL=low-density lipoprotein; Lyso-Gb3=globotriaosylsphingosine; SF-36=36-Item 
Short Form Survey; WOCBP=Women of childbearing potential. 
1. Laboratory tests include complete hematology, blood urea nitrogen, electrolytes, phosphate, creatinine (with eGFR calculation), cholesterol (total, LDL and 
HDL), triglycerides, glycemia, bilirubin (total and direct), aspartate and alanine aminotransferases, alkaline phosphatase, total proteins, albumin, gamma 
glutamyl transferase, first morning urine and urine albumin-creatinine ratio. 
2. Vital signs include heart rate, respiratory rate, body temperature, and blood pressure. 
3. After intervention discontinuation, instead of following sequential procedures planned in the study, the participant should receive telephone follow-up at 
same timepoints of all following planned visits to evaluate general health condition. 
Study Period 
Procedure 
Time of Intervention 
Discontinuation 
Early Discontinuation Visit 
(participant withdrawn) 
Full physical examination 
● 
● 
Urine pregnancy test (WOCBP only) 
● 
● 
Laboratory tests1 (hematology and biochemistry)  
 
● 
12-lead ECG 
● 
● 
Echocardiogram 
● 
● 
Vital signs2 
● 
● 
SF-36 
● 
● 
BPI-short form 
● 
● 
Phone contact – follow-up 
●3 
Anti-AGA antibodies 
● 
● 
Lyso-Gb3 (serum) 
● 
● 
IARs and AE assessment 
● 
● 
Concomitant medication review 
● 
● 

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2.0 INTRODUCTION 
Biosidus’ Agalsidase Beta is being developed as a proposed biosimilar product to 
Fabrazyme® which is planned to meet the need for alternatives to high-priced biologic agents 
in enzyme replacement therapy (ERT) treatments for Fabry disease (FD). 
2.1 
Study Rationale 
This Phase III trial will evaluate the efficacy and safety of Agalsidase Beta Biosidus (AGA 
BETA BS) in a switch over study with participants with FD previously stabilized with 
Fabrazyme®. 
The AGA BETA BS clinical development follows the currently understood concepts from 
regulation 7729/2011 of the Argentine National Administration of Drugs, Food and Medical 
Devices (ANMAT) for biosimilar development. The approach is to demonstrate a similar 
behavior in terms of identity, potency and purity profile compared with the reference drug, 
and a comparable profile of safety and efficacy. 
Biosidus’ Agalsidase Beta is being developed as a proposed biosimilar product to Fabrazyme, 
a recombinant human α-galactosidase A used for enzyme replacement therapy in patients with 
Fabry disease (FD). AGA BETA BS already have shown biosimilarity with Fabrazyme in 
7 nonclinical studies involving pharmacodynamics (PD), pharmacokinetics (PK) and toxicit, 
and in a phase I clinical study.  
The latter was a comparative study of pharmacokinetics and pharmacodynamics between 
AGA BETA BS and Fabrazyme® in healthy volunteers carried out between 2021 and 2022 in 
the Province of Buenos Aires. It was a sequential, open-label, randomized, parallel two-arm 
study. Each participant received a single dose of 1 mg/kg body weight of the drug assigned at 
randomization, at a 1:1 ratio. Participants were followed for 35 days after infusion for safety 
assessment. Pharmacokinetics, pharmacodynamics and safety results are detailed below: 
(1)From the average values obtained for pharmacokinetics parameters (Cmax, AUC0-12h and 
AUC0-∞),  the biosimilarity between formulations was analyzed by calculating the ratio of 
Test/Reference formulations and its 90% confidence interval. All three parameters were found 
to be within the accepted biosimilarity range of 0.80 - 1.25. (2) The average enzyme activity at 
the end of infusion (5h) for the Biosidus Agalsidase product was 78.38 ± 20.89 mU/ml and for 
Fabrazyme® 80.81 ± 28.60 mU/ml. These results showed an enzyme activity ratio at 5h 
Test/Referent of 0.97. No significant differences were observed between the two treatment 
groups (p= 0.8210). (3) Regarding the safety profile, AGA BETA BS showed a similar 
behavior to the comparator, both in the number of adverse events and in the category and 
degree of severity. There were no serious adverse events.  All adverse events were classified 
as mild by the principal investigator. Those classified as "possible" in terms of causality 
relationship with the investigational drug were expected and were described in the 
investigator's brochure and the reference product package insert. No neutralizing anti-

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agalsidase antibodies were detected in any volunteer, neither in the pre-dose samples, nor at 
12h post start of infusion nor at 35 days post administration.  
 
In line with the ANMAT Provision 7729/2011, it is proposed to carry out this clinical trial to 
evaluate the similarity of AGA BETA BS, in terms of safety and efficacy, with the innovator 
product. Using the same reference product as in previous studies. This is a comparative study, 
under the same conditions as the authorized use of the innovator product (IV infusion every 
two weeks, at a dose of 1 mg/kg of body mass), in the indication approved for the innovator 
product (Fabry disease) adapted to the recommendations accepted in other regulatory agencies 
for low prevalence diseases.   
2.2 
Background 
Fabry disease is a rare X-chromosomal-linked lysosomal storage disorder due to various 
pathogenic mutations in the GLA gene, responsible for codifying the lysosomal enzyme 
α-galactosidase A (α-Gal A). The reduction or complete lack of activity of this enzyme results 
in slow and progressive accumulation of glycosphingolipids, mainly globotriaocylceramide 
(Gb3 or GL3) and its deacylated derivative globotriaosylsphingosine (Lyso-GL3, also called 
Lyso-Gb3) in several cell types throughout the body, affecting the heart, kidneys, skin, eyes, 
central nervous system, and gastrointestinal system, ultimately generating severe, potentially 
life-threatening target-organ complications.1,2,3 Together, the numerous signs and symptoms 
of FD significantly reduce quality of life and shorten life expectancy by 10 to 20 years.4 
Fabry disease encompasses a spectrum of phenotypes ranging from the more severe classic 
phenotype to atypical late onset forms. The classic manifestation of FD occurs predominantly 
in men that generally show less than 1% α-Gal A enzyme activity and it usually has its onset 
in childhood or adolescence.1,2,5 The nonclassical or atypical phenotype of FD involves 
residual enzyme activity that leads to generally milder symptoms, with a later onset of 40 to 
60 years of age.6 The clinical presentation of FD in women is highly variable, ranging from 
asymptomatic patients to patients with symptoms as severe as those observed in males with 
the classic phenotype.1 
Until a few decades ago, there was no effective treatment available for inherited lysosomal 
storage diseases such as FD. The management consisted only of supportive care and 
pharmacologic management for symptoms control.5 Today, even if it is not a cure, patients 
with FD have 2 therapeutic modalities available: ERT and oral pharmacological chaperones 
(PCT).4 Enzyme replacement therapy, which consists of systemic α-Gal A infusion and was 
the first approved treatment for FD,4 increases the enzyme levels in the body, while PCT have 
been shown to promote the correct folding of amenable mutated glycosidases and retrieve 
residual activity levels.5 Other strategies, such as substrate reduction therapy, messenger 
RNA-based therapy, and gene therapy are in development.4 

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There are 2 available pharmaceutical preparations of recombinant human α-Gal A approved 
and used worldwide: agalsidase alfa (Replagal® by Shire) and agalsidase beta (Fabrazyme® 
by Sanofi Genzyme). While agalsidase alfa is produced by overexpression in human 
fibroblasts, agalsidase beta is produced by overexpression in chinese hamster ovary cells.4 
Both preparations are administered intravenously every 14 days and have similar 
glycosylation patterns, specific activities, enzyme kinetics,4 and both have been shown to be 
clinically equally efficacious,1,2 decreasing the accumulation of GL3 in kidney, heart, and 
dermal cells, improving pain and maintaining kidney functions. Both were approved in 2001 
by the European Agency for Evaluation of Medical Products; only Fabrazyme® was approved 
by the Food and Drugs Administration (FDA) for use in the United States (US).2 
Although ERT (Enzyme Replacement Therapy) consists in an efficacious treatment with good 
tolerance, the treatment leads to high costs, with an average of 250,000 €/year per patient 
(considering an adult weighing 70 kg).7 Therefore, other treatment options in addition to those 
already approved are under study. 
2.3 
Benefit/Risk Assessment 
Participants enrolled into this equivalence trial are expected to derive similar benefit and risk 
from the treatment already experienced before the enrollment, with Fabrazyme®. This is 
based on the similarity observed during PD, PK, and toxicological testing between the 
investigational medicinal product and Fabrazyme®. In addition, the safety profile of AGA 
BETA BS observed in the Phase I trial was similar to that of Fabrazyme®, therefore, in this 
clinical trial, adverse events (AEs) beyond those already known are not expected. 
Based on PD, PK, and toxicological testing carried out prior to initiation of this trial, and the 
Phase I clinical trial’s data described above, AGA BETA BS, as a proposed biosimilar 
product, may be seen to provide similar efficacy, safety, and immunogenicity to Fabrazyme® 
in patients with FD. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of agalsidase beta may be found in the current Investigator’s Brochure. 
The Sponsor will immediately notify the Principal Investigator if any additional safety or 
toxicology information becomes available during the study. 
This study will be performed in compliance with the protocol, International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP), European Union (EU) Clinical Trial Regulation, and applicable 
regulatory requirements. 

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2.3.1 
Risk Assessment 
The risk arising from the treatment is based on the occurrence of adverse reactions. It is 
expected that many patients will develop Immunoglobulin G antibodies upon treatment with 
agalsidase beta, and patients with antibodies have a higher risk of infusion-associated 
reactions (IARs). In clinical trials with Fabrazyme®, IARs were assessed as mild or moderate 
in intensity and were the most frequently reported related AEs, including chills, fever, 
temperature change sensation, hypertension, nausea, vomiting, flushing, paresthesia, fatigue, 
pain, headache, chest pain, and pruritus.8 Life-threatening anaphylactic and severe allergic 
reactions are uncommon.9 
The IARs have been successfully managed using standard medical practices, such as reduction 
in infusion rate and/or premedication with, or additional administration of nonsteroidal 
anti-inflammatory drugs, antipyretics, antihistamines and/or corticosteroids.8 
As most IARs occur in the first few months of treatment,9 all participants will have their 
infusions at the study center, with direct physician supervision, so as to manage and treat  any 
adverse reactions that could be presented, even if they already are receiving Fabrazyme® for a 
considerable amount of time, where the IAR’s frequency is low or null due to the continued 
use of agalsidase beta and.8 Additionally, antihistamine will be administered to avoid IARs 
obligatorily in the first 2 infusions with the experimental drug. 
Additionaly, patients must remain in observation at the study center for at least 1 hour after 
each infusion during the first four AGA BETA BS infusions. In subsequent infusions, the 
center staff will contact each patient within 24 hours after infusion to check their clinical 
condition. 
Participant risk will be minimized by implementing conservative eligibility criteria, regular 
and long-term safety monitoring, including immunogenicity testing. 
2.3.2 
Benefit Assessment 
Despite still having aspects to be explored and understood, ERT is a well-established 
treatment that has been shown to delay the progression of a multisystemic disease and organ 
involvement and represents the current standard-of-care therapeutic option for FD.10  
The response to ERT varies considerably and appears to depend on gender, genotype (classic 
or later onset/nonclassic), stage of disease or age and agalsidase inhibition by antiagalsidase 
antibodies (anti-AGA).10 
The benefit of ERT for patients with FD has been documented in the clinical literature. A 
Cochrane review of randomized controlled trials showed that ERT reduces microvascular 
endothelial GL3 deposits and improves pain‐related quality of life compared with placebo.11 
This review was complemented by a pooled analysis of cohort studies that showed that 

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patients taking agalsidase beta had a significantly lower incidence of renal, cardiovascular, 
and cerebrovascular events than patients not taking ERT.12 A meta-analysis of double-blind 
and randomized clinical trials suggests that ERT with agalsidase alfa or beta reduces the 
severity of neuropathic pain, improves pain-related quality of life, brings about minor changes 
in left ventricular mass, reduces serum, urine and tissue levels of GL3, and is able to slow 
down the progression of FD.13 Additionally, a 10-year study of ERT efficacy in adults 
reported a survival rate of 94% and most patients (81%) had no severe clinical events during 
this time. Patients who initiated treatment at a younger age and with less kidney involvement 
benefited the most from therapy, suggesting that early initiation of ERT could slow or even 
prevent renal disease progression.14 The results of Fabrazyme®’ published randomized 
controlled clinical trials and their extension studies showed clearance of GL3 in renal cells 
and cardiac endothelial cells after 6 months of treatment, significant risk reduction (-61%) of 
renal, cardiac, cerebrovascular complications and death, significant improvement in pain 
scores and quality of life, as well as significant reductions in school absences due to sickness 
and gastrointestinal symptoms.8,15 
Therefore, participants of this trial will have the benefit of receiving a potentially effective 
Fabrazyme®’s biosimilar drug free of charge, in addition to being able to contribute to the 
process of developing a therapy as effective as the current treatment and at a lower cost. In 
addition, during the study the participant will receive medical evaluations and laboratory tests 
free of charge as part of the trial. 
2.3.3 
Overall Benefit Risk Conclusion 
Considering the measures taken to minimize risk to participants participating in this study, the 
potential risks identified in association with study intervention are justified by the anticipated 
benefits that may be afforded to participants with FD. 

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3.0 OBJECTIVES AND ENDPOINTS 
Table 3 presents the primary, secondary, and safety objectives and corresponding endpoints. 
Table 3 
Study Objectives and Corresponding Endpoints 
 
Objectives 
Endpoints 
Primary 
 
• 
The primary objective of the study is to evaluate 
the equivalence in efficacy between AGA BETA 
BS and Fabrazyme® after 6 months of treatment 
in participants with Fabry disease previously 
stabilized with Fabrazyme, by measuring disease 
biomarker. 
• 
Mean serum Lyso-Gb3 marker ratio after 
26 weeks of treatment, defined as plasma level of 
the marker Lyso-Gb3 after 26 weeks (6 months) 
divided by plasma level of the marker Lyso-Gb3 
at baseline.  
Secondary 
 
• 
To evaluate the difference in efficacy between 
AGA BETA BS and Fabrazyme® after 1 year of 
treatment in participants with Fabry disease 
previously stabilized with Fabrazyme®, by 
measuring disease biomarker. 
• 
Mean serum Lyso-Gb3 marker ratio after 
54 weeks of treatment, defined as plasma level of 
the marker Lyso-Gb3 after 54 weeks (12 months) 
divided by plasma level of the marker Lyso-Gb3 
at baseline.  
• 
To compare the pain severity before and after the 
treatment with AGA BETA BS in participants 
with Fabry disease previously stabilized with 
Fabrazyme®, as measured by the BPI-short 
form. 
• 
Change from baseline in pain severity as 
assessed by BPI-short form pain severity items 
scores after 26 and 54 weeks of treatment.  
• 
To compare the impact of pain on daily functions 
before and after the treatment with AGA BETA 
BS in participants with Fabry disease previously 
stabilized with Fabrazyme®, as measured by the 
BPI-short form. 
• 
Change from baseline in pain interference as 
assessed by BPI-short form pain interference 
items scores after 26 and 54 weeks of treatment. 
• 
To compare the participants’ perception of their 
own health before and after the treatment with 
AGA BETA BS in participants with Fabry 
disease previously stabilized with Fabrazyme®, 
as measured by the SF-36. 
• 
Change from baseline in SF-36 scores after 26 
and 54 weeks of treatment. 
Safety  
 
• 
To characterize the safety of AGA BETA BS 
treatment in participants with Fabry disease 
previously stabilized with Fabrazyme®. 
• 
Evaluation of general health based on the 
analysis of laboratory values for hematology and 
clinical chemistry from blood samples collected 
at baseline and after 14, 26, and 54 weeks of 
treatment. 
• 
Evaluation of renal function based on the 
analysis of laboratory values for BUN, eGFR, 
urine albumin-creatinine ratio, electrolytes, and 
phosphate, from blood and urine samples 
collected at baseline and after 14, 26, and 
54 weeks of treatment. 
• 
Evaluation of cardiac function based on the 
analysis of electrocardiogram and bidimensional 

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Objectives 
Endpoints 
echocardiogram exams performed at baseline 
and after 26 and 54 weeks of treatment. 
• 
Evaluation of immunogenicity based on the 
analysis of anti-AGA levels from blood samples 
collected at baseline and after 14, 26, and 
54 weeks of treatment. 
• 
Analysis of data obtained from clinical and 
physical assessments, and from reported adverse 
events and infusion-related reactions throughout 
the clinical trial. 
Abbreviations: Anti-AGA=antiagalsidase antibodies; AGA BETA BS=Agalsidase Beta Biosidus; BPI=Brief 
Pain Inventory; BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; Lyso-
Gb3=globotriaosylsphingosine; SF-36=36-Item Short Form Health Survey. 

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4.0 STUDY DESIGN 
4.1 
Overall Design 
This is a Phase III, prospective, multicenter, open-label, single-group, baseline-controlled, 
switch over clinical trial to evaluate the efficacy and safety of AGA BETA BS treatment in 
patients with FD already treated and previously stabilized with Fabrazyme. 
The planned clinical trial aims to establish the equivalence of AGA BETA BS to 
Fabrazyme®. 
A schema of the trial design is shown in Section 1.2. 
Approximately 20 participants aged ≥16 years and ≤60 years with FD who are receiving 
Fabrazyme® for at least 6 months, have received at least 80% of the prescribed dose during 
the last 3 months, and with disease status considered clinically stabilized at the Investigators’ 
discretion, will be enrolled in this trial.  
Screening will be performed between 35 to 42 days prior to the first dose of study 
experimental treatment. After all protocol-required safety laboratory tests (refer to 
Section 10.4), eligible participants will enter the study that comprises 2 periods: 
1. Lead-in period: all participants will receive 2 intravenous (IV) infusions of 
Fabrazyme®, provided by Biosidus, at a dose of 1 mg/kg of body mass, with 14 days 
between doses. The participant’s baseline status will be assessed at the end of this 
period. 
2. Treatment period: all participants will switch treatment to AGA BETA BS, 
administered at dose of 1 mg/kg of body mass, infused every 2 weeks as an IV 
infusion, for up to 54 weeks. Participants will receive a total of 27 infusions. 
During each infusion, participants will be monitored constantly to ensure prompt treatment for 
eventual IARs that could be presented. Prophylactic pretreatment with antihistamines to avoid 
IARs will be at the Investigator’s discretion during the study, except during the first 2 
infusions in period 2 in which administration will be compulsory. In addition, patients must 
remain in observation at the study center for at least 1 hour after each infusion during the first 
four AGA BETA BS infusions. In subsequent infusions, the center staff will contact each 
patient within 24 hours after infusion to check their clinical condition (refer to Section 6.8).  
 
 
Preferably, all infusions should be performed at the study sites. The population to be evaluated 
in this study is already being treated with Fabrazyme® and, in accordance with the clinical 

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practice for patients receiving ERT9, in most cases it is at home. To allow full participation in 
the study and to avoid a significant number of drop-outs, infusions may be administered at the 
participant's home after 4 infusions of AGA BETA BS at the site, at the discretion of the 
Investigator. Before making this decision, the Investigator must ensure that AGA BETA BS 
infusions can be safely, effectively and reliably administered at the participant's home. Among 
other requirements that the Investigator may consider, it is recommended that the participant 
meet at least the following main criteria: 
• The participant is considered medically stable. A comprehensive assessment must be 
completed prior to deciding on transfer of therapy. 
• The participant must have a proven pattern of well-tolerated infusions. 
• The participant must have a history of compliance with the prescribed infusion 
schedule. 
 
The study site personnel are required to contact the participant by phone call or message texts 
in 2 situations: (1) before each study appointment or visit, for all participants, and (2) within 
24 hours after infusion from the fifth infusion of AGA BETA BS. Refer to Section 8.1.5 for 
detailed information. 
The trial will last approximately 60 weeks (including a 5-week Lead-in period and a treatment 
period of up to 54 weeks) and will have 5 key medical visits. Participants will undergo visits 
and trial procedures as shown in Schedule of Activities (SoA) in Section 1.3. 
Refer to Section 10.3.5 for details on informed consent and to Section 10.3.11 for a definition 
of study start and a definition of “enrollment”. 
4.2 
Scientific Rationale for Study Design 
An open-label design was selected as all participants will switch Fabrazyme® for 
AGA BETA BS treatment. 
Standard statistical, clinical, and laboratory procedures will be utilized in this study. All 
efficacy and safety-related measurements in this study are standard for assessing disease 
activity in participants with FD. All clinical and laboratory procedures in this study are 
standard and generally accepted. 
This historical-controlled switch over design is the basis for rare disease trials due to the very 
limited pool of eligible patients to be studied, and follows that of 3 clinical trials using ERT 
treatment in participants with FD (NCT03180840, NCT03018730, and specially the Japanese 
Phase II/III bioequivalence trial for the first Fabrazyme® biosimilar drug –JR‑05116– 
approved in a highly regulated market, by Japan’s Ministry of Health, Labor, and Welfare in 
September 2018).The efficacy of AGA BETA BS will be measured by comparing the value of 

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the surrogate marker (Lyso-Gb3) at baseline - after at least 6 months of treatment with 
Fabrazyme® - compared to the value at 6 and 12 months of treatment with AGA BETA BS. 
This will be a paired comparison that maximizes the ability to detect variations in treatment 
efficacy.  
 
According to the FDA, in its document: "Rare Diseases: Common Issues in Drug 
Development Guidance for Industry 2019 Feb.", a historical control, is acceptable in two 
situations: (1) diseases where the course of the disease can be objectively verified and 
measured, and (2) in cases where concurrent controls are impractical.   
 
We consider that this study is framed in both situations for the following reasons:  
 
- 
Since FD is a low prevalence disease and considered rare (orphan), two-arm clinical 
trials are more complex, as it is very difficult to achieve a sufficient sample size (n).  
- 
Lyso-Gb3 is a verifiable and objective marker of disease course, widely accepted as a 
short-term follow-up parameter.17  
- 
Lyso-Gb3 also meets FDA surrogate marker criteria (1992 FDA's Accelerated 
Approval regulations).    
- 
This single arm design has already been used and approved by the regulatory agency 
in Japan16, where a formulation of agalsidase beta was shown to be biosimilar to the 
original formulation (also using a biomarker as an efficacy criterion). This biosimilar 
was approved by the regulatory agency at the end of the study, and is currently 
commercialized.  
- 
This design has also been used in the comparative study of agalsidase beta conducted 
in South Korea that led to the approval and commercialization of FABAGAL®18. 
 
Serum Lyso-Gb3 is a standard worldwide biomarker useful for both diagnosis and therapeutic 
evaluation of patients during ERT treatment, and therefore, comprises the primary endpoint in 
this trial. This primary endpoint is proposed as a surrogate endpoint that is reasonably likely to 
predict clinical benefit. A clinical benefit is a positive therapeutic effect that is clinically 
meaningful in the context of a given disease. For FD, a clinical benefit could be demonstrated 
by evaluation of the core disease progression manifestation (eg, renal failure, cardiovascular 
disease, cerebrovascular disease) but that may take many years, and, therefore, this type of 
evaluation may not be feasible in a clinical trial setting. In addition, it is unknown which 
phase of the disease may be most amenable to demonstrating a clinical impact of treatment, 
and so it is unknown if the most sensitive portion of the disease population is being studied in 
this trial. 
In fact, for rare diseases such as FD, the FDA recognizes that it can sometimes take many 
years to learn whether a drug actually provides a real effect on how a patient survives, feels, or 
functions. Mindful of the fact that it may take an extended period of time to measure a drug’s 
intended clinical benefit, in 1992 FDA instituted the Accelerated Approval regulations. These 

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regulations allowed drugs for serious conditions that filled an unmet medical need to be 
approved based on a surrogate endpoint. 
Furthermore, AGA BETA BS is being developed as a biosimilar product to Fabrazyme®. 
Fabrazyme® has already demonstrated acceptable clinical benefit and was approved by the 
most recognized regulatory agencies worldwide. Therefore, it would be scientifically 
unnecessary and unethical to submit participants to invasive tests (such as kidney biopsies) or 
require a long stay in a clinical trial setting. 
Although it is not recognized as a direct measure of clinical benefit, but rather a surrogate 
endpoint, the scientific literature has been suggesting that there is a direct correlation between 
high levels of Lyso-Gb3 and worse clinical outcomes.17 
4.3 
Justification for Dose 
In Argentina, EU, US, and many other countries, Fabrazyme® has received health authority 
approval for long-term ERT in patients with a confirmed diagnosis of FD. As a biosimilar 
product, the dose of AGA BETA BS selected for this trial is based on the clinically effective 
dose of the currently available dosage form of Fabrazyme®. 
The primary focus of this trial is to demonstrate equivalence of AGA BETA BS (proposed 
biosimilar to Fabrazyme®) with Argentina-licensed Fabrazyme®. The recommended dose of 
Fabrazyme®, administered as an IV infusion, is 1.0 mg/kg of body weight given once every 
2 weeks.8 Therefore, in this study, participants enrolled will receive AGA BETA BS 
1.0 mg/kg once every 2 weeks. 
4.4 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if he/she has completed all periods of 
the study including the last visit. 
4.5 
Study Stopping Criteria 
4.5.1 
Stopping Criteria for Individual Participants 
Criteria for discontinuing of study intervention for an individual participant and the criteria for 
discontinuing the study for an individual participant are presented in Section 7.0. 
4.5.2 
Criteria for Stopping the Study 
The Sponsor may terminate this study prematurely, either in its entirety or at any site. Refer to 
Section 10.3.11 for more information. 

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The Investigator may also stop the study at his/her site if he/she has safety concerns. If the 
Sponsor terminates the study for safety reasons, the Sponsor will promptly notify the 
Investigators, the Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs), 
the regulatory authorities, and any contract research organization(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. 

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5.0 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
Sex and Age 
1. Male or female participant with ≥16 and ≤60 years of age at the time of signing the 
informed consent form (ICF). 
Reproduction 
2. Female participants who are not pregnant, breastfeeding, donating eggs (ova, oocytes), or 
considering becoming pregnant during the study and for 3 months after the last dose of 
study treatment. 
3. All women of childbearing potential (WOCBP) must have a negative urine pregnancy test 
at the Screening visit and at Baseline visit (prior to the first dose of experimental 
intervention). 
4. WOCBP must use one highly effective form of birth control contraception through the 
study and for 3 months after the last dose of study treatment (refer to Appendix 1 in 
Section 10.1). 
5. Male participants who are not considering fathering a child during the study and for 
3 months after the last dose of study treatment. 
6. Male sexually active participant with female partner(s) of childbearing potential must 
agree to use male condoms during the study and for 3 months after the last dose of study 
treatment or have documented successful surgical sterilization. 
Informed Consent 
7. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
Type of Participant and Characteristics 
8. Confirmed previous diagnosis of FD. 
a) Women: preferably present genetic testing showing pathogenic GLA mutation 
consistent with FD at screening. 

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b) Men: preferably present leukocyte α-Gal A activity below normal range and/ or 
pathogenic GLA mutation consistent with FD at screening. 
c) Male with classic FD phenotype, female with classic FD and men with late onset may 
be included. 
9. Participants who have been on stable Fabrazyme® treatment for at least 6 months prior to 
Baseline visit.  
10. Patients that in the last 3 months before the baseline visit have been receiving ≥80% of 
Fabrazyme®’s labeled dose/kg, this calculation includes both infusions provided by 
Biosidus during the Lead-in period. 
11. Disease status considered clinically stabilized, at Investigators’ discretion. 
12. Estimated glomerular filtration rate (eGFR) ≥45 mL/minute/1.73 m2 by CKD-EPI 
equation at Screening visit. 
13. If receiving pain killers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II 
receptor blockers (ARBs), participants must be in a stable dose for ≥ 4 weeks. 
 
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Chronic kidney disease in stage 3b, 4, or 5. 
2. History of dialysis, kidney transplant or participants who are on the waiting list for a 
kidney transplant. 
3. Proteinuria ≥1 g/day at screening. 
4. Participants who have suffered a clinical cardiovascular event (such as but not limited to 
myocardial infarction, transient ischemic attack) within 6 months prior to Screening visit. 
5. Participants who have clinically significant unstable cardiac disease (such as but not 
limited to uncontrolled symptomatic arrhythmia, unstable angina, congestive heart failure 
New York Heart Association class III or IV). 
6. Participants who have suffered a clinical cerebrovascular event (such as but not limited to 
stroke, transient ischemic attack) within 6 months prior to Screening visit. 
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8. History of acute kidney injury in the 12 months prior to Screening visit (such as but not 
limited to acute interstitial nephritis, acute renal failure of glomerular origin or caused by 
vasculitis). 
9. Presence of any medical, emotional, behavioral, or psychological condition that, according 
to the Investigator, would interfere with the participant's compliance with the requirements 
of the study. 
Prior/Concomitant Therapy 
10. Treatment initiation or change of dose of ACE inhibitors or ARBs in the 4 weeks before 
the screening. 
Prior/Concurrent Clinical Trial Experience 
11. Current participation in an interventional study, in which the participant received any drug 
within 90 days before the Screening visit. 
 
5.3 
Lifestyle Considerations 
No lifestyle restrictions are required during any of the study periods. 
5.4 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study is 
not subsequently entered in the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened, at Investigator’s discretion. Rescreened participants should be assigned a new 
identification number for every screening/rescreening event. For rescreened participants, the 
same previously signed ICF should be used unless more than 30 days have passed since the 
first ICF was signed. In these cases, another ICF must be signed. 

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6.0 STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
6.1 
Study Intervention(s) Administered 
The study has a single-arm. First, all participants will receive 2 doses of Fabrazyme® with 
approximately 14 days between them, and afterwards all participants will switch treatment and 
receive AGA BETA BS for 54 weeks. Details of both medications are provided in Table 4. 
Table 4 
Study Intervention(s) Administered 
Intervention Label 
Fabrazyme® 
AGA BETA BS 
Intervention Name 
Recombinant human 
alpha-galactosidase A (agalsidase 
beta) 
Recombinant human alpha-galactosidase 
A (agalsidase beta) 
Intervention Description 
Agalsidase beta from Sanofi Genzyme Agalsidase beta from Biosidus 
Type  
Biological 
Biological 
Dose Formulation 
Lyophilized powder for reconstitution Lyophilized powder for reconstitution 
Unit Dose Strength(s) 
35 mg and/or 5 mg 
35 mg and/or 5 mg 
Dosage Level(s) 
1 mg/kg of body mass every 2 weeks 1 mg/kg of body mass every 2 weeks 
Route of Administration 
IV infusion 
IV infusion 
Use 
Lead-in intervention/background 
intervention (study period 1) 
Experimental intervention (study period 
2) 
IMP and NIMP/AMP 
IMP 
IMP 
Sourcing 
Provided centrally by the Sponsor 
Provided centrally by the Sponsor 
Packaging and Labeling 
Study intervention will be provided in 
cartons containing 1, 5, or 10 
single-use glass vials with 35 mg or 
5 mg of agalsidase beta. 
Each carton will be labeled as 
required per country requirement. 
Study intervention will be provided in 
cartons containing 1, 5, or 10 single-use 
glass vials with 35 mg or 5 mg of 
agalsidase beta. 
Each carton will be labeled as required 
per country requirement. 
Abbreviations: AMP=auxiliary medicinal products; IMP=investigational medical product; IV=intravenous; 
NIMP=noninvestigational medical product. 
6.2 
Preparation, Handling, Storage, Administration and Accountability 
6.2.1 
Packaging and Labeling 
The study interventions will be provided by the Sponsor in sufficient quantity to supply the 
treatment of all participants included in the trial. 

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Each carton of study intervention will be labeled per local requirements and this label must 
remain affixed to the carton. Upon receipt, study treatment should be stored as specified on 
the label and kept in a secure location. The two investigational drugs (Fabrazyme® and 
AGA BETA BS) will be distinguishable. Study intervention will only be used for the conduct 
of this study. 
6.2.2 
Storage and Accountability 
Both investigational drugs must be stored at 2°C to 8°C (36°F to 46°F). All investigational 
product provided by the Sponsor must be stored according to the storage conditions on the 
clinical label. The investigational products are for investigational use only and are to be used 
only within the context of this study. The study treatment supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label until 
dispensed for participant use or returned to the Sponsor, as appropriate. The Investigator or 
designee must confirm appropriate temperature conditions have been maintained during 
transit for all study treatment received, and any discrepancies are reported and resolved before 
use of the study treatment. 
Only participants enrolled in the study may receive study intervention, and only authorized 
study site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized study site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
The Investigator, a member of the study site staff, or the institution’s pharmacist must 
maintain an adequate record of the receipt and distribution of all study intervention using the 
Drug Accountability Form. These forms must be available for inspection at any time. 
All unused study interventions must be returned to the Sponsor at the end of the trial in 
accordance with current legislation. 
6.2.3 
Reconstitution and Administration 
Guidance about reconstitution and dose preparation for Fabrazyme® and AGA BETA BS and 
the necessary materials for the infusion are provided in Appendix 2 (Section 10.2). 
For both investigational drugs, the initial IV infusion rate will be no more than 
0.25 mg/minute (15 mg/hour). The infusion rate may be slowed in the event of IARs. After 
participant tolerance to the infusion is well established, the infusion rate may be increased 
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subsequent infusion. For participants weighing ≥30 kg, the administration duration should not 
be less than 1.5 hours (based on individual participant tolerability). 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
This is a nonrandomized, open-label study. There are no stratification factors in this study. 
At the Screening visit, all participants who consent will be assigned a unique identification 
number using a trial supply management system. For participants who do not meet the study 
selection criteria, the site personnel must log on to the system and identify the participant as a 
screen failure. Each participant will be assigned only one identification number. Identification 
numbers must not be reused for different participants. Rescreened participants should be 
assigned a new identification number for every screening/rescreening event. 
Participants who are enrolled will retain their identification numbers assigned at the Screening 
visit throughout the study. Upon receipt of study treatment, the site will acknowledge receipt 
in the system. 
6.4 
Study Intervention Compliance 
Participants will be dosed at the study site, directly from the Investigator or designee. The date 
and time of start of each infusion, as well as the dose and total volume infused, will be 
recorded in the source documents. 
The prescribed dosage, timing, and mode of administration may not be changed. Any 
departures from the intended regimen must be recorded in the electronic case report form 
(eCRF). 
Noncompliance is defined as taking less than 80% of study treatment during any evaluation 
period (visit to visit). 
6.5 
Participants showing poor compliance as assessed by appointments 
and/or visits attendance for their drug infusions must be counseled on 
the importance of good compliance to the trial dosing regimen.Dose 
Modification 
Dose modifications are not planned or allowed in this study. 
Any dose deviation must be recorded in the eCRF. 
In the event of a life-threatening reaction, including anaphylactic or severe allergic reactions, 
AGA BETA BS will be discontinued, and necessary emergency treatment will be initiated. 

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6.6 
Continued Access to Study Intervention After the End of the Study 
Following ANMAT Disposition Nº6677/10, the Sponsor will grant participants who have 
completed all the study visits and interventions, including all the AGA BETA BS IV 
infusions, access to the intervention that has been beneficial and medical follow-up, according 
to individual medical judgment, or to an alternative intervention until access to it is guaranteed 
by any other means. 
6.7 
Treatment of Overdose 
The Sponsor does not recommend specific treatment for an overdose. There have been no 
reports of overdose with agalsidase beta. In clinical trials, participants received doses up to 
3.0 mg/kg body weight. 
In the event of an overdose, the Investigator should: 
• Contact Biosidus’ pharmacovigilance department immediately. 
• Evaluate the participant to determine, in consultation with the Biosidus’ 
pharmacovigilance department, whether study intervention should be interrupted or 
whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically (at least 12 hours). 
• Document the quantity of the excess dose as well as the duration of the overdose. 
6.8 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded on the eCRF along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
• For vaccines (if applicable) include brand name and manufacturer (plus lot number, if 
available) 
The participant will receive a diary to record any concomitant medication that he or she may 
use during the study. The delivery of the diary to the participant and its collection for 
evaluation is described in the SoA (Section 1.3). The participant must be instructed to take the 
diary with them to each medical visit and each infusion appointment for evaluation. All 
information collected in the diary must be recorded on the eCRF. 
Any questions regarding concomitant or prior therapy should be raised to the Sponsor’s 
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Non-investigational pretreatment with antihistamine will be administered to avoid IARs at the 
Investigator’s discretion in period 1 but will be compulsory during the first 2 infusions in 
period 2. The antihistamine pretreatment will also be at Investigator’s discretion on the 
following infusions. This medication will be provided by Biosidus to study sites and is 
described in Table 5. When used, the antihistamine medication must be recorded as 
concomitant medication. 
Table 5 
Noninvestigational Antihistaminic Pretreatment 
Drug Name 
Loratadine 
Study Treatment Name: 
Loratadine 
Type 
Drug 
Dosage Formulation: 
Tablet 
Unit Dose Strength(s)/Dosage Level(s): 
10 mg 
Route of Administration 
Oral 
Dosing Instructions: 
1 tablet 1-2 hours before infusions 
Packaging and Labeling 
As required per country requirement 
Manufacturer 
Any approved and commercially available 
formulation will be used 
Other medications such as antipyretic and/or corticosteroid may be administered at the 
Investigator’s discretion to avoid or manage IARs in participants who had experienced them 
during agalsidase beta treatment or those who developed them during the trial. The selection 
of pretreatment medication and dose should be based on the participant’s age, weight, and 
severity of the reaction. The time of administration should be based on the onset of action of 
the medication selected. All medications administered as pretreatment or to manage IARs 
must be recorded as concomitant medication on the eCRF. 
6.8.1 
Prohibited and Allowed Concomitant Medications 
There are no prohibited medications during the trial. However, use of drugs that increase 
thrombosis risk, such as contraceptives, should be made with special caution and after a risk 
benefit assessment performed by the Investigator in each case, since they may theoretically 
additionally increase the risk of transient ischemic attack/cerebrovascular accident in females 
with FD. 
Vaccination with live vaccines while on study is prohibited. Administration of inactivated 
vaccines is allowed (eg, inactivated influenza vaccines or severe acute respiratory syndrome 
coronavirus 2 vaccines). 
Antiproteinuric drugs and pain killers are allowed as long as they haven't been started or the 
dose changed in the 4 weeks before screening (refer to inclusion criterion number 12 and 

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exclusion criteria number 10). Dose adjustments in these medications must be reported to the 
Investigator and recorded in the eCRF. 
6.8.2 
Rescue Medicine 
There is no rescue medication planned for this study. 
If the participant is presenting a failure of expected pharmacological action and the disease 
progression or signs or symptoms of disease progression are more severe than expected for the 
participant’s condition under treatment, will be left to the Investigator’s discretion whether the 
participant should be discontinued from the clinical trial and go back to his or her former 
treatment. 
In the presence of clinically significant changes or biochemical modifications of the Lyso-Gb3 
biomarker, each investigator must distinguish if the observed changes are still related to the 
natural history of disease or to an eventual lack of efficacy. In such case, the investigator will 
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7.0 DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Discontinuation of specific study sites or of the study as a whole are detailed in 
Section 10.3.11. 
7.1 
Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue study intervention. If study 
intervention is permanently discontinued, the participant will remain in the study but instead 
of following the sequential procedures established in the SoA, he/she will only receive 
telephone follow-up, if he/she agrees, at the same planned timepoints to evaluate his or her 
general condition. See the SoA in Section 1.3 for data to be collected at the time of 
discontinuation of study intervention and follow-up and for any further evaluations that need 
to be completed. 
Participants will discontinue study intervention if any of the following occur: 
• Eligibility criteria violation was noted after the participant started study treatment. In that 
case, the Sponsor, or Sponsor designee, must be contacted. An exception may be granted 
in rare circumstances for which there is a compelling safety reason to allow the participant 
to continue with study intervention. In these rare cases, the Investigator must obtain 
documented approval from the Sponsor, or Sponsor designee, to allow the participant to 
continue with study intervention. 
• Participant is significantly noncompliant with study procedures which would put the 
participant at risk for continued participation in the study. 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued study 
treatment. 
• Clinically significant changes or biochemical modifications of the Lyso-Gb3 biomarker, 
that, at the Investigator's discretion, represent a lack of efficacy of the investigational 
product. 
Participants who discontinue study intervention might be replaced. 
7.1.1 
Temporary Discontinuation 
Temporary discontinuations (ie, dose delays or interruptions) are not allowed in this study 
unless in case of clinical signs of infection (coronavirus disease 2019 [COVID-19] or not), in 
which the participant must wait for clinical recovery (ie, 48 hours being afebrile) to receive 
the infusions. If clinical recovery is not established when an infusion is scheduled, the dose 
must be delayed, and the infusion delay and its reason must be recorded in the eCRF. 

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7.2 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, lack of efficacy, 
behavioral, noncompliance, or administrative reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted, as shown in the SoA (Section 1.3). See SoA for data to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need to be 
completed. The participant will be permanently discontinued from the study intervention and 
the study at that time. 
Participants who become pregnant during the study will be discontinued from the study and 
will be followed as described in Section 8.4.5. 
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the study site study records. 
Should a participant request or decide to withdraw from the study, all efforts must be made to 
complete and report the observations as thoroughly as possible up to the date of withdrawal. 
Participants withdrawing due to an AE should be followed up as provided in Section 8.4.3. 
Participants who voluntarily withdraw are termed dropouts. Dropouts and participants 
withdrawn due to protocol violations may be replaced following discussion with the 
Investigator and Sponsor. 
Participants withdrawn due to an AE might be replaced. Data collected from the replaced 
participants will be used. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit or appointment: 
• The study site must attempt to contact the participant and reschedule the missed 
visit/appointment as soon as possible, counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain whether the participant wishes to 
and/or should continue in the study. 

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• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, 
message texts, and if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
• Study site personnel, or an independent third party, will attempt to collect the vital status 
of the participant within legal and ethical boundaries for all participants randomized, 
including those who did not get study intervention. Public sources may be searched for 
vital status information. If vital status is determined as deceased, this will be documented 
and the participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 

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8.0 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers 
or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention. 
Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening purposes provided 
the procedures met the protocol-specified criteria and were performed within the timeframe 
defined in the SoA (Section 1.3). 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 240 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. 
The order of each procedure will be determined by the study site. However, when multiple 
procedures are scheduled at the same day, they all need to be performed before the infusion 
takes place. 
8.1 
General Assessments 
8.1.1 
Inclusion and Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee 
at Screening visit. 
For participants whose blood and urine samples are collected for laboratory tests at the 
Screening visit, the inclusion and exclusion criteria must be reassessed as soon as the results 
are available, prior to the first Fabrazyme® infusion. 
At Baseline visit, all inclusion and exclusion criteria will be reviewed to ensure that the 
participant qualifies for the study, especially the inclusion criterion 10 where the 2 

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Fabrazyme® infusions administrated on the Lead-in period will be included in the time 
calculation for the assessment of dose stability. 
8.1.2 
Assignment of an Identification Number 
All participants who consent will be given a unique identification number that will be used to 
identify the participant for all procedures that occur during the study. Each participant will be 
assigned only 1 identification number. Identification numbers must not be reused for different 
participants. 
8.1.3 
Demographics 
Demographics and baseline characteristics will be evaluated at Screening visit and include 
age, gender, race, ethnicity (Hispanic or Latin origin), body weight, height, BMI, and general 
medical history. 
8.1.4 
Medical History 
A complete medical history, including history of endocrine, neurological, cardiovascular, 
renal, pulmonary, immunologic and dermatology disorders, along with a history of illicit 
drugs, alcohol, and tobacco use will be obtained by the Investigator or qualified designee. 
Special attention should be given to the medical-related inclusion and exclusion criteria 
(Section 5.1 and 5.2). 
The documented confirmed diagnosis of FD, if available, will be reviewed by the Investigator 
or qualified designee for all participants and recorded in the eCRF. 
8.1.5 
Phone Calls or Text Messages 
The study site personnel will contact the participant by phone call or text message in 
2 situations: 
• For all participants, 24 to 48 hours before each study appointment or visit to check on 
symptoms compatible with COVID-19 or other infection. If suspected or positive 
infection, to receive the infusions the participants must wait for clinical recovery, ie, 48 
hours being afebrile. Refer to Section 7.1.1. 
• From the fifth infusion of AGA BETA BS onwards, within 24 hours after infusion to 
check the patient’s clinical condition. 
All contact attempts, whether calls or text messages, must be recorded in the source 
documents. 
8.2 
Efficacy Assessments 
The following assessments will be made at the time points indicated in the SoA (see 
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8.2.1 
Serum Lyso-Gb3 Marker 
Serum Lyso-Gb3 levels will be assessed by a central laboratory using standardized and 
validated methods in addition to applicable calibrated equipment. 
8.2.2 
Brief Pain Inventory-Short Form 
Pain severity and impact of pain on daily functions will be assessed by Brief Pain Inventory 
(BPI)-short form questionnaire. 
The BPI-short form is a self-report measure that has, over time, become a standard for the 
assessment of pain and its impact. The BPI-short form uses a 24-hour recall period for 
9 questions: 
• Questions number 1 and 2 are about existence and location of pain. 
• Questions number 3 to 6 correspond to pain severity items (pain rated on 0 - 10 scales at 
its “worst”, “least”, “average”, and “now”). 
• Questions number 7 and 8 are about medications and amount of pain relief. 
• Question 9 is divided into 7 others (from A to G), which correspond to pain interference 
items (rated on 0 - 10 scales how much pain has interfered with general activity, walking 
ability, normal work, mood, enjoyment of life, relations with others, and sleep). 
Despite the participant answering the questionnaire in full, the questions 1, 2, 7, and 8 will not 
be evaluated as an endpoint in this trial. 
Sufficient copies of the questionnaire in the Spanish language will be provided to the study 
sites by the Sponsor. Participants should be instructed to complete the entire questionnaire at 
the site, when applicable. The Investigator must present the questionnaire to the participant, 
explain its purpose, give the participant time to read the questionnaire, and ensure that the 
participant understands how to respond. Immediately after filled, the questionnaire must then 
be reviewed by study site personnel to ensure that all questions have been properly answered. 
If partial completion is detected, study site personnel must return the same questionnaire to the 
participant to have it fully completed. 
8.2.3 
36-Item Short Form Health Survey 
The 36-Item Short Form Health Survey (SF-36) is an often-used, well-researched, self-
reported measure of a person's quality of life. It comprises 36 questions which cover 8 
domains of health: 
1. Limitations in physical activities because of health problems 
2. Limitations in social activities because of physical or emotional problems 
3. Limitations in usual role activities because of physical health problems 
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5. General mental health (psychological distress and well-being) 
6. Limitations in usual role activities because of emotional problems 
7. Vitality (energy and fatigue) 
8. General health perceptions 
Sufficient copies of the questionnaire in the Spanish language will be provided to the study 
sites by the Sponsor. Participants should be instructed to complete the entire questionnaire at 
the site, when applicable. The Investigator must present the questionnaire to the participant, 
explain its purpose, give the participant time to read the questionnaire, and ensure that the 
participant understands how to respond. Immediately after filled, the questionnaire must then 
be reviewed by study site personnel to ensure that all questions have been properly answered. 
If partial completion is detected, study site personnel must return the same questionnaire to the 
participant to have it fully completed. 
8.3 
Safety Assessments 
8.3.1 
Physical Examinations 
Physical examinations will be performed at the time points indicated in the SoA (see 
Section 1.3). In addition, a symptom-directed physical examination can be performed at any 
time as deemed necessary by the Investigator. 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height will be 
measured and recorded at Screening visit only. Weight will be measured and recorded at each 
visit and infusion appointment. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Physical examination abnormalities noted at the Screening visit prior to the first dose of study 
intervention should be recorded in the participant’s medical history. Any significant physical 
examination findings after the first dose of study intervention will be recorded as AEs. 
8.3.2 
Vital Signs 
Vital signs measurements will be performed at time points indicated in the SoA (see 
Section 1.3). 
Body temperature, heart rate, respiratory rate, and blood pressure (systolic and diastolic) will 
be assessed. 
For all measurements including before and hourly during the infusions, blood pressure, heart 
rate, and respiratory rate will be assessed in a sitting position after 5 minutes rest for the 
participant in a quiet setting without distractions (eg, television, cell phones), with a device 
previously calibrated or as determined by the manufacturer. 

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Three readings of blood pressure and heart rate will be taken. The first reading should be 
rejected. The second and third readings should be averaged to give the measurement to be 
recorded. 
8.3.3 
Electrocardiograms 
Single 12-lead electrocardiogram (ECG) will be obtained as outlined in the SoA (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. In case  there are no automatic electrocardiographs in the 
study center, calculations may be performed manually. The ECG will be performed as part of 
routine cardiac safety monitoring of participants. 
ECGs will be acquired after the participant has been in either the supine or semi supine 
position (the same position will be consistently used during ECG collections) for at least 
5 minutes. Participants will be instructed to remain completely stationary (no talking, 
laughing, deep breathing, sleeping, or swallowing) during the ECG recording. While ECGs 
are being acquired, electrical devices (such as cellular telephones, fans, heaters, etc) that emit 
electrical interference in the room must be turned off or removed from the room to the extent 
that is possible. 
This exam will be taken at the study sites. The original ECG traces and variables must be 
stored in the participants’ medical records as source data. The Investigator or designee will 
evaluate the ECG from a clinical perspective and the result (whether the ECG result is normal 
or abnormal) will be recorded on the appropriate section of the eCRF and on the ECG trace 
signed and dated by Investigator or designee. If the result is abnormal, the Investigator or 
designee will provide further information (eg, sinus bradycardia, arrhythmia). 
8.3.4 
Echocardiograms 
Two-dimensional transthoracic echocardiogram will be obtained as outlined in the SoA (see 
Section 1.3), to estimate the thickness of the left ventricular wall, left ventricular mass, and 
left ventricular ejection fraction. The echocardiogram will be performed as part of routine 
cardiac safety monitoring of participants. 
This exam will be taken and evaluated at the study sites, if available, or at a local diagnostic 
laboratory by an appropriately trained physician, preferably a cardiologist. 
In case the echocardiogram be performed outside of study site, the exam will have a window 
of ±2 days to be performed, except for the test scheduled for the Screening visit that only a 
+2 days will be allowed. For example, for a participant with a 3-month study visit scheduled 
for Day 100, the echocardiogram needs to be performed from Day 98 to Day 102 (even if the 
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The Investigator or designee will evaluate the echocardiogram from a clinical perspective and 
the result (whether the result is normal or abnormal) will be recorded on the appropriate 
section of the eCRF. If the result is abnormal, the Investigator or designee will provide further 
information. The original echocardiographic report must be stored in the participants’ medical 
records as source data. 
8.3.5 
Clinical Safety Laboratory Tests 
Clinical laboratory assessments will be performed at time points indicated in the SoA 
(Section 1.3). Section 10.4 presents the list of clinical laboratory tests to be performed. 
Local laboratories will be utilized to process and provide results for clinical laboratory tests. 
The Investigator or designee must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study as an AE. The laboratory 
reports must be filed with the source documents. 
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the Investigator to be more severe than expected for the 
participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the Investigator. 
If clinically significant values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor notified. 
All protocol-required laboratory tests, as defined in Section 10.4, must be conducted in 
accordance with the laboratory manual and the SoA (Section 1.3). 
If laboratory values from nonprotocol-specified laboratory tests performed at the institution’s 
local laboratory require a change in participant management or are considered clinically 
significant by the Investigator (eg, SAE or AE or dose modification), then the results must be 
recorded. 
8.3.6 
Anti-algasidase Antibodies 
Antibodies to AGA BETA BS will be evaluated in serum samples collected from all 
participants according to the SoA (Section 1.3), by a central laboratory. Additionally, serum 
samples should also be collected at the final visit from participants who discontinued study 
intervention or were withdrawn from the study. 
Serum samples will be screened for antibodies binding to AGA BETA BS and the titer of 
confirmed positive samples will be reported. Other analyses may be performed to verify the 
stability of anti-AGA and/or further characterize the immunogenicity of AGA BETA BS. 

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The detection and characterization of anti-AGA will be performed using a validated assay 
method by a central laboratory. Samples may be stored for the maximum period of time 
according to local regulations following the last participant’s last visit for the study at a 
facility selected by the Sponsor to enable further analysis of immune responses to AGA 
BETA BS. 
8.3.7 
Pregnancy Testing 
Women of childbearing potential should only be included after a negative highly sensitive 
urine pregnancy test at Screening visit and at Baseline visit (prior to the first dose of 
experimental treatment). 
Additional pregnancy testing should be performed every 4 weeks in WOCBP. If there is no 
protocol visit scheduled in that period, the urine pregnancy test will be arranged in the closest 
infusion appointment. 
Also, pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
Pregnancy testing will be performed using the test kit approved by the Sponsor and in 
accordance with instructions provided in its package insert. 
8.4 
Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of AEs and SAEs can be found in Section 10.5. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative) to the Investigator or delegate, 
and by the Investigator or delegate to the Sponsor. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up all AEs. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.5. 
8.4.1 
Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Event Information 
All AEs and SAEs will be collected from the signing of the ICF until the last visit, at the time 
points specified in the SoA (Section 1.3). 
The participant will receive a diary to record any AE that may occur during the study. The 
delivery of the diary to the participant and its collection for evaluation is described in the SoA 
(Section 1.3). The participant must be instructed to take the diary with them to each medical 

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visit and each infusion appointment for evaluation. All information collected in the diary must 
be recorded on the eCRF. 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded as medical history/current medical conditions, not as AEs. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of the Investigator’s awareness of the event, as 
indicated in Section 10.5. The Investigator will submit any updated SAE data to the Sponsor 
or designee within 24 hours of their awareness of the updated information. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation. However, if the Investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 
event/cause of death to be reasonably related to the study intervention or study participation, 
the Investigator must promptly notify the Sponsor or designee. 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting safety reports are provided in Section 10.5. 
8.4.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs and SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.5. 
8.4.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Board (IRBs)/IECs, and Investigators. 

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An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
8.4.5 
Pregnancy 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until 3 months after last 
dose of study intervention. 
If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor or designee within 24 hours of learning of the 
female participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) pregnancy and should follow the procedures 
outlined in Section 10.5. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication (or 
elective termination) for medical reasons will be reported as an AE or SAE. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus, stillbirth, or neonatal death]) the Investigator will report according to the SAE 
reporting procedures described in Section 10.5. 
The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy until delivery of baby. The Investigator will collect follow-up information on the 
participant/pregnant female partner and the neonate, and the information will be forwarded to 
the Sponsor or designee. In the event of pregnancy occurring in a participant’s partner during 
the study, written informed consent from the partner must be obtained prior to collection of 
any such information. The Sponsor will provide a separate consent form for this purpose. 
Any poststudy pregnancy-related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as described in Section 8.4.4. While the 
Investigator is not obligated to actively seek this information in former study 
participants/pregnant female partner, he or she may learn of an SAE through spontaneous 
reporting. 
Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 

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8.4.6 
Infusion-associated Reactions 
In the event of a suspected IAR, the infusion should be stopped, close observation should be 
initiated, management should be initiated at the Investigator’s discretion, and institutional 
standard support care should also be administered. 
Premedications such as nonsteroidal anti-inflammatory drugs, antipyretics, antihistamines 
and/or corticosteroids may be used to manage an IAR, at the Investigator’s discretion. A 
decrease in infusion rate should also be considered upon reinitiation or subsequent infusions. 
If the infusion proceeds without incident, consideration may be given to increasing infusion 
rates in a stepwise manner and to reducing premedication. 
All IAR will be recorded as an AE in the eCRF. An IAR can be serious or nonserious and will 
be reported as detailed in Section 10.5. 
8.4.7 
Adverse Events of Special Interest 
Adverse events will be monitored throughout the study to identify any of interest that may 
indicate a trend or risk to participants. There is no adverse event of special interest defined for 
this study. 
8.5 
Pharmacokinetics 
Pharmacokinetics parameters are not evaluated in this study. 
8.6 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7 
Genetics 
Genetics are not evaluated in this study. 
8.8 
Biomarkers 
Biomarkers other than the primary endpoint (serum Lyso-Gb3, Section 8.2.1) are not 
evaluated in this study. 
8.9 
Immunogenicity Assessments 
Antibodies other than the safety endpoint (anti-AGA, Section 8.3.6) are not evaluated in this 
study. 
8.10 Health Economics 
Health economics parameters are not evaluated in this study. 

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9.0 STATISTICAL CONSIDERATIONS 
The statistical analysis plan (SAP) will be finalized prior database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.1 
Statistical Hypotheses 
The null hypotheses and alternative hypotheses to be tested in the primary analysis are: 
H0: Ratio of Plasma level of Lyso-Gb3 marker at week 26 and plasma level of the marker 
LysoGb3 at baseline is less than 80% or greater than 125%. This means that there is a 
difference between AGA BETA BS (Test) and Fabrazyme® (Reference) after 6 months. 
H1: Ratio of Plasma level of Lyso-Gb3 marker at week 26 and plasma level of the marker 
Lyso-Gb3 at baseline is in between 80% and 125%. This means that there is no difference 
between AGA BETA BS (Test) and Fabrazyme® (Reference) after 6 months. 
9.1.1 
Multiplicity Adjustment 
Not applicable. 
9.2 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Intent To Treat (ITT) set: Intent To Treat will include all participants who are part of the 
Lead-in period. The ITT population will be used for efficacy analyses. 
Safety Set: Safety population will include all participants who receive at least one dose of 
study treatment (AGA BETA BS). The Safety population will be used for all safety analyses. 
Per Protocol (PP) set: Per Protocol set will include all participants who satisfactorily 
complete the study and comply with the requirements of the protocol. It is a subset of the ITT 
population without any major protocol deviations. The PP population will be used for 
exploratory efficacy analyses. Final determinations of the PP population will be made at the 
data review meeting before database lock. 
9.2.1 
General Considerations 
All data listings, summaries, and analyses will be performed under the guidance and approval 
of the Sponsor. The SAP will be developed and finalized before database lock and will 
describe the participant analysis sets to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. 

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The analysis of complete data for the study will be performed when all the participants have 
either completed the study or discontinued early from the study, all data from the study are in 
the database, and the database is locked. 
All data collected in the clinical database will be presented in participant data listings. 
Detailed methodology about summary and statistical analysis of the data collected in this 
study will be given in the SAP which will be finalized prior to the database lock. 
All analyses, summaries, and listings will be performed using SAS® software (version 9.4 or 
higher) unless otherwise noted. All details regarding the statistical analysis and the preparation 
of tables, listings and figures will be described in the SAP. The following descriptive statistics 
will be used as applicable to summarize the study data unless otherwise specified: 
• Continuous variables: number of observations sample size (n), mean, standard 
deviation (SD), median, minimum, and maximum. 
• Categorical variables: frequencies (number) and percentages (the percentage of 
participant in each category relative to the total number of participants in the relevant 
analysis set or relative to the total number of participants in the relevant analysis set, 
with assessments available [where appropriate]) in each category will be the default 
summary presentation. 
Baseline definition: Unless otherwise specified, baseline is defined as the last observed value 
of the parameter of interest prior to the first intake of AGA BETA BS (this includes 
unscheduled visits). 
Any assessment collected prior to intake of AGA BETA BS will be part of Lead-in period. 
9.2.2 
Primary Endpoint(s) Analysis 
The primary efficacy analysis will aim to demonstrate the equivalence in efficacy based on the 
mean serum Lyso-Gb3 marker ratio after 26 weeks of treatment, considering plasma level of 
the marker Lyso-Gb3 after 26 weeks divided by plasma level of the marker Lyso-Gb3 at 
baseline. 
A paired t-test will be fit to the log-transformed change from baseline to after 26 weeks of 
treatment mean plasma Lyso-Gb3 marker. 
Mean change from baseline of serum Lyso-Gb3 for after 26 weeks of treatment will be 
calculated and a 95% confidence interval (CI) for the difference will be computed. The mean 
change from baseline and its CI will be exponentiated to obtain the ratio of the means between 
after 26 weeks of treatment and baseline and its CI. Equivalence will be determined if the 95% 
CI for the postbaseline and baseline ratio lies completely within the range 0.80 to 1.25. 

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Analysis will be performed based on both ITT and PP populations. Descriptive statistics will 
be presented overall. 
Table 6 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
• The primary efficacy variable will be analyzed using a paired t-test. 
• Mean change from baseline of serum Lyso-Gb3 after 26 weeks of 
treatment will be calculated and a 95% CI for the difference will be 
computed. 
• Equivalence will be declared if the 95% CI for the postbaseline and 
baseline ratio is entirely contained within the prespecified equivalence 
margin of 80% to 125%. 
• Analysis will be performed based on ITT and PP. 
Secondary 
• Mean serum Lyso-Gb3 marker ratio after 54 weeks of treatment will be 
analyzed in an analogous way to the primary endpoint. 
• For the other continuous secondary efficacy variables: the pain severity 
score and the pain interference score - change from baseline at each 
scheduled assessment will be presented in a descriptive statistics 
manner. 
• Also, the change in health perception before and after treatment with 
AGA BETA BS in participants with Fabry disease previously stabilized 
with Fabrazyme® will be measured by the SF-36 at each scheduled 
assessment. 
Exploratory 
Will be described in the SAP finalized before database lock. 
Abbreviations: CI=confidence interval; Lyso-Gb3=globotriaosylsphingosine; ITT=Intent to Treat; PP=Per 
Protocol; SF-36=36-Item Short Form Health Survey. 
9.2.3 
Secondary Endpoint(s) Analysis 
Mean serum Lyso-Gb3 marker ratio after 54 weeks of treatment will be analyzed in an 
analogous way to the primary endpoint. Analysis will be based on both ITT and PP 
populations. 
Change from baseline in pain severity and pain interference will be assessed through 
BPI-short form pain severity and pain interference items scores respectively. The change from 
baseline value will be described after 26 weeks and 54 weeks of treatment, using the n, mean, 
SD, median, minimum value, and maximum value based on the ITT population. 
The change in health perception before and after treatment with AGA BETA BS in 
participants with FD previously stabilized with Fabrazyme® will be measured by the SF-36. 
For this, change from baseline will be calculated and described using descriptive statistics (n, 
mean, SD, median, minimum value, and maximum value) at week 26 and week 54. 

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9.2.4 
Pharmacokinetic/Pharmacodynamic Analyses 
Not applicable. 
9.2.5 
Safety Analyses 
For laboratory parameters and other safety variables, both the actual value and the change 
from the baseline value will be summarized at each visit using the n, mean, SD, median, 
minimum value, and maximum value. 
Change from baseline, frequency counts and percentage as applicable after 14, 26, and 
54 weeks of treatment will be summarized for laboratory parameters including hematology, 
clinical chemistry, blood urea nitrogen, eGFR, urine albumin-creatinine ratio, electrolytes, and 
phosphate, from blood and urine samples collected. 
Change from baseline analyses after 26 weeks and 54 weeks of treatment will be summarized 
for cardiac function tests including electrocardiogram and bidimensional echocardiogram 
exams. 
For the immunogenicity variable, anti-AGA levels from blood samples will be analyzed at 
baseline, after 14, 26, and 54 weeks of treatment, and will be summarized by counts and 
percentages. 
Physical assessments, AEs and IARs will be summarized by frequency counts and percentage. 
Duration of exposure to investigational product and number of injections will be summarized 
descriptively by treatment group. 
For all safety and immunogenicity variables, no formal statistical analysis will be performed. 
All safety analyses will be performed on the Safety Analysis Set. 
9.2.6 
Other Analyses 
Not applicable. 
9.3 
Interim Analysis 
No interim analysis is planned. 
9.3.1 
Sample Size Reevaluation 
A sample size re-estimation is planned to be carried out when 50% of the total number of 
participants is reached. The objective is to recalculate the sample size according to the pooled 
variability (% coefficient of variation) observed so far. 

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9.4 
Sample Size Determination 
For the sample size calculation, the coefficient of variation of GL3 was estimated as 0.2, and 
the equivalence acceptance range was 20% (80% to 125%). Based on these values, the 
required sample size to detect equivalence with 95% confidence intervals, with a type I error 
of 5% and a power of 80%, was calculated as approximately 16 participants. Accounting for 
possible early termination, we therefore set a dropout rate of 20%, elevating the sample size to 
20 participants. 
The sample size of 16 is considered appropriate based on the prevalence of the disease under 
study and it is like previous clinical trial that evaluated a Fabrazyme® biosimilar drug.16 
Nevertheless, a sample size re-estimation is planned to be carried out as described in 
Section 9.3.1. 

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10.0 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Contraceptive and Barrier Guidance and Collection of 
Pregnancy Information 
10.1.1 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
a) Documented hysterectomy. 
b) Documented bilateral salpingectomy. 
c) Documented bilateral oophorectomy. 
NOTE: Documentation can come from the study site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female: 
a) A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
b) Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the non estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
10.1.2 
Contraception Guidance 
Male participants 
• Male participants with female partners of childbearing potential are eligible to participate 
if they agree to one of the following during the study: 
o Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent for the 
duration of the study and for 3 months after study last dose. 

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o Agree to use a male condom and have their partner use a contraceptive method with a 
failure rate of <1% per year as described in Table 7 when having penile-vaginal 
intercourse with a WOCBP who is not currently pregnant. 
• Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the study. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the 
Table 7. 
Table 7 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation 
• 
Oral. 
• 
Intravaginal. 
• 
Transdermal. 
• 
Injectable. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral. 
• 
Injectable. 
• 
Implantable. 
Highly Effective Methods That Are User Independenta  
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal occlusion. 
Vasectomized partner 
A vasectomized partner is a highly effective birth control method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.  
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.  
NOTES: 

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a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
Pregnancy testing: 
• Woman of childbearing potential should only be included after a negative highly sensitive 
urine pregnancy test. 
• Additional pregnancy testing should be performed at times specified in the SoA 
(Section 1.3) and as required locally. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
• Pregnancy testing will be performed using the test kit approved by the Sponsor and in 
accordance with instructions provided in its package insert. 
Collection of pregnancy information 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor or designee within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor or designee within 24 hours of learning of a 
participant’s pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor or designee. Generally, 
follow-up will not be required for longer than 6 to 8 weeks beyond the estimated delivery 
date. Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. If the outcome of the pregnancy meets the criteria for 

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immediate classification as an SAE (ie, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly [including that in an aborted fetus, stillbirth, or neonatal death]), the 
Investigator will report according to the SAE reporting procedures described in 
Appendix 5 (Section 10.5). 
• Any poststudy pregnancy-related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to the Sponsor or designee as described in 
Section 8.4.4.While the Investigator is not obligated to actively seek this information in 
former participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study and be followed in accordance with country’s current 
regulations. 
 
 

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10.2 Appendix 2: Reconstitution and Dose Preparation for Fabrazyme or 
AGA BETA BS 
Instructions 
• Vials are for single use only. 
• Excessive agitation of this product should be avoided. Do not use filter needles during the 
preparation of the infusion. 
• Prolonged exposure of Fabrazyme® or AGA BETA BS to the air/liquid interface, either 
through time or by agitation, may cause the formation of protein particles. 
The following items are suggested for the reconstitution and administration of Fabrazyme® or 
AGA BETA BS: 
• Fabrazyme® or AGA BETA BS (Vials) 
• Sterile Water for Injection, USP 
• 0.9% Sodium Chloride Injection, USP (Normal Saline) 
• Tape 
• Two syringes for reconstitution and dilution 
• Two needles 
• In-line low protein binding particulate filter (0.2 μm) 
• Administration set with flow-regulating device or IV infusion pump and tubing 
• IV kit 
• Anaphylaxis kit 
• Angiocatheter 
• Gloves 
• Alcohol wipes 
• Arm board 
• Medication label 
Reconstitution and dilution (using aseptic technique): 
1. Fabrazyme® or AGA BETA BS vials and diluent should be allowed to reach room 
temperature prior to reconstitution (approximately 30 minutes). The number of vials 
needed is based on the participant’s body weight (kg) and the recommended dose of 
1.0 mg/kg. Select the appropriate number of vials so that the total number of mg is equal 
to or greater than the participant’s number of kg of body weight. 
2. Reconstitution 
a) Reconstitute each 35 mg vial of Fabrazyme® or AGA BETA BS by slowly 
injecting 7.2 mL of Sterile Water for Injection, USP down the inside wall of each 
vial and not directly onto the lyophilized cake. Roll and tilt each vial gently. Do 
not invert, swirl, or shake the vial. Each vial will yield a 5.0 mg/mL clear, colorless 
solution (total extractable dose per vial is 35 mg, 7.0 mL). 

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b) Reconstitute each 5 mg vial of Fabrazyme® or AGA BETA BS by slowly 
injecting 1.1 mL of Sterile Water for Injection, USP down the inside wall of each 
vial and not directly onto the lyophilized cake. Roll and tilt each vial gently. Do 
not invert, swirl, or shake the vial. Each vial will yield a 5.0 mg/mL clear, colorless 
solution (total extractable dose per vial is 5 mg, 1.0 mL). 
3. Visually inspect the reconstituted vials for particulate matter and discoloration. Do not use 
vials exhibiting particulate matter or discoloration. Report lot number for vials exhibiting 
particulate matter or discoloration. 
4. After reconstitution, it is recommended to promptly dilute the vials. Failure to promptly 
dilute the vials could result in particle formation. 
5. Slowly withdraw the reconstituted solution from each vial and further dilute with 0.9% 
Sodium Chloride Injection, USP to a total volume based on participant weight specified 
in Table 8 below. To minimize the air/liquid interface, remove the airspace within the 
infusion bag prior to adding the reconstituted Fabrazyme® or AGA BETA BS. Be sure to 
inject the reconstituted Fabrazyme® or AGA BETA BS solution directly into the sodium 
chloride solution. Total infusion volumes as low as 50 mL have been used in a clinical 
trial. Discard any vial with unused reconstituted solution. 
Table 8 
Minimum Total Volume According to the Participant's Weight 
Participant Weight (kg) 
Minimum Total Volume (mL) 
≤35 
50 
35.1 – 70 
100 
70.1 – 100 
250 
>100 
500 
6. Gently invert infusion bag to mix the solution, avoiding vigorous shaking and agitation. 
Use immediately. 
7. Fabrazyme® or AGA BETA BS should not be infused in the same intravenous line with 
other products. 
8. The diluted solution should be filtered through an in-line low protein binding 0.2 μm filter 
during administration. 
Reconstituted and diluted solutions should be used immediately. The products contain no 
preservatives. If immediate use is not possible, the diluted solution may be stored for up to 24 
hours at 2 to 8°C (36 to 46°F). 
 
 

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10.3 Appendix 3: Regulatory, Ethical, and Study Oversight Considerations 
10.3.1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
international ethical guidelines 
• Applicable ICH GCP guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs, or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the study site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and 
all other applicable local regulations 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative. The study will not start at any study 
site at which the Investigator has not signed the protocol. 
10.3.2 
Adequate Resources 
The Investigator is responsible for supervising any individual or party to whom the 
Investigator delegates study-related duties and functions conducted at the study site. 

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If the Investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the Investigator/institution should ensure this individual or 
party is qualified to perform those study-related duties and functions and should implement 
procedures to ensure the integrity of the study-related duties and functions performed and any 
data generated. 
10.3.3 
Financial Disclosure 
Investigators and subinvestigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and after completion of the study. 
10.3.4 
Insurance 
Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the participants in this study, valid throughout the trial and 1 year after last 
participant finishes the trial. The terms of the insurance will be kept in the study files. 
10.3.5 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participant or their legally authorized representative and answer all 
questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy, and data protection 
requirements, where applicable, and the IRB/IEC or study site. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date. 

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10.3.6 
Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant who will be required to give consent for their data to be 
used as described in the informed consent. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.3.7 
Committees Structure 
This study does not have an independent safety monitoring committee. 
10.3.8 
Dissemination of Clinical Study Data 
The results of the study should be reported within 1 year from the end of the clinical study. 
Irrespective of the outcome, the Sponsor will submit to any relevant database a summary of 
the results of the clinical study within 1 year from the end of the clinical study. It shall be 
accompanied by a summary written in a manner that is understandable to laypersons. 
10.3.9 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
• Guidance on completion of eCRFs will be provided in a separated document. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the Study Monitoring Plan. 
• Details of study monitoring, including possible action required due to COVID-19, will be 
included in the Study Monitoring Plan. 

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• The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (eg, 
contract research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 10 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor. 
10.3.10 
Source Documents 
According to the ICH E6 (R2) definition, source data is all information in original records and 
certified copies of original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies). 
The Investigator/institution should maintain adequate and accurate source documents and 
study records that include all pertinent observations on each of the study site’s participants. 
Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original entry, 
and should be explained if necessary (eg, via an audit trail). 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may need 
to request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized study site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 

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10.3.11 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first study site open and will be the study start date. 
Definitions of a subject’s status are as follows: 
• Entered: a subject who has signed the ICF to be screened. 
• Enrolled: a subject who has met all eligibility criteria. 
Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to: 
For study termination: 
• Discontinuation of further study intervention development. 
For study site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the Investigator 
• Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 

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10.3.12 
Publication Policy 
The data generated by this study are confidential information of the Sponsor. The Sponsor will 
make the results of the study publicly available. The publication policy with respect to the 
Investigator and study site will be set forth in the Clinical Trial Agreement. 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual study site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
 
 

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10.4 Appendix 4: Clinical Laboratory Tests 
The tests detailed in Table 9 will be performed by the local laboratory and the tests detailed in 
Table 10 will be performed by a central laboratory. For all tests, participant’s preparation 
should follow each laboratory's standard procedure. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.0 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
Investigators must document their review of each laboratory safety report. 

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Table 9 
Protocol-required Safety Laboratory Tests – Local Laboratory 
Laboratory 
Assessments 
Parameters 
Hematology 
Complete hemogram: 
%Reticulocytes 
 
Platelet count  
White blood cell count with differential: 
 
Red blood cell count 
Neutrophils 
 
Hemoglobin 
Lymphocytes 
 
Hematocrit 
Monocytes 
 
Red blood cell indices: 
Eosinophils 
 
Mean corpuscular volume 
Basophils 
 
Mean corpuscular hemoglobin 
 
 
Mean cell hemoglobin concentration 
 
Clinical Chemistry 
Blood urea nitrogen 
Electrolytes: 
 
Phosphate 
Sodium 
 
Creatininea 
Potassium 
 
Total cholesterol 
Chlorine 
 
Cholesterol LDL 
Bicarbonate 
 
Cholesterol HDL 
Magnesium 
 
Triglycerides 
Calcium 
 
Glycemia 
 
 
Total bilirubin 
Alkaline phosphatase 
 
Direct bilirubin 
Total proteins 
 
Aspartate aminotransferase 
Albumin 
 
Alanine aminotransferase 
Gamma glutamyl transferase 
Urinalysis 
First morning urineb  
Urine albumin-creatinine ratio 
Other tests 
Highly sensitive urine human chorionic gonadotropin pregnancy test (as needed for 
WOCBP)c. 
NOTES: 
The results of each test must be entered into the eCRF. 
a The eGFR should be calculated using CKD-EPI equation. 
b This exam should include visual exam, dipstick test and microscopic exam (color, clarity, pH, specific 
gravity, glycose, blood, ketones, protein, urobilinogen, bilirubin, leukocyte esterase, nitrite, blood, white 
blood cells, red blood cells, epithelial cells, crystals, and casts). 
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/IEC. 
eCRF=electronic case report form; IEC=Independent Ethics Committee; IRB=Institutional Review Board; 
WOCBP=women of childbearing potential. 

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Table 10 
Protocol-required Safety Laboratory Tests – Central Laboratory 
Laboratory 
Assessments 
Parameters 
Biomarker 
Serum Lyso-Gb3 
 
Immunology 
Anti-AGA 
 
Anti-AGA=anti-agalsidase antibodies; Lyso-Gb3=globotriaosylsphingosine. 
 
 

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10.5 Appendix 5: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting for Study 
Intervention 
10.5.1 
Definition of Adverse Event 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant administered a 
medicinal product and which does not necessarily have a causal relationship with that product. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention/treatment, whether or not considered related to the 
study intervention/treatment. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, echocardiogram, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific judgment of 
the Investigator (ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New condition detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention interaction. 
• 
Lack of efficacy or failure of expected pharmacological action per se will not be reported as an 
AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or 
SAE if they fulfill the definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
that are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if 
the surgery/procedure is being performed for a preexisting condition and the surgery/procedure 
has been preplanned prior to study entry. However, if the preexisting condition deteriorates 
unexpectedly during the study (eg, surgery performed earlier than planned), then the 

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deterioration of the condition for which the elective surgery/procedure is being done will be 
considered an AE. 
• 
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
10.5.2 
Definition of Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of 
the criteria listed: 
a. Results in death 
• 
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate case report form. 
b. Is life-threatening 
• 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been admitted (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether hospitalization 
occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a preexisting condition that did not worsen from baseline 
is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) that may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
• 
The term congenital anomaly/birth defect means there is suspect that exposure to a medical 
product prior to conception or during pregnancy may have resulted in an adverse outcome in the 
child. 
f. Other situations: 
• 
Medical or scientific judgment should be exercised by the Investigator in deciding whether SAE 
reporting is appropriate in other situations such as significant medical events that may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious. 

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o 
Examples of such events include invasive or malignant cancers, intensive treatment for 
allergic bronchospasm, blood dyscrasias, convulsions or development of intervention 
dependency or intervention abuse. 
10.5.3 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records 
to the Sponsor or designee in lieu of completion of the applicable/required report form. 
• 
There may be instances when copies of medical records for certain cases are requested by the 
Sponsor or designee. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the Sponsor 
or designee. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The intensity of an AE is an estimate of the relative severity of the event made by the Investigator 
based on his or her clinical experience and familiarity with the literature. The following definitions 
are to be used to rate the severity of an AE: 
• 
Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
• 
Moderate: Minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental Activities of Daily Living (ADL). Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc. 
• 
Severe: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling, limiting self-care ADL. Self-care ADL 
refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. The Investigator will use clinical judgment to determine the 
relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration, will be 
considered and investigated. 

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• 
For causality assessments, events assessed as having a reasonable possibility of being related to 
study intervention will be considered "related." Events assessed as having no reasonable 
possibility of being related to study intervention will be considered "unrelated." 
• 
The Investigator will also consult the Investigator’s Brochure and/or product information, for 
marketed products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor or designee. However, it is very 
important that the Investigator always makes an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor or designee. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, 
the Investigator will provide the Sponsor or designee with a copy of any postmortem findings 
including histopathology. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The Investigator will submit any updated SAE data to the Sponsor or designee within 24 hours 
of the Investigator’s awareness of the information. 
10.5.4 
Reporting of SAEs 
SAE Reporting to the Sponsor or Designee via an Electronic Data Collection System 
• 
The primary mechanism for reporting an SAE to the Sponsor or designee will be the 
electronic data collection system. The study site will enter the event into the electronic data 
collection system within 24 hours of the Investigator’s awareness of the event. 
• 
If the electronic system is unavailable, then the study site will use the paper SAE report form 
(see next section) to report the event and will enter the event into the electronic data 
collection system as soon as the system becomes available. 
• 
After the study is completed at a given study site, the electronic data collection system will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a study site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection system has been taken 

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offline, then the study site can report this information on a paper SAE report form (see next 
section) to the Sponsor or designee. 
Contacts for SAE reporting: 
• 
Emails: i.clinica@biosidus.com.ar, farmacovigilancia@biosidus.com.ar, and 
f.amato@biosidus.com.ar 
• 
Contact telephone numbers: 0800 666 2527 or +54 11 6324 4707 
 
SAE Reporting to the Sponsor or Designee via Paper SAE Report Form 
• 
The primary mechanism for reporting an SAE to the Sponsor or designee will be the paper 
SAE report form. The study site will submit the SAE report form, via email, within 24 hours 
of the Investigator’s awareness of the event. Facsimile transmission may be utilized as an 
alternative mode of submission, if necessary. 
• 
Notification of SAE information via telephone does not replace the need for the Investigator 
to complete, sign and submit the paper SAE report form to the Sponsor or designee within 
24 hours of the Investigator’s awareness of the event. 
Contacts for SAE reporting: 
• 
Emails: i.clinica@biosidus.com.ar, farmacovigilancia@biosidus.com.ar, and 
f.amato@biosidus.com.ar 
• 
Contact telephone numbers: 0800 666 2527 or +54 11 6324 4707 
 
 

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10.6 Appendix 6: Abbreviations and Definitions 
Abbreviation 
Definition 
ACE 
Angiotensin-converting enzyme 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AGA BETA BS 
Agalsidase Beta Biosidus 
ANMAT 
The National Administration of Drugs, Foods and Medical 
Devices (Argentina) 
Anti-AGA 
Anti-agalsidase antibodies 
ARBs 
Angiotensin II receptor blockers 
BPI-short form 
Brief Pain Inventory short form 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ERT 
Enzyme replacement therapy 
EU 
European Union 
FD 
Fabry disease 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GL3 or Gb3 
Globotriaocylceramide 
HRT 
Hormone replacement therapy 
IARs 
Infusion-associated reactions 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent To Treat 
IV 
Intravenous 
Lyso-Gb3 
Globotriaosylsphingosine 

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Abbreviation 
Definition 
PCT 
Pharmacological chaperones 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PP 
Per Protocol 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SF-36 
36-Item Short Form Health Survey 
SoA 
Schedule of activities 
US 
United States 
WOCBP 
Women of childbearing potential 
α-Gal A 
α-galactosidase A 
 
 

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11.0 REFERENCES 
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6. Chan B, Adam DN. A Review of Fabry Disease. Skin Therapy Lett. 2018;23(suppl 2):4-6. 
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manifestations. Gut Microbes. 2022;14(1):2027852 
8. Sanofi Genzyme. Product Monograph Fabrazyme - Agalsidase Beta (Recombinant human 
α-galactosidase A) - Lyophilized Powder 5 mg and 35 mg. 
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2022 
9. Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: Management and 
treatment recommendations for adult patients. Mol Genet Metab. 2018;123(4):416-427. 
10. Oder D, Nordbeck P, Wanner C: Long Term Treatment with Enzyme Replacement 
Therapy in Patients with Fabry Disease. Nephron. 2016;134:30-36. 
11. El Dib R, Gomaa H, Carvalho RP, et al. Enzyme replacement therapy for Anderson-Fabry 
disease. Cochrane Database Syst Rev. 2016;7(7):CD006663. 
12. El Dib R, Gomaa H, Ortiz A, Politei J, Kapoor A, Barreto F. Enzyme replacement therapy 
for Anderson-Fabry disease: A complementary overview of a Cochrane publication 
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15. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. 

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16. Nakamura K, Kawashima S, Tozawa H, et al. Pharmacokinetics and pharmacodynamics of 
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18. A Phase II Multicenter, Open-label Trial to Evaluate the Safety and Efficacy of Fabagal® 
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Signature of Investigator 
PROTOCOL TITLE: Phase III, Open-label, Switch Over Trial of the Efficacy and Safety of 
Agalsidase Beta Biosidus (AGA BETA BS) in Fabry Disease Patients Previously Stabilized 
with Fabrazyme®. 
PROTOCOL NO: 
BIO-AGA-Fase III-001 
VERSION:  
 
5.0 
This protocol is a confidential communication of the Sponsor. I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol. I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki and 
that are consistent with Good Clinical Practices and the applicable laws and regulations. 
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from the 
Sponsor. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the 
study center in which the study will be conducted. Return the signed copy to Sponsor or CRO. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:  
___________________________ 
Date: ________ 
Printed Name:  
 
___________________________ 
Investigator Title:  
 
___________________________ 
 
Name/Address of Center: 
 
___________________________ 
 
 
 
 
 
___________________________ 
 
 
 
 
 
___________________________