Clinical trial NCT03454893
Conditions: Fabry Disease
Keywords: Fabry disease Cell therapy Gene therapy Lysosomal storage disorder Lenti-viral
Sponsor: AVROBIO
Start date: 2018-02-21; Completion date: 2022-03-14
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a multinational, open-label study to assess the efficacy and safety of AVR-RD-01 in approximately 15 male subjects, who were 16 years of age or older and postpubertal with a confirmed diagnosis of classic Fabry disease based on deficient alpha galactosidase A (AGA) enzyme activity who were considered treatment naïve, i.e., had not previously received treatment with enzyme replacement therapy (ERT) and/or chaperone therapy within 3 years of the time of Screening.

Detailed description:
The duration of each subject's participation in this study was approximately 64 weeks (or 1 year, 12 weeks), comprised of five study periods (Screening, Baseline, Pre-transplant, Transplant, and Post-transplant Follow-up). During the Screening Period (approximately 8 weeks), written informed consent (and assent, if applicable) was obtained and the subject had completed other Screening procedures to confirm study eligibility. Once study eligibility was confirmed, the subjects entered the Baseline Period (up to 3 days) during which time assessments would have been performed to establish a pre-transplant baseline. Once baseline assessments were completed, the subject entered the Pre-transplant Period (approximately 6 weeks) during which time mobilization, apheresis, AVR-RD-01 investigational drug product preparation and testing for release, and conditioning regimen administration to achieve myeloablation took place. Following completion of the Pre-transplant Period, the subject entered the Transplant Period (1 day) during which time AVR-RD-01 infusion took place. After AVR-RD-01 infusion, the subject entered the Post-transplant Follow-up Period (approximately 48 weeks), during which time periodic safety and efficacy assessments were performed to assess measures of engraftment, clinical response, and safety post-transplant.

In January 2022, the study was terminated early due to a decision by the study sponsor, to deprioritize its Fabry disease development program, and therefore, some subjects (n=5) did not complete the study (i.e., Week 48). Subsequently, in August 2023, the long-term follow-up study (AVRO-RD-01-LTF01), was also terminated early due to the decision by the sponsor to terminate the development program for Fabry disease, and therefore, no subjects completed the 15-year long-term follow-up study. This decision to terminate was not based on any safety or medical reasons.

Arms: arm 1: AVR-RD-01 is an autologous CD34+-enriched cell fraction transduced with LV/AGA containing an RNA transcript that, after reverse transcription, results in codon-optimized cDNA that, upon its integration into the human genome, encodes for functional human AGA.
Interventions: intervention 1: AVR-RD-01
Intervention descriptions: intervention 1: Single IV infusion of between 3 - 20 x 10\^6 CD34+ cells/kg.

Protocol documents:
Prot_002.pdf: 




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I have received and read the 
-RD-01. I have read the 
AVRO-RD-01-201 study protocol and agree to conduct the study in accordance with this 
protocol, all applicable government regulations, the principles of the International Council for 
Harmonisation (ICH) E6 Guidelines for Good Clinical Practices (GCP), and the principles of the 
World Medical Association Declaration of Helsinki. I also agree to maintain the confidentiality 
of all information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
Site Number 
 




















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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2
 ...............................................................................................3
1. 
SYNOPSIS ...................................................................................................................4
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18
4. 
INTRODUCTION ......................................................................................................22
5. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................25
5.1. 
Study Objectives .........................................................................................................25
5.1.1. 
Primary Objectives .....................................................................................................25
5.1.2. 
Secondary Objectives .................................................................................................25
5.1.3. 
Exploratory Objectives ...............................................................................................26
5.2. 
Endpoints ....................................................................................................................26
5.2.1. 
Efficacy Endpoints ......................................................................................................26
5.2.1.1. 
Primary Efficacy Endpoint .........................................................................................26
5.2.1.2. 
Secondary Efficacy Endpoints ....................................................................................27
5.2.1.3. 
Exploratory Efficacy Endpoints .................................................................................27
5.2.2. 
Safety Endpoints .........................................................................................................28
5.2.2.1. 
Primary Safety Endpoints ...........................................................................................28
5.2.2.2. 
Exploratory Safety Endpoint ......................................................................................29
6. 
INVESTIGATIONAL PLAN .....................................................................................30
6.1. 
Summary of Study Design ..........................................................................................30
6.2. 
Discussion of Design and Control ..............................................................................36
6.2.1. 
Overall Study Design and Study Population ..............................................................36
6.2.2. 
Stem Cell Mobilization and Conditioning Regimens .................................................37
6.2.2.1. 
Stem Cell Mobilization ...............................................................................................37
6.2.2.2. 
Conditioning ...............................................................................................................37
6.2.3. 
Efficacy and Safety Measures ....................................................................................39
7. 
STUDY POPULATION .............................................................................................41
7.1. 
Inclusion Criteria ........................................................................................................41


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7.2. 
Exclusion Criteria .......................................................................................................42
7.3. 
Rationale for Inclusion or Exclusion of Certain Study Candidates ............................44
7.4. 
Discontinuations .........................................................................................................45
7.4.1. 
Discontinuation of Subjects ........................................................................................45
7.4.2. 
Discontinuation of Study Sites/Site Terminated by Sponsor .....................................46
7.4.3. 
Discontinuation of the Study/Study Terminated by Sponsor .....................................46
7.4.4. 
Study Stopping Rules .................................................................................................46
8. 
TREATMENT ............................................................................................................47
8.1. 
Treatments Administered ............................................................................................47
8.1.1. 
Pre-transplant Period (Approximately 6 to 8 Weeks) .................................................47
8.1.1.1. 
Mobilization and Apheresis ........................................................................................47
8.1.1.2. 
Investigational Product Preparation/Testing for Release ...........................................48
8.1.1.3. 
Conditioning ...............................................................................................................48
8.1.2. 
Transplant Period (1 Day) ..........................................................................................50
8.1.3. 
Post-transplant Follow-up Period (Approximately 48 Weeks) ..................................50
8.2. 
Materials and Supplies ................................................................................................50
8.3. 
Dosing Considerations ................................................................................................51
8.3.1. 
Rationale for Selection of Doses in the Study ............................................................51
8.3.2. 
Other Important Treatment Considerations ................................................................51
8.4. 
Blinding ......................................................................................................................52
8.5. 
Concomitant Medications and Non-Pharmacologic Therapies and 
Procedures ...................................................................................................................52
9. 
STUDY ASSESSMENTS ..........................................................................................53
9.1. 
Efficacy Measures ......................................................................................................53
9.1.1. 
Primary Efficacy Measure: Globotriaosylceramide (Gb3) Inclusions in 
Peritubular Capillaries (PTC) on Kidney Biopsy .......................................................53
9.1.2. 
Secondary Efficacy Measures .....................................................................................53
9.1.3. 
Exploratory Efficacy Measures ..................................................................................54
9.2. 
Safety Assessments .....................................................................................................56
9.2.1. 
Physical Examinations ................................................................................................56
9.2.2. 
Vital Signs ..................................................................................................................56
9.2.3. 
Serum Chemistry, Hematology, and Urinalysis .........................................................57
9.2.4. 
Electrocardiograms .....................................................................................................57


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9.2.5. 
Pulmonary Function ....................................................................................................58
9.2.6. 
Chest X-ray .................................................................................................................58
9.2.7. 
Immunogenicity ..........................................................................................................58
9.2.8. 
Testing for Replication Competent Lentivirus ...........................................................58
9.2.9. 
Reproductive Potential ................................................................................................58
9.2.10. 
Samples to be Archived for Possible Future Testing ..................................................59
9.3. 
Safety Monitoring .......................................................................................................59
9.3.1. 
Adverse Events ...........................................................................................................59
9.3.1.1. 
Exemptions to Adverse Event Recording/Reporting ..................................................60
9.3.1.2. 
Severity Assessment ...................................................................................................60
9.3.1.3. 
Causality Assessment .................................................................................................61
9.3.1.4. 
Outcome Assessment ..................................................................................................62
9.3.1.5. 
Serious Adverse Events ..............................................................................................63
9.3.1.6. 
Suspected Unexpected Serious Adverse Reactions ....................................................64
9.3.1.7. 
Reporting Adverse Events ..........................................................................................64
9.3.1.8. 
Sponsor Reporting Requirements ...............................................................................64
9.3.1.9. 
Investigator Reporting Requirements .........................................................................65
9.3.2. 
Exposure During Pregnancy .......................................................................................65
9.4. 
Appropriateness of Measurements .............................................................................65
10. 
DATA QUALITY ASSURANCE ..............................................................................66
10.1. 
Data Collection and Storage .......................................................................................66
11. 
STATISTICAL METHODS AND PLANNED ANALYSES ...................................67
11.1. 
General Considerations ...............................................................................................67
11.2. 
Determination of Sample Size ....................................................................................67
11.3. 
Analysis Sets ...............................................................................................................67
11.4. 
Demographics and Baseline Characteristics ...............................................................68
11.5. 
Subject Disposition .....................................................................................................68
11.6. 
Concomitant Medications and Non-Pharmacologic Therapies and 
Procedures ...................................................................................................................68
11.7. 
Treatment Compliance ................................................................................................68
11.8. 
Efficacy Analyses .......................................................................................................69
11.8.1. 
Primary Efficacy Analysis ..........................................................................................69
11.8.2. 
Secondary Efficacy Analyses .....................................................................................69


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11.8.3. 
Exploratory Efficacy Analyses ...................................................................................69
11.9. 
Safety Analyses ..........................................................................................................69
11.9.1. 
Physical Examination and Vital Signs ........................................................................69
11.9.2. 
Serum Chemistry, Hematology, and Urinalysis .........................................................69
11.9.3. 
Adverse Events ...........................................................................................................70
11.9.4. 
Reproductive Potential ................................................................................................71
11.9.5. 
Other Safety Assessments ...........................................................................................71
11.10. 
Subgroup Analyses .....................................................................................................71
11.11. 
Other Statistical Issues ................................................................................................71
11.11.1. 
Significance Levels .....................................................................................................71
11.11.2. 
Missing or Invalid Data ..............................................................................................71
11.12. 
Interim Analyses .........................................................................................................72
12. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS ..................................................................................................73
12.1. 
Informed Consent .......................................................................................................73
12.2. 
Data Monitoring Committee .......................................................................................73
12.3. 
Ethical Review ............................................................................................................74
12.4. 
Regulatory Considerations ..........................................................................................74
12.4.1. 
Investigator Information .............................................................................................74
12.4.2. 
Protocol Signatures .....................................................................................................74
12.4.3. 
Final Report Signature ................................................................................................75
12.5. 
Publication Policy .......................................................................................................75
13. 
LIST OF REFERENCES ............................................................................................76
14. 
APPENDICES ............................................................................................................80
14.1. 
Study AVRO-RD-01-201: Schedule of Assessments (Screening through 
Investigational Product Preparation and Testing for Release in the Pre-
Transplant Period) ......................................................................................................81
14.2. 
Study AVRO-RD-01-201: Schedule of Assessments (Pre-Transplant 
Conditioning Period through Transplant [Day 0]) ......................................................87
14.3. 
Study AVRO-RD-01-201: Schedule of Assessments for the Post-Transplant 
Follow-up Period (Study Week 1 [Day 1] through Study Week 48 [Day 
336]) ............................................................................................................................91
 


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LIST OF TABLES 
Table 1: 
PK- and Weight-based Guided Busulfan Conditioning Regimen ..............................49
Table 2: 
Causality Definitions ..................................................................................................62
LIST OF FIGURES 
Figure 1: 
Overall Study Design for AVRO-RD-01-201 ............................................................32
Figure 2: 
Overview of the Pre-transplant and Transplant Periods of Study AVRO-RD-
01-201 .........................................................................................................................34
 
  


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ADL 
Activities of daily living 
AE 
Adverse event(s) 
AGA 
Alpha-galactosidase A 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (classification) 
ATS 
American Thoracic Society 
AUC 
Area-under-the-curve 
BID 
Twice a day 
BLISS 
Barisoni Lipid Inclusion Scoring System 
BMT 
Bone marrow transplant 
BPI-SF 
Brief Pain Inventory-Short Form 
CABG 
Coronary artery bypass grafting 
CAD 
Coronary artery disease 
CBER 
Center for Biologics Evaluation and Research 
c/dg 
Copy per diploid genome 
cDNA 
Complementary deoxyribonucleic acid 
cGMP 
Current Good Manufacturing Practice 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology 
CMIA 
Chemiluminescent microplate immunoassay 
CS 
Clinically significant 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ddPCR 
Droplet digital polymerase chain reaction 
DIBSS-D 
Diary for Irritable Bowel Syndrome Symptoms-Diarrhea 
DLCO 
Diffusing capacity of the lung for carbon dioxide 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic case report form 


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Abbreviation  
Definition 
eGFR 
Estimated glomerular filtration rate  
EIA 
Enzyme immunosorbent assay 
EIU 
Exposure in-utero 
EMA 
European Medicines Agency 
ERS 
European Respiratory Society 
ERT 
Enzyme replacement therapy 
EU 
European Union 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
Gb3 
Globotriaosylceramide 
GCP 
Good Clinical Practices 
G-CSF 
Granulocyte-colony stimulating factor 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
HBV 
Hepatitis B virus 
HCT 
Hematopoietic cell transplant 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HREC 
Human research ethics board 
HSC 
Hematopoietic stem cell(s) 
HSCT 
Hematopoietic stem cell transplantation 
HTLV 
Human T-cell lymphotropic virus 
IBS 
Irritable bowel syndrome 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional review board 
ISA 
Integration site analysis 
IV 
Intravenous 
LSD 
Lysosomal storage disorder 
LV 
Lentiviral vector 
LVEF 
Left ventricular ejection fraction 
LVMI 
Left ventricular mass index 
Lyso-Gb3 
Globotriaosylsphingosine 


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Abbreviation  
Definition 
MCS 
Mental Component Summary 
t-MDS 
Therapy-related myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mGFR 
Measured glomerular filtration rate 
MI 
Myocardial infarction 
MLD 
Metachromatic leukodystrophy 
MRI 
Magnetic resonance imaging 
MS/MS 
Tandem mass spectrometry 
NAT 
Nucleic acid-amplification testing 
NCS 
Not clinically significant 
NHANES 
National Health and Nutrition Examination Survey  
NK 
Natural killer 
NOD 
Nonobese diabetic 
NSF 
Nonobese diabetic (NOD)/severe combined immunodeficiency 
(SCID)/Fabry 
PCS 
Physical Component Summary 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PTC 
Peritubular capillary 
q6h 
Every 6 hours 
qPCR 
Quantitative polymerase chain reaction 
RBC 
Red blood cell 
RCL 
Replication competent lentivirus 
REB 
Research ethics board 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event(s) 
SAP 
Statistical analysis plan 
SC 
Subcutaneously 
SCD 
Sickle cell disease 
SCID 
Severe combined immunodeficiency 
scRNAseq 
Single-cell RNA sequencing 
SD 
Standard deviation 
SF-36 
Short Form 36 
SmPC 
Summary of Product Characteristics 




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4. 
INTRODUCTION 
Fabry disease is a rare lysosomal storage disorder (LSD), associated with significant morbidity 
and early mortality, that is caused by deficiency of alpha-galactosidase A (AGA) enzyme activity 
due to mutations in the GLA gene (MIM 301500). This deficiency in enzyme activity leads to 
accumulation of glycosphingolipids (eg, globotriaosylceramide [Gb3] and its deacylated form, 
globotriaosylsphingosine [lyso-Gb3]), resulting in multi-organ damage. Fabry disease is a 
chronic, progressive disorder that ultimately leads to end-organ damage in the kidneys (end-stage 
renal disease), heart (hypertrophic cardiomyopathy, diastolic heart failure, and arrhythmias), and 
brain (vascular stroke). Due to end-stage renal disease and other life-threatening complications 
associated with the disease, average life expectancy in affected males is reduced to 
approximately 50 years of age (Germain, 2010). Variant late-onset Fabry disease phenotypes 
also exist, with disease limited primarily to cardiac or renal involvement (Mehta, 2002; Germain, 
2010).  
Although therapeutic options are currently available for treatment of Fabry disease, including 
two enzyme replacement therapies (ERT) and one chaperone therapy, there are limitations 
associated with each of these therapies for which consideration of alternative treatment strategies 
is warranted.  
Despite availability of the ERTs Fabrazyme® (agalsidase beta) and Replagal® (agalsidase alfa), 
some patients have proven either refractory to or have achieved suboptimal response to ERT 
(Germain, 2010; Biffi, 2016). Due to its very short half-life in plasma (a few hours), ERT 
provides only periodic therapeutic levels of AGA to patients over a very short duration; given 
that current dosing is via intravenous (IV) infusion every two weeks, patients are left with 
sub-therapeutic levels of enzyme for a significant period of time between scheduled infusions. 
Hence, at best, ERT can only slow disease progression. Enzyme replacement therapies also 
exhibit safety concerns, particularly early in the treatment course; in the pivotal clinical studies 
of both Fabrazyme and Replagal, over 50% of patients treated experienced mild to moderate 
infusion reactions (Eng, 2001; Schiffmann, 2001). With both ERTs, some patients have also 
demonstrated immunogenic response to treatment (IgG seroconversion). Importantly, a few 
patients treated with Fabrazyme have also tested positive for plasma IgE antibodies and/or have 
had a positive skin test in conjunction with urticaria or skin rash (Germain, 2010), posing a 
challenge for continued treatment.  
l small molecule pharmacological chaperone therapy, is also 
approved for treatment of Fabry disease. Galafold (migalastat) works by binding and stabilizing 
specific mutant forms of the AGA enzyme in the endoplasmic reticulum, thereby preventing 
misfolding and subsequent premature degradation, and facilitating trafficking to lysosomes for 
functional enzyme expression and resulting substrate reduction. Although an alternative 
treatment strategy for Fabry disease, its utility is limited to the Fabry patient population 
(approximately 50%) who have specific GLA gene mutations (amenable mutations) associated 
with mutant forms of the AGA enzyme that have been confirmed to be amenable to binding and 
stabilization (Benjamin, 2017). Furthermore, data on the long-term safety and efficacy of 
Galafold (migalastat) treatment are currently limited. 
Considering the limitations of the currently approved treatments for Fabry disease, AVROBIO is 
developing AVRO-RD-01, an ex vivo, lentiviral vector (LV)-mediated gene-modified autologous 


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cell therapy. This therapy involves the autologous transplantation of CD34+ cells augmented 
with a therapeutic version of the GLA gene inserted into their genome via a LV. Mobilized 
autologous CD34+ hematopoietic s
 blood 
are genetically modified ex vivo with a LV containing a ribonucleic acid (RNA) transcript that, 
after reverse transcription, results in codon-optimized complementary deoxyribonucleic acid 
(cDNA) that, upon its integration into the human genome, encodes for functional human AGA. 
After the patient has undergone a conditioning regimen to achieve myeloablation, the 
genetically-modified cells are returned to the patient by IV infusion. This infusion of 
genetically-modified cells is intended to permanently engraft into the bone marrow, 
ted cells, 
circulated, and taken up through mannose-6-phosphate receptors and trafficked to the lysosomes 
of bystander cells. Once inside the lysosome, the functional enzyme reduces glycosphingolipid 
storage, allowing the reconstitution of lysosomal function, cell survival, and avoidance of end-
organ damage associated with early morbidity and mortality in affected patients. Unlike ERTs, 
AVR-RD-01 is intended for single administration, having the potential to provide sustained 
therapeutic levels of functional 
need for bi-weekly IV infusions, resulting in a beneficial effect on patient quality of life and 
healthcare burden associated with Fabry disease management. 
AVROBIO obtained exclusive licensing rights to the ex vivo, LV-mediated gene-modified 
autologous cell therapy program for Fabry disease from University Health Network (UHN). 
University Health Network has completed a number of nonclinical studies to support this 
program. Results of completed nonclinical studies in mice suggest that HSCs transduced with a 
LV containing a RNA transcript that, after reverse transcription, results in codon-optimized 
cDNA that, upon its integration into the genome, encodes for functional human AGA, can 
produce sustained levels of functional human AGA for up to 6 months, thus demonstrating 
proof-of-concept. No overt toxicity nor tumorigenicity attributed to test article were observed in 
concert with stable and persistent expression of AGA enzyme activity for up to 6 months (the 
last time point evaluated) in male Fabry mice and up to 12 weeks (the median lifespan in 
sublethally irradiated highly-immunodeficient mice) in non-obese diabetic (NOD)/severe 
combined immunodeficiency (SCID)/Fabry (ie, NSF) mice. In both animal models, concomitant 
reductions in enzyme substrate (ie, Gb3) were also observed. In two independent (non-Good 
Laboratory Practice [GLP]) toxicology studies, neither test article-related toxicity nor adverse 
changes were observed. 
Currently, there is one other ongoing clinical study (Study OZM-074), UHN-sponsored in 
Canada, to support the ex vivo, LV-mediated gene-modified autologous cell therapy program for 
Fabry disease. This study is a multi-center, non-randomized, open-label prospective pilot study 
that enrolled a total of five adult male subjects with classic Fabry disease on ERT. The primary 
objective of the study is to evaluate the overall safety and tolerability of autologous stem cell 
transplantation with mobilized CD34+ cells transduced with a LV containing a RNA transcript 
that, after reverse transcription, results in codon-optimized cDNA that, upon its integration into 
the human genome, encodes for functional human AGA, after conditioning. The secondary 
objective of the study is to obtain evidence of the efficacy of the transplantation procedure in 
subjects with Fabry disease. Preliminary results from this study indicate presence of vector and a 
trend in increased AGA enzyme activity post-AVR-RD-01 transplant in enrolled subjects, 


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providing early evidence that the LV is effective in delivering and integrating the GLA transgene 
into the human genome, enabling expression of endogenous functional AGA. From a safety 
perspective, preliminary data indicate AVR-RD-01 was generally well-tolerated and confirm the 
feasibility of the pre-treatment plan involving CD34+ cell mobilization, apheresis, and 
conditioning for the Fabry patient population under study. 
Further details on the completed nonclinical studies and the ongoing clinical studies supporting 
the AVR-RD-01 program, as well as information about the known and expected benefits, risks, 
and reasonably anticipated adverse events (AEs) of AVR-RD-01, can be found in the current 
-RD-01. 


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5. 
STUDY OBJECTIVES AND ENDPOINTS 
Study objectives and associated endpoints are presented in Sections 5.1 and 5.2, respectively; the 
frequency and timing of study measurements are provided in the Schedule of Assessments 
(Sections 14.1, 14.2, and 14.3). Information regarding sample and data collection are presented 
in Section 9. 
5.1. 
Study Objectives 
5.1.1. 
Primary Objectives 
The primary objectives of this study are to: 
 Evaluate the effect of AVR-RD-01 on substrate (ie, Gb3) in kidney biopsies  
 Evaluate the safety and tolerability of AVR-RD-01, including, but not limited to: 
 Evaluation of AEs/serious adverse events (SAEs) 
 Evaluation of immunogenicity of AVR-RD-01  
 Testing for the presence of replication competent lentivirus (RCL) 
 Performance of integration site analysis (ISA) to assess for potential aberrant 
clonal expansion(s) 
5.1.2. 
Secondary Objectives 
The secondary objectives of the study are to: 
 Evaluate AGA enzyme activity in plasma and peripheral blood leukocytes 
 Evaluate the effect of AVR-RD-01 on biomarkers for Fabry disease (ie. Gb3 and its 
deacylated form, lyso-Gb3) in plasma and urine 
 Evaluate the effect of AVR-RD-01 on substrate (ie, Gb3) in skin biopsies  
 Evaluate the effect of AVR-RD-01 on other clinical indices of Fabry disease, 
including: 
 Clinical laboratory measures of renal function, including measured glomerular 
filtration rate (mGFR), estimated glomerular filtration rate (eGFR), and urine total 
protein and albumin excretion 
 Cardiac structure assessed by left ventricular mass index (LVMI) on cardiac 
magnetic resonance imaging (MRI) 
 Abdominal pain and stool consistency assessed by the Diary for Irritable Bowel 
Syndrome Symptoms - Diarrhea (DIBSS-D) 
 Pain assessed by the Brief Pain Inventory Short Form (BPI-SF) questionnaire 
 Functional status assessed by the Physical Component Summary (PCS) and 
Mental Component Summary (MCS) scores of the 36-Item Short Form Health 
Survey (SF-36) 


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 Assess measures of engraftment of gene-augmented hematopoietic stem cells by 
determining average vector copy number (VCN) in peripheral blood leukocytes and 
bone marrow stem and progenitor cells using quantitative polymerase chain reaction 
(qPCR) and/or droplet digital polymerase chain reaction (ddPCR) analysis 
5.1.3. 
Exploratory Objectives 
The exploratory objectives of the study are to: 
 Evaluate the effect of AVR-RD-01 on:  
 Microscopic findings on kidney biopsy 
 AGA enzyme activity in skin and kidney biopsies 
 Podocyturia (shedding of podocytes into urine) 
 Other gastrointestinal (GI) symptoms associated with Fabry disease assessed by 
the DIBSS-D, including stool frequency, urgency, recurrent bowel movements, 
and the abdominal symptom subscale 
 Functional status assessed by the eight subscale scores (ie, Vitality, Physical 
Functioning, Bodily Pain, General Health Perceptions, Physical Role Functioning, 
Emotional Role Functioning, Social Role Functioning, and Mental Health) of the 
SF-36 
 Exploratory biomarkers for Fabry disease in plasma and urine (for subjects with 
written informed consent to optional genetic biomarker research) 
 Assess reconstitution dynamics by immunophenotyping the fluorescence-activated 
peripheral blood subpopulation and bone marrow CD34+ subpopulations, and by 
studying changes in cell populations composition by single-cell RNA sequencing 
(scRNAseq) 
 Assess engraftment dynamics by determining average VCN, and performing ISA, on 
fluorescence-activated cell-sorted peripheral blood subpopulations and bone marrow 
CD34+ subpopulations 
 Evaluate subject experience with respect to AVR-RD-01 treatment and perception of 
changes in Fabry disease burden and quality of life by qualitative interview (for 
subjects, and caregivers or other qualified observers of subjects, who provide separate 
written informed consent)  
 Assess the impact of the conditioning regimen on reproductive potential 
5.2. 
Endpoints  
5.2.1. 
Efficacy Endpoints 
5.2.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline in the average number of Gb3 inclusions 
(ie, myelinosomes) per kidney peritubular capillary (PTC) per subject at Week 48. 


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5.2.1.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following: 
 Change from baseline in AGA enzyme activity level in plasma and peripheral blood 
leukocytes at Weeks 24 and 48 
 Change from baseline in biomarkers for Fabry disease (ie, Gb3 and its deacylated 
form, lyso-Gb3) in plasma and urine at Weeks 24 and 48 
 Change from baseline in substrate (ie, Gb3) in skin biopsy at Weeks 24 and 48 
 Change from baseline in mGFR at Week 48 
 Change from baseline in eGFR and urine total protein and albumin at Weeks 24 and 
48 
 Change from baseline in LVMI assessed by cardiac MRI at Week 48 
 Change from baseline in abdominal pain and stool consistency assessed by the 
DIBSS-D at Weeks 24 and 48 
 Change from baseline in BPI-SF questionnaire scores at Weeks 24 and 48 
 Change from baseline in physical and mental functioning assessed by the SF-36 PCS 
and MCS scores at Weeks 24 and 48 
 Average VCN in peripheral blood leukocytes assessed by qPCR and/or ddPCR at 
Weeks 24 and 48 
 Average VCN in bone marrow stem and progenitor cells assessed by qPCR and/or 
ddPCR at Week 48 
5.2.1.3. 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include the following: 
 Change from baseline in microscopic findings on kidney biopsy at Week 48 
 Change from baseline in AGA enzyme activity in skin biopsy (Weeks 24 and 48) and 
kidney biopsy (Week 48) 
 Change from baseline in the number of podocytes shed into the urine (podocyturia) at 
Weeks 24 and 48 
 Change from baseline in other GI symptoms associated with Fabry disease assessed 
by the DIBSS-D, including stool frequency, urgency, recurrent bowel movements, 
and the abdominal symptom subscale, at Weeks 24 and 48 
 Change from baseline in physical and mental functioning assessed by the eight SF-36 
subscale scores (ie, Vitality, Physical Functioning, Bodily Pain, General Health 
Perceptions, Physical Role Functioning, Emotional Role Functioning, Social Role 
Functioning, and Mental Health) at Weeks 24 and 48 


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 Change from baseline in exploratory biomarkers for Fabry disease in plasma and 
urine at Weeks 24 and 48 (for subjects with written informed consent to optional 
genetic biomarker research) 
 Changes from baseline in peripheral blood cell subpopulations (ie, T cells [CD3+], 
natural killer [NK] cells [CD56+], B cells [CD19+], granulocytes [CD15+], and 
monocytes [CD14+]) and bone marrow CD34+ subtypes (ie, HSCs [HSC 
CD34+CD38-CD90+CD45RA-] and multipotent progenitors [MPP CD34+CD38-
CD90-CD45RA-], multilymphoid progenitors [MLP CD34+CD38-CD90-
CD45RA+], common myeloid progenitors [CMP CD34+CD38+CD7-CD10-
CD135+CD45RA-], granulocytes/monocytes progenitors [GMP CD34+CD38+CD7-
CD10-CD135+CD45RA+], megakaryocyte/erythroid progenitors [MEP 
CD34+CD38+CD7-CD10-CD135-CD45RA-], and Pre-B/NK progenitors 
[CD34+CD38+CD7-CD10+] cells) analyzed by immunophenotyping and scRNAseq 
over time 
 Average VCN and ISA results in both peripheral blood cell subpopulations (ie, 
T cells [CD3+], NK cells [CD56+], B cells [CD19+], granulocytes [CD15+], and 
monocytes [CD14+]) and bone marrow CD34+ subtypes (ie, HSCs [HSC 
CD34+CD38-CD90+CD45RA-] and multipotent progenitors [MPP CD34+CD38-
CD90-CD45RA-], multilymphoid progenitors [MLP CD34+CD38-CD90-
CD45RA+], common myeloid progenitors [CMP CD34+CD38+CD7-CD10-
CD135+CD45RA-], granulocytes/monocytes progenitors [GMP CD34+CD38+CD7-
CD10-CD135+CD45RA+], megakaryocyte/erythroid progenitors [MEP 
CD34+CD38+CD7-CD10-CD135-CD45RA-], and Pre-B/NK progenitors 
[CD34+CD38+CD7-CD10+] cells) over time 
 Change from baseline in Fabry disease burden and quality of life, including 
exploration of the impact of pre-treatment conditioning on participating subjects and 
perception of changes in disease burden and quality of life, assessed by qualitative 
interview conducted at Weeks 12, 24, and 48 (for subjects, and caregivers or other 
qualified observers of subjects, who provide separate written informed consent) 
5.2.2. 
Safety Endpoints 
5.2.2.1. 
Primary Safety Endpoints 
Primary safety endpoints include the following: 
 Incidence and severity of AEs and SAEs 
 Change from baseline in clinical laboratory values relevant to safety 
 Incidence of abnormal clinical laboratory values relevant to safety 
 Change from baseline in vital signs 
 Change from baseline in electrocardiogram (ECG) findings 
 Presence of anti-AGA antibodies 
 Presence of RCL 


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 Identification of mononuclear cells with integration site profiles suggestive of 
aberrant clonal expansion(s) 
5.2.2.2. 
Exploratory Safety Endpoint 
The exploratory safety endpoint is change from baseline in sperm count, sperm motility, and 
sperm morphology. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Summary of Study Design 
This is a multinational, open-label study to assess the efficacy and safety of AVR-RD-01 in 
approximately 8 to 12 adult (de
postpubertal, where permitted by region) male subjects up to 50 years of age with a confirmed 
diagnosis of classic Fabry disease based on deficient AGA enzyme activity who are treatment-
naïve. For this study, treatment-naïve is defined as having received no ERT and/or chaperone 
therapy for Fabry disease within 3 years of Screening. 
Five study periods (Screening, Baseline, Pre-transplant, Transplant, and Post-transplant 
Follow-up) comprise the study. During the Screening Period (approximately 8 weeks), written 
informed consent (and assent, if applicable) will be obtained and the subject will complete other 
Screening procedures to confirm study eligibility. Once study eligibility is confirmed, subjects 
will enter the Baseline Period (up to 3 days) during which time assessments will be performed to 
establish a pre-transplant baseline. Once baseline assessments are complete, the subject will enter 
the Pre-transplant Period (approximately 6 to 8 weeks) during which time mobilization, 
apheresis, AVR-RD-01 preparation and testing for release, conditioning regimen administration 
to achieve myeloablation, and conditioning washout period will take place (see Section 8.1.1). 
Following completion of the Pre-transplant Period, the subject will enter the Transplant Period (1 
day) during which time AVR-RD-01 infusion will take place (see Section 8.1.2). After 
AVR-RD-01 infusion, the subject will enter the Post-transplant Follow-up Period (approximately 
48 weeks) (see Section 8.1.3), during which time periodic safety and efficacy assessments will 
be performed to assess measures of engraftment, clinical response, and safety post-transplant. 
Post-transplant follow-up will occur at the following time points: Week 1 (Days 1 through 7), 
Week 2 (Days 10 and 14), Week 4 (Day 28), Week 8 (Day 56), Week 12 (Day 84), Week 24 
(Day 168), Week 36 (Day 252), and Week 48 (Day 336). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened once upon discussion between the Investigator and Medical Monitor. Subjects who 
discontinue from the study prior to infusion of AVR-RD-01 will be replaced. 
An independent Data Monitoring Committee (DMC) will be established for the study to review 
safety information during the Pre-transplant, Transplant, and Post-transplant Follow-up Periods 
to assess for signals that may preclude continued study enrollment and/or necessitate changes to 
the subject has received the transplant and completed the Week 4 follow-up visit. Once the DMC 
has reviewed these Week 4 data and determined that there are no significant clinical safety 
events (SAEs related to AVR-RD-01 transplantation), the next 2 subjects can begin the 
mobilization phase of the study. The DMC will meet again after these 2 subjects have completed 
the Week 4 follow-up visit. Once the DMC has reviewed the Week 4 data from subjects 2 and 3 
and determined that there are no significant clinical safety events (SAEs related to AVR-RD-01 
transplantation), any currently enrolled subjects that have completed the baseline assessments 
can begin the mobilization phase of the study, and the study will be opened to enrollment. After 
the 6th subject has completed the Week 4 follow-up visit, the DMC will review all available 
safety data (ie, accumulated safety data available from subjects 1 through 6) to assess for signals 
that may preclude continued study enrollment and/or necessitate changes to the protocol, as well 


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as make recommendations on the timing of any future periodic DMC meetings. Ad-hoc safety 
review meetings will also take place if stopping rules for the study are met, or for any other 
safety reason(s), at the discretion of the DMC. Further details on the DMC, including its 
composition and responsibilities, will be outlined in the DMC Charter for the study. 
Final statistical analysis for the study will be performed after all enrolled subjects complete the 
Week 48 assessments (or prematurely discontinue the study). Full analytical details for the study 
will be outlined in a statistical analysis plan (SAP). 
An overview of the overall study design can be found in Figure 1 (with a detailed overview of 
the Pre-transplant and Transplant Periods provided in Figure 2).




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Abbreviations: AGA = alpha-galactosidase A; cDNA = complementary deoxyribonucleic acid; G-CSF = granulocyte-colony stimulating factor; IV = intravenous; LV = lentiviral vector; RNA = 
ribonucleic acid 




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*For investigational sites with only prefilled syringes, a G-CSF dose from 10 µg/kg body weight up to 12 µg/kg body weight, administered in either a single or divided twice a day (BID) dose, may be 
administered. The G-CSF dose may be administered subcutaneously (SC) or IV. 
**Levetiracetam will be administered. If levetiracetam is contraindicated, an alternative anticonvulsant medication (eg, benzodiazepines or valproic acid) may be used. 
Abbreviations: AGA = alpha-galactosidase A; cDNA = complementary deoxyribonucleic acid; G-CSF = granulocyte-colony stimulating factor; IV = intravenous(ly); LV = lentiviral vector; RNA = 
ribonucleic acid; TDM = therapeutic drug monitoring 
 


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An overview of required assessments for the study (including the timing of each) can be found in 
Section 14.1 (Schedule of Assessments from Screening through Investigational Product 
Preparation and Testing for Release in the Pre-Transplant Period), Section 14.2 (Schedule of 
Assessments from the Pre-Transplant Conditioning Period through Transplant [Day 0]), and 
Section 14.3 (Schedule of Assessments for the Post-Transplant Follow-up Period [Study Week 1 
(Day 1) through Study Week 48 (Day 336)]). 
After study completion, consenting subjects will continue periodic safety and efficacy 
assessments for approximately 14 years (for a total of 15 years post-transplant follow-up) in 
long-term follow-up study AVRO-RD-01-LTF01.  
6.2. 
Discussion of Design and Control 
6.2.1. 
Overall Study Design and Study Population 
The open-label design without concurrent control was deemed appropriate for the early phase, 
proof-of-concept nature of the study. Only male subjects with classic Fabry disease who are 
treatment-naïve (ie, received no ERT and/or chaperone therapy for Fabry disease within 3 years 
of Screening) are being included in this study, to eliminate the variability in heterozygous 
subjects and to provide the best opportunity to evaluate AVR-RD-01 without the potential 
confounding effects associated with prior Fabry disease-specific therapies. 
Only subjects at least 18 years of age (the mandated lower age limit for inclusion in the United 
tted by region) are being 
included in the study to provide the best opportunity to evaluate AVR-RD-
<18 years of age with full pubertal development are considered appropriate for inclusion, where 
permitted by region; this approach is a physiologic/developmental approach, rather than a more 
arbitrary age cutoff approach. This approach is validated, in part, by ICH E11(R1), Addendum, 
Clinical Investigation of Medicinal Products in the Pediatric Population, 2017, which states that 
chronological age alone may not serve as an adequate categorical determinant to define 
developmental subgroups, and that physiological development and maturity of organs are factors 
to be considered. In some regions, the age of 16 years constitutes a regulatory definition for the 
end of pediatrics (ICH E11, Clinical Investigation of Medicinal Products in the Pediatric 
Population, 2000). With regard to Fabry disease, the average age at diagnosis for patients with 
the classic form of the disease is in the late teens to early 20s (Eng, 2007; Waldek, 2009); thus, 
identifying subjects that are ERT 
and/or chaperone therapy-naïve for recruitment into the study. 
For the first three subjects who receive the AVR-RD-
will be reviewed by the DMC after the subject receives the transplant and completes the Week 4 
follow-up visit. The DMC will review the Week 4 safety data and mobilization of additional 
subjects will be staggered based on the schedule described in Section 6.1. Assessment of safety 
data through Week 4 post-transplant for the first three subjects allows for appropriate evaluation 
of short-term safety related to the mobilization, conditioning, and infusion of AVR-RD-01 prior 
to continuing mobilization for additional subjects. This time interval also allows for early 
evaluation of engraftment of transduced cells and enzyme production via those cells. 


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6.2.2. 
Stem Cell Mobilization and Conditioning Regimens  
6.2.2.1. 
Stem Cell Mobilization 
Both granulocyte-colony stimulating factor (G-CSF) and plerixafor are being used in the study 
for stem cell mobilization. Superiority of G-CSF and plerixafor over G-CSF alone in stem cell 
mobilization of patients has been demonstrated (Yannaki, 2013; Baiamonte, 2015; Goker, 2015); 
in combination with G-CSF, plerixafor has been shown to increase peripheral blood CD34+ cell 
counts, including increased frequency of more primitive CD34+ cell subtypes and clonogenic 
capacity. 
6.2.2.2. 
Conditioning 
A four-day conditioning regimen of IV busulfan using a prior weight-based test dose of 0.8 
mg/kg on Day -6 of Conditioning will be used in this study. The myeloablative cumulative target 
for busulfan exposure in the AVRO-RD-01-201 study will be a cumulative area-under-the curve 
(AUC) of 90(day 0-4) +/- 0% mg hr/L. Busulfan will be administered once-daily, with the initial 
doses on Days -4 and -3 of Conditioning based on the pharmacokinetics (PK) from the busulfan 
test dose. The United States FDA, European Medicines Agency (EMA), and Health Canada 
recommend an initial IV busulfan weight-based dose of 0.8 mg/kg IV every 6 hours (q6h), or 
3.2 mg/kg IV daily for conditioning, with consideration for modified dosing strategies for 
patients with less than ideal body-weight (Busulfan Prescribing Information, Busulfan Product 
Monograph, Busulfan Summary of Product Characteristics [SmPC]). However, Bartelink et al. 
(Bartelink, 2012) investigated the covariates related to the PK of busulfan and determined that 
body-weight was the most predictive covariate that explained variability in busulfan exposure 
between patients. The relationship between body-weight and clearance was characterized by an 
allometric equation with a scaling component (Bartelink, 2012). The scaling range for 
adolescents and adults was from 2.7 to 4.1 mg/kg/day, and allowed for individualized initial 
dosing based on body-weight. However, further studies evaluating the PK of busulfan by Davis 
et al. (Davis, 2018) and Weil et al. (Weil, 2017) determined that administration of a busulfan test 
dose prior to the 4 day myeloablative conditioning regimen allowed for the use of a personalized 
PK-guided dosing strategy, based on the PK from the test dose and the patients individual 
body-weight, which resulted in significant improvement in target AUC attainment and less 
interpatient variability compared to using the weight-based dosing regimen alone as described by 
Bartelink et al. (Bartelink, 2012). The personalized PK- and weight-based guided dosing strategy 
as suggested by Weil et al. (Weil, 2017) and Davis et al. (Davis, 2018), in addition to therapeutic 
drug monitoring (TDM) of the PK of the test dose and during conditioning, has resulted in more 
accurate cumulative AUC outcomes versus previous weight-based and TDM-guided dosing 
without test dose. 
This PK- and weight-based guided, individualized dosing regimen of busulfan defines a 
once-daily regimen for myeloablative conditioning at an AUC (day0-4) of 90 mg h/L, which 
equates to 21.6 µmol min/L total, or 5400 µmol min/L. Because busulfan PK display large 
interpatient and intrapatient variability, TDM of busulfan is routinely performed as standard 
clinical care in patients undergoing hematopoietic stem cell transplantation (HSCT) 
(Long-Boyle, 2015).  


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For this study, busulfan TDM will be performed on the test dose on Conditioning Day -6 to 
inform the dose on Conditioning Days -4 and -3. Busulfan TDM will also be performed on 
Conditioning Days -4 and -3 to inform the doses on Days -2 and -1, respectively. Collective 
information from TDM on all days during Conditioning (Days -4 to Day -1) will be used to 
calculate the cumulative AUC in Study AVRO-RD-01-201, with plasma samples taken at 
periodic intervals post-busulfan administration as described in Section 8.1.1.3 (and the Schedule 
of Assessments in Section 14.2). All laboratories performing TDM will use validated methods to 
quantify busulfan in plasma, according to GLP.  
The busulfan dose-versus-concentration relationship over time will be evaluated to obtain an 
individualized dosing strategy that balances efficacy and toxicity. Optimizing the target for 
cumulative busulfan exposure has a significant impact on outcomes (Bartelink, 2016). In 
transfusion-
-thalassemia (TDT) patients who underwent autologous HSCT for 
LV-mediated gene therapy, a four-day myeloablative conditioning regimen, with an average 
busulfan daily dose range of 4,670 to 5,212 µmol min/L per day, was used (Thompson, 2018). 
In 400 children and young adults who underwent allogeneic HSCT for non-oncology indications, 
a busulfan AUC of 78 to 101 mg hr/L was considered optimal for targeting a balance between 
acute toxicity and patient outcomes, including graft failure (Bartelink, 2016). 
In the AVRO-RD-01-201 study, a centralized, web-based program will be used to determine the 
daily busulfan dose required by each subject to achieve the busulfan target cumulative AUC. 
Using this centralized, web-
or 
each time point collected. Based on the data entered, the investigative site will be provided with 
model-based Bayesian forecasting method. Reports in the literature indicate that cumulative 
AUCs are sometimes calculated with methods that vary by institution, and use of a PK modeling 
software program can provide a consistent, standardized approach in dosing strategies between 
sites (Bartelink, 2016).  
Busulfan does cross the blood-brain barrier and can cause neurotoxicity, including seizures, 
when administered at higher doses. Therefore, anticonvulsant medication is routinely prescribed 
for patients undergoing myeloablative therapy with busulfan in preparation for HSCT. Consistent 
with this practice, anticonvulsant prophylaxis will be administered concurrent with busulfan 
administration for conditioning in this study. Levetiracetam will be administered in this study as 
described in Section 8.1.1.3. The dosing regimen selected for levetiracetam has been shown in 
the literature to be effective at preventing seizures in adults receiving conditioning with busulfan 
in preparation for HSCT, and to have an acceptable safety profile when administered in 
combination with busulfan (Akiyama, 2018). For subjects with contraindication to levetiracetam, 
an alternative anticonvulsant medication (eg, benzodiazepines or valproic acid) may be used 
before and after busulfan treatment (Busulfan Prescribing Information). 
The most frequent, serious consequence of treatment with busulfan at the approved dose and 
schedule is profound myelosuppression, occurring in all patients. Hematologic changes have 
been observed in subjects receiving myeloablative busulfan conditioning regimens used in other 
autologous LV-mediated gene therapy studies for TDT, sickle cell disease (SCD), and 
metachromatic leukodystrophy (MLD) (Thompson, 2018; Biffi, 2013; Tisdale, 2018; see also the 
Inve
-RD-01). 


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In addition, busulfan may be a human carcinogen as secondary malignancy has been reported in 
patients treated with busulfan. Recently a case of therapy-related myelodysplastic syndrome 
(t-MDS) was reported in an individual who underwent busulfan conditioning before 
LV-mediated gene therapy for SCD (Kanter, 2018). While secondary malignancies have been 
reported among individuals exposed to busulfan during treatment for hematologic cancers, less is 
known about the carcinogenic risk among individuals exposed to busulfan conditioning in the 
management of non-malignant disorders. To address this concern, AVROBIO conducted a 
literature review of busulfan conditioning in conjunction with bone marrow transplant (BMT) or 
hematopoietic cell transplant (HCT) for non-malignant conditions (literature references available 
upon request).  Similarly, AVROBIO reviewed the literature for busulfan conditioning before 
LV-mediated gene therapy for non-malignant conditions (literature references available upon 
request). With the exception of the single case of t-MDS noted above, no other cases of t-MDS, 
leukemia, cancer, or pre-cancerous lesions were reported in over 700 exposures to busulfan 
conditioning for non-malignant conditions. Based on this literature review, the risk of t-MDS or 
leukemia due to busulfan conditioning before LV-mediated gene therapy for non-malignant 
conditions appears to be low. Nevertheless, bone marrow aspirate and peripheral blood samples 
will be collected at baseline and stored for subsequent evaluation should hematologic cancer be 
observed. 
The potential impact, if any, of the conditioning regimen used in this study is not fully 
understood and may result in infertility. To off-set the potential risk of infertility in the study, 
males will be offered sperm cryopreservation. The impact of the conditioning regimen on the 
baseline in sperm count, morphology, and motility. Reproductive outcomes, if any, will be 
monitored and recorded during this study. 
6.2.3. 
Efficacy and Safety Measures 
In the AVRO-RD-01-201 study, measures of engraftment of gene-augmented HSCs will be 
evaluated by determining average VCN in peripheral blood and bone marrow stem and 
progenitor cells using qPCR and/or ddPCR. To ensure subject safety, a CD34+ stem-cell back-up 
of nontransduced cells will be collected and stored at the investigational site for use as rescue 
treatment in the unlikely event that there is a transplant failure or prolonged bone marrow aplasia 
after AVR-RD-01 transplant (see Section 8.1.1.1). 
Efficacy measures chosen for the planned AVRO-RD-01-201 study have been commonly used to 
measure treatment effects in trials of ERT and chaperone therapy for Fabry disease (Eng 2001; 
Schiffmann 2001; Ries 2006; Germain 2007; Germain 2012; Ramaswami 2007; van Breemen 
2011; Hughes 2017). The following were considered in the choice of efficacy and safety 
endpoints, and the timing of related assessments: 
 The natural history of Fabry disease, and the clinical progression of signs/symptoms 
known to impact morbidity and mortality in patients with the disease.  
 Regulatory guidelines for follow-up of subjects receiving gene therapy products (ie, 
United States Department of Health and Human Services, FDA, Center for Biologics 
Evaluation and Research [CBER], Guidance for Industry, Long Term Follow-Up 
After Administration of Human Gene Therapy Products, January 2020; United States 
Department of Health and Human Services, FDA, CBER, Guidance for Industry, 


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Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication 
Competent Retrovirus During Product Manufacture and Patient Follow-up, January 
2020; EMA, Guideline on Follow-up of Patients Administered with Gene Therapy 
Medicinal Products, October 2009).  


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7. 
STUDY POPULATION 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened once upon discussion between the Investigator and Medical Monitor.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
7.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria for participation in this study: 
1. 
defined as: 
 
 
 
l, defined as having adult male testicular 
volume (where permitted by region) 
2. Subject has a confirmed diagnosis of classic Fabry disease based on deficient AGA 
enzyme activity in peripheral blood leukocytes (defined as <1% of normal) at the time of 
Screening. 
3. Subject with female spouse/partner of childbearing potential (defined as all women 
physiologically capable of becoming pregnant; this includes any female who has 
experienced menarche and who has not undergone successful surgical sterilization [ie, 
hysterectomy, bilateral tubal ligation, or bilateral ovariectomy] or is not postmenopausal 
[defined as amenorrhea >12 consecutive months and increased serum follicle-stimulating 
hormone level (ie, >30 IU/L) on at least 2 occasions (in the absence of hormone 
replacement therapy, dietary phytoestrogens) or estradiol concentration <10 pg/mL]) 
must be willing to remain sexually abstinent or use double-barrier method while sexually 
active from conditioning therapy administration until 48 weeks post transplantation (ie, 
the Week 48 study visit). Barrier contraception is required even with documented 
medical assessment of surgical success of a vasectomy. For female spouse/partner, 
acceptable methods of barrier contraception include diaphragm, cervical cap, or 
contraceptive sponge. 
4. Subject must be willing to refrain from donating sperm any time after receiving 
conditioning therapy. For subjects planning on (or for whom there is a possibility of) 
fathering children in the future, sperm banking prior to administration of the conditioning 
regimen will be recommended.  
5. Subject must be willing to refrain from donating blood, organs, tissues, or cells for 
transplantation at any time after AVR-RD-01 transplant. 
6. Subject and/or parent (or legal guardian) must be willing and able to provide written 
informed consent (and assent, if applicable) for the study in accordance with applicable 
regulations and guidelines and to comply with all study visits and procedures, including 
the use of any data collection device(s) that may be used to directly record subject data.


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7.2. 
Exclusion Criteria 
Subjects will be excluded from participation in this study if they meet any of the following 
exclusion criteria: 
1. Subject has a GLA gene mutation associated with late-onset cardiac variant Fabry 
disease, including: 
 N215S (c.644A>G [p.Asn215Ser]) 
 M296V (c.886A>G [p.Met296Val]) 
 R301Q (c.902G>A [p.Arg301Gln]) 
 Q279E (c.835C>G [p.Gln279Glu]) 
 A20P (c.58G>C [p.Ala20Pro]) 
2. Subject has received any ERT and/or chaperone therapy for Fabry disease within 3 years 
of Screening. Subjects who received ERT and/or chaperone therapy more than 3 years 
from Screening are eligible for study participation as long as all other study 
inclusion/exclusion criteria are met. 
3. Subject has histopathologic findings on skin biopsy at Screening that indicate no or trace 
Gb3 accumulation (ie, score of 0 as defined in Thurberg, 2011). 
4. Subject has tested positive for anti-AGA antibodies at the time of Screening. 
5. 
Screening. 
6. 
een on a stable dose of an appropriate 
anti-proteinuric medication for at least 3 months. Subjects with significant proteinuria 
Screening may be rescreened for study participation after they have been on a stable dose 
of an appropriate anti-proteinuric medication for at least 3 months. 
7. Subject has evidence of any clinically relevant renal disease, in the opinion of the 
Investigator, not attributed to Fabry disease (eg, nephrotic syndrome, repeated episodes 
of pyelonephritis, obstructive uropathy, red blood cell [RBC] casts on urinalysis, kidney 
size discrepancy >1.5 centimeters, evidence of other renal disease on kidney biopsy 
performed at Screening). 
8. Subject has a prior history of myocardial infarction (MI). 
9. Subject has a history of coronary artery disease (CAD) with angina requiring 
percutaneous transluminal coronary angioplasty (with or without stent placement) and/or 
coronary artery bypass graft (CABG). 
10. Subject has a history of moderate to severe valvular heart disease requiring valve 
replacement. 


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11. Subject has a history of heart failure, moderate to severe diastolic dysfunction, and/or left 
at Screening. 
12. Subject has a history of clinically significant cardiac arrhythmia (eg, heart block [second 
or third degree], atrial fibrillation requiring therapy [history of intermittent atrial 
fibrillation not requiring treatment is allowed], ventricular fibrillation, ventricular 
tachycardia, supraventricular tachycardia, or cardiac arrest). 
13. 
at 
screening may be rescreened for study participation after they have been on a stable dose 
of an appropriate antihypertensive medication for at least 3 months. 
14. Subject is on (or requires treatment with) any anticoagulant (warfarin, dabigatran, or 
other oral anticoagulant; or heparin) from 30 days prior to signing informed consent at 
Screening (ie, study enrollment) through the Week 48 study visit. Use of antiplatelet 
agents are permitted, however should be withheld in the presence of bleeding or platelet 
counts <50 x 109/L. 
15. Subject has a prior history of stroke and/or transient ischemic attack (TIA). 
16. Subject has aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
 times the upper limit of normal (ULN) at Screening. 
17. Subject has forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), 
(corrected for hemoglobin) on pulmonary function testing performed at Screening. 
18. Subject has diabetes mellitus (type 1 or type 2). 
19. Subject has an active chronic infection during the Screening, Baseline, or Pre-transplant 
Period of the study. 
20. Subject has an active uncontrolled acute bacterial, viral, fungal, parasitic, or 
prion-associated infection during the Screening, Baseline, or Pre-transplant Period of the 
study. 
21. Subject has a history of (or current) tuberculosis. 
22. Subject tests positive for hepatitis B virus (HBV), hepatitis C virus (HCV), human 
immunodeficiency virus (HIV, type 1 or 2), human T-cell lymphotropic virus (HTLV)-1, 
HTLV-2, and/or syphilis on Venereal Disease Research Laboratory (VDRL) test, 
chemiluminescent microplate immunoassay (CMIA), or enzyme immunosorbent assay 
(EIA) at Screening. 
23. Subject has a prior history of (or current) malignancy; the one exception is a prior history 
of resected basal cell carcinoma. 
24. Subject has any other medical condition that predisposes him to (or conveys increased 
risk of) malignancy. 
25. Subject has undergone, or is scheduled to undergo, bone marrow transplant and/or solid 
organ transplant. 


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26. Subject has hematological compromise evidenced by white blood cell count (WBC) 
<3.0 x 109/L, platelet count <100 x 109/L, hemoglobin <100 g/L, and/or uncorrected 
bleeding disorder from signing informed consent at Screening (ie, study enrollment) 
through the Transplant Period of the study (ie, the day of AVR-RD-01 infusion). 
27. Subject has clinically significant immunodeficiency disease or condition, in the opinion 
of the Investigator, at Screening. 
28. Subject is on (or requires treatment with) cytotoxic or immunosuppressive agents from 
60 days prior to signing informed consent at Screening (ie, study enrollment) through the 
Week 48 study visit; the one exception is treatment with cytotoxic or immunosuppressive 
agents required per protocol for stem cell transplant.  
29. Subject has contraindication to iohexol. 
30. Subject has any condition that makes it impossible to perform MRI studies (including 
allergies to anesthetics). 
31. Subject has medical conditions(s) and/or is receiving medication(s) that would 
contraindicate ability to undergo mobilization (including contraindication to G-CSF 
and/or plerixafor), apheresis, or receive myeloablative therapy for conditioning. 
32. Subject has any medical, psychological, or other condition that, in the opinion of the 
Investigator: 
 
to procedures); and/or 
 Poses any additional risk to the subject; and/or  
 Might confound the results of any study-required assessments. 
33. Subject has previously received treatment with AVR-RD-01 or any other gene therapy. 
34. Subject is participating in (or plans to participate in) any other investigational drug trial, 
or plans to be exposed to any other investigational agent, device and/or procedure, from 
30 days prior to signing informed consent at Screening (ie, study enrollment) through 
study completion. 
7.3. 
Rationale for Inclusion or Exclusion of Certain Study Candidates 
AVR-RD-01 is an ex vivo LV-mediated gene-modified autologous cell therapy intended for the 
durable provision of functional AGA for patients with Fabry disease. It was determined that for 
this early phase proof-of-concept study, the most robust assessment of safety and efficacy would 
be generated in adult male subjects with classic Fabry disease without any recent ERT and/or 
chaperone therapy for Fabry disease (ie, a treatment-naïve Fabry disease patient population), to 
eliminate the variability in heterozygous subjects and to provide the best opportunity to evaluate 
AVR-RD-01 without the potential confounding effects associated with prior Fabry disease-
specific therapies. Thus: 
 Inclusion criteria [1] and [2] specify the study population as adult male subjects with 
 


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 Exclusion criterion [1] explicitly states subjects with certain mutations that have been 
associated with late-onset cardiac variant Fabry disease are excluded from the study 
population. 
 Exclusion criterion [2] eliminates subjects that have received any ERT and/or chaperone 
therapy for Fabry disease within 3 years of Screening. 
 Both ERT and chaperone therapy have been shown to have an effect on 
increasing functional AGA enzyme (either through direct replacement or 
modification of endogenous enzyme), with the therapeutic goal of reducing the 
substrates (glycosphingolipids) that accumulate in Fabry disease, including Gb3 
and its deacylated form, lyso-Gb3. Considering this, inclusion of subjects with 
any recent exposure to ERT and/or chaperone therapy for Fabry disease may 
confound efficacy results for Study AVRO-RD-01-201. Based on the progression 
of renal Fabry disease described in natural history studies, as well as the data 
evaluating the impact of previous ERT shortage (Smid, 2011; Weidemann, 2014), 
one would expect reaccumulation of substrate to pre-treatment levels within 3 
years in patients who discontinue ERT or chaperone therapy. 
 Exclusion criterion [3] eliminates subjects that have histopathologic findings on skin 
biopsy at Screening that indicate no or trace Gb3 accumulation (ie, score of 0 as defined 
in Thurberg, 2011). 
 Histopathologic findings on skin biopsy at Screening that are essentially normal 
suggest that these subjects may have insufficient substrate accumulation to permit 
evaluation of substrate-related efficacy endpoints (including the primary efficacy 
endpoint) for the study. 
 Exclusion criterion [4] eliminates subjects that test positive for anti-AGA antibodies at 
the time of Screening 
 Inclusion of subjects with recent ERT and/or chaperone therapy for Fabry disease 
may confound safety results, considering Study AVRO-RD-01-201 is assessing 
development of immunogenic response to AVR-RD-01 through anti-AGA 
antibody assay. 
Other exclusion crite
transplantation. 
7.4. 
Discontinuations 
7.4.1. 
Discontinuation of Subjects 
The criteria for enrollment must be followed explicitly. If it is discovered that a subject who did 
not meet enrollment criteria was inadvertently enrolled prior to AVR-RD-01 infusion, the subject 
will be discontinued from the study. If the subject received any study-related treatments or 
experienced an AE, they will be followed for 30 days or until the AE resolves, whichever is 
longer (see Section 9.3). 
Subjects who discontinue from the study prior to infusion of AVR-RD-01 will be replaced. 


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In addition, subjects may be discontinued from the study in the following circumstances: 
 The subject 
requests to be withdrawn from the study 
 Sponsor Decision 
 
participation in the study for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and Good Clinical Practice (GCP)
 The Sponsor or its designee discontinues the clinical study at a particular 
investigative site 
 Adverse Event  
 If the Investigator decides that the subject should be withdrawn because of an 
SAE or a clinically significant laboratory value, study-related procedures are to be 
discontinued and appropriate safety measures taken. The Sponsor or its designee 
is to be alerted immediately.  
7.4.2. 
Discontinuation of Study Sites/Site Terminated by Sponsor 
Study site participation may be discontinued if the Sponsor or its designee, the Investigator, or 
the Research Ethics Board/Human Research Ethics Committee/Institutional Review Board 
(REB/HREC/IRB) of the study site judges it necessary for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and GCP. 
7.4.3. 
Discontinuation of the Study/Study Terminated by Sponsor 
The study will be discontinued if the Sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 
7.4.4. 
Study Stopping Rules 
If either of the following occur, transplantation procedures in additional subjects will be 
temporarily suspended, and a safety review meeting will take place with the DMC and the 
Sponsor: 
 Death of a subject that is attributed as probably or definitely related to AVR-RD-01
 Any individual subject shows no evidence of engraftment at the Week 4 or Week 24 
assessments (based on average VCN or AGA enzyme activity in plasma) 
Transplantation procedures may resume if appropriate changes to study conduct are identified 
and implemented to reduce any risks to subjects going forward. 


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8. 
TREATMENT 
8.1. 
Treatments Administered 
The Sponsor identifier for the investigational product is AVR-RD-01. The active substance in 
AVR-RD-01 is autologous CD34+-enriched cell fraction transduced with LV/AGA containing a 
RNA transcript that, after reverse transcription, results in codon-optimized cDNA that, upon its 
integration into the human genome, encodes for functional human AGA. The finished 
investigational product is presented as a cryopreserved cell solution which is thawed 
immediately prior to use. The investigational product is intended for one-time IV infusion of 
between 3 and 20 x 106/kg body weight autologous CD34+ transduced cells.  
In addition to AVR-RD-01, subjects will receive the following as part of the autologous 
transplant procedure in this study: 
 Four to eight G-CSF and two plerixafor injections for HSC mobilization prior to 
AVR-RD-01 infusion 
 Additional G-CSF injections may also be administered beginning Day 5 after 
AVR-RD-01 transplant until defined absolute neutrophil count (ANC) is achieved 
 Five IV infusions of busulfan, one test dose to inform the conditioning dose and four 
for myeloablative conditioning, prior to AVR-RD-01 transplant 
 Anticonvulsant medication administration, concurrent with busulfan administration, 
for seizure prophylaxis 
 Levetiracetam will be administered. If levetiracetam is contraindicated, an 
alternative anticonvulsant medication (eg, benzodiazepines or valproic acid) may 
be used. 
Further details on treatment administration (including dosing regimens) are described in 
Sections 8.1.1 through 8.1.3. Additional details can also be found in the Study Treatment 
Manual. 
8.1.1. 
Pre-transplant Period (Approximately 6 to 8 Weeks) 
8.1.1.1. 
Mobilization and Apheresis 
 
On Mobilization Days 1 through 4, subjects meeting eligibility criteria for study participation 
will receive a daily G-CSF dose of 10 µg/kg body weight administered IV or subcutaneously 
(SC) (for sites with only prefilled syringes, a G-CSF daily dose from 10 µg/kg body weight up to 
12 µg/kg body weight, administered in either a single or divided twice a day [BID] dose, may be 
administered). On the evening of Mobilization Day 4, subjects will receive an injection of 
plerixafor (0.24 mg/kg).  
Between 10 and 12 hours after the plerixafor injection (ie, the morning of Apheresis Day 1), 
peripheral blood by apheresis, using standard institutional procedures at the participating 
investigational study site. The apheresis unit obtained on Apheresis Day 1 will be shipped to the 


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manufacturing site for cell transduction and processing (see Section 8.1.1.2). On the evening of 
Apheresis Day 1, subjects will receive a second injection of plerixafor (0.24 mg/kg).  
On the morning of Apheresis Day 2, subjects will undergo an additional harvest of mononuclear 
eral blood by apheresis, using 
standard institutional procedures at the participating investigational study site. CD34+ cells 
harvested from this apheresis (nontransduced cells) will be retained and stored at the 
investigational site for use as rescue treatment in the unlikely event that there is a transplant 
failure or prolonged bone marrow aplasia after AVR-RD-01 transplant. 
After each apheresis (ie, on Apheresis Days 1 and 2), total cell count (per µL) and CD34+ cell 
enumeration by flow cytometry will be performed at the participating investigational study site 
to ensure an adequate number of cells have been procured for CD34+ cell selection. The target 
number of cells for the Apheresis Day 1 collection is 6.5 x 1010 total cells and 6.5 x108 CD34+
cells (shipped to the manufacturing site for transduction) and the target number of cells for the 
Apheresis Day 2 collection is at least 3 x 106 CD34+ cells/kg body weight (retained at the site). 
Details on timing for mobilization and apheresis are outlined in the Schedule of Assessments in 
Section 14.1, and details on the processes may be found in the Study Treatment Manual. 
8.1.1.2. 
Investigational Product Preparation/Testing for Release 
Following harvest on Apheresis Day 1, the apheresis unit from that day will be transported under 
temperature-controlled conditions (2 to 8ºC) to a manufacturing site for further processing. The 
manufacturing of AVR-RD-01 investigational product is compliant with applicable current Good 
Manufacturing Practices (cGMP). 
AVR-RD-01 investigational product will be tested for identity, potency, purity, and safety prior 
to release for clinical use. Transduction efficiency and the number of transduced cells for each 
product are reported on certificate of analysis. AVR-RD-01 Drug Product lot must meet drug 
product release specification prior to use in the clinic. 
Once the release testing is complete, AVR-RD-01 investigational product will be dispositioned 
for clinical use and sent to the investigational site in a dry shipper with Certificate of 
Analysis(es), documenting that all release testing specifications for clinical use have been met, 
and that the investigational product can be used in humans. 
8.1.1.3. 
Conditioning 
After receipt of the investigational product dispositioned for clinical use at the investigational 
site, the subject will enter the Conditioning phase. During this phase of the study, subjects will 
receive a 4-day myeloablative conditioning regimen of IV busulfan, informed by a weight-based 
test dose of 0.8 mg/kg administered on Conditioning Day -6, prior to the 4-day myeloablative 
conditioning regimen administered on Conditioning Days -4 to -1. The test dose will serve to 
establish the predicted PK for each individual subject, as part of the TDM.  
For Conditioning Days -4, -3, -2, and -1, a centralized, web-based dose simulation program will 
be used to determine the busulfan dose required for each subject to achieve the busulfan target 
AUC. The myeloablative cumulative target AUC for busulfan is 90(day 0-4) +/- 0% mg hr/L. 
Therapeutic drug monitoring will be performed to target the cumulative busulfan AUC for the 


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4 days of conditioning. Once-daily dosing of IV busulfan with TDM will be administered as 
follows (see also Table 1): 
 On Conditioning Days -4 and -3, a PK- and weight-based guided IV busulfan dose, based 
on TDM PK of the test dose on Day -6 and the respective calculated AUC generated from 
the web-based dose simulation program, will be administered (Table 1). 
 For Conditioning Day -2, the web-based dose simulation program will be used to 
determine the busulfan dose required for each subject to achieve the busulfan target AUC 
based on TDM PK of the test dose and Day -4 (Table 1). 
 For Conditioning Day -1, the web-based dose simulation program will be used to 
determine the busulfan dose required for each subject to achieve the busulfan target AUC 
based on TDM PK of the test dose, Day -4, and Day -3 (Table 1). 
 If AUC of the previous dose is outside of +/- 0% of the AUCtarget determined by the 
web-based dose simulation program, the busulfan dose will be adjusted accordingly. 
Table 1: 
PK- and Weight-based Guided Busulfan Conditioning Regimen 
 
Dosing Day 
Busulfan Dose (mg/kg/day) 
TDM PK Schedule for 
Busulfan Dose Determination 
Day -6 
Test dose of 0.8 mg/kg 
PK sampling at 1, 3, 5 and 7 
hours post dose; TDM PK 
results will be used to inform the 
dose on Day -4 and Day -3 
Day -4 
Dose based on TDM PK of test 
dose 
 
PK sampling at 1, 3 and 5 hours 
post dose; TDM PK results will 
be used to inform the dose on 
Day -2 together with TDM PK 
results from the test dose
Day -3 
Dose based on TDM PK of test 
dose 
PK sampling at 1, 3 and 5 hours 
post dose; TDM PK results will 
be used to inform the dose on 
Day -1 together with TDM PK 
results from the test dose and 
Day -4  
Day -2 
Dose based on TDM PK of test 
dose and Day -4 
PK sampling at 1, 3 and 5 hours 
post dose; TDM PK results will 
be used to inform the 
cumulative AUC
Day -1 
Dose based on TDM PK of test 
dose, Day -4, and Day -3 
PK sampling at 1, 3 and 5 hours 
post dose; TDM PK results will 
be used to inform the 
cumulative AUC
Abbreviations: AUC = area-under-the curve; PK = pharmacokinetics; TDM = therapeutic drug monitoring 
Anticonvulsant medication will also be administered for seizure prophylaxis concurrent with 
busulfan administration. Levetiracetam will be administered at a dosage of 1000 mg per day, 
beginning on Conditioning Day -8 (ie, two days prior to administration of the busulfan test dose), 
and continuing until one day after administration of the 4-day busulfan conditioning regimen. 
For subjects with a contraindication to levetiracetam, alternative anticonvulsant medications (eg, 


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benzodiazepines or valproic acid) may be used before and after busulfan treatment (Busulfan 
Prescribing Information). 
After the 4-day conditioning regimen is administered, a busulfan washout period of a minimum 
of 48 up to a maximum of 72 hours, is required prior to AVR-RD-01 administration. 
Details on the timing of all Conditioning procedures, including the busulfan washout period, are 
outlined in the Schedule of Assessments in Section 14.2, with additional information included in 
the Study Treatment Manual. 
8.1.2. 
Transplant Period (1 Day) 
After completion of the busulfan washout period (ie, a minimum of 48 up to a maximum of 
72 hours after the last busulfan infusion), AVR-RD-01 will be administered once by IV infusion. 
Prior to the IV infusion, subject identifiers on the AVR-RD-01 investigational product must be 
checked against the intended recipient, and investigational product must be thawed at 37ºC.  
Further details on the transplant process can be found in the Study Treatment Manual. 
8.1.3. 
Post-transplant Follow-up Period (Approximately 48 Weeks) 
After AVR-RD-01 infusion, the subject will enter the Post-transplant Follow-up Period, during 
which time periodic safety and efficacy assessments will be performed to monitor safety 
post-transplant, and to assess measures of engraftment and clinical response.  
In particular, safety laboratory assessments will be performed daily for the first 7 days after 
AVR-RD-
 
9/L, G-CSF 
injections of 5 µg/kg body weight (for sites with only prefilled syringes, a G-CSF dose from 
4 µg/kg body weight up to 6 µg/kg body weight, administered in either a single or divided BID 
dose, may be administered) will be administered every morning, and a blood sample for ANC  
collected, until the subject achieves an ANC >1.5 x 109/L.   
8.2. 
Materials and Supplies 
AVR-RD-01 
The finished investigational product is presented as a cryopreserved product which is thawed at 
37ºC immediately prior to use. The thawed investigational product is intended for one-time IV 
infusion of between 3 and 20 x 106/kg body weight autologous CD34+-enriched HSCs that have 
been genetically modified. 
Upon receipt at the investigational site, cryopreserved investigational product must be 
maintained cryopreserved in vapor-phase liquid nitrogen until ready to thaw for clinical use. 
Thawed investigational product maintained at controlled room temperature in cryopreservation 
media is stable for up to 3 hours.  
Traceability from the initiation of autologous HSC procurement through the completion of 
AVR-RD-01 infusion must be ensured through labeling and documentation control at each step. 
Investigational sites are required to maintain labeling control and documentation to support these 
steps.  


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Any unused AVR-RD-01 investigational product should be disposed of in accordance with local 
biosafety requirements. 
Further details can be found in the Study Treatment Manual. 
Other Study Treatments 
For storage requirements, handling, and stability of other study treatments (ie, pre-transplant 
G-CSF and plerixafor injections, busulfan infusions, and levetiracetam [or other anticonvulsant 
 
8.3. 
Dosing Considerations 
8.3.1. 
Rationale for Selection of Doses in the Study 
The goal of the transplant is to provide as many CD34+ transduced cells as possible. Due to 
variables in individual apheresis results, the actual number of infused transduced cells will vary 
per subject. The AVR-RD-01 dose range to be administered is between 3 and 20×106/kg body 
weight autologous CD34+-enriched cells that are genetically modified ex vivo with a LV 
containing a RNA transcript that, after reverse transcription, results in codon-optimized cDNA 
that, upon its integration into the human genome, encodes for functional human AGA. This is 
based on well-established and accepted safe practices commonly used in autologous HSCT and 
has been shown to safely achieve hematopoietic reconstitution along with long-term engraftment. 
There is general consensus that a minimum dose of 3×106 cells/kg of mobilized CD34+ cells is 
required for favorable engraftment. Therefore, to be consistent with best practice, the lowest dose 
of AVR-RD-01 selected for the study is 3×106 cells/kg. The upper dose limit of 20×106 
CD34+ cells/kg is supported by preclinical safety studies conducted to date, which demonstrated 
tolerability at twice the maximum planned dose. 
8.3.2. 
Other Important Treatment Considerations 
AVR-RD-01 is not tested for transmissible infectious agents. Healthcare professionals handling 
AVR-RD-01 should therefore take appropriate precautions to avoid potential transmission of 
infectious diseases. 
A summary of precautions required and key toxicities associated with G-CSF, plerixafor, 
busulfan, and levetiracetam (or other anticonvulsant medication used) can be found in the 
-RD-01. Investigators should refer to the most current local 
prescribing information for full details regarding precautions required and a complete list of 
toxicities associated with G-CSF, plerixafor, busulfan, and levetiracetam (or other anticonvulsant 
medication used). 
Precautions should be taken during apheresis to avoid conditions such as hypotension, electrolyte 
abnormalities, citrate toxicity, thrombocytopenia, and coagulation abnormalities.  
Stem cell infusion can cause tightness in chest, hypotension, coughing, chest pain, decreased 
urine output, weakness, hypersensitivity reactions, electrolyte disturbances, and rarely, 
engraftment syndrome (fever, rash, non-cardiogenic pulmonary edema). Subjects should be 
cautioned on these and other potential side effects of stem cell infusion. 
Complete details regarding study treatments are contained in the Study Treatment Manual. 


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8.4. 
Blinding 
This is an open-label study. 
8.5. 
Concomitant Medications and Non-Pharmacologic Therapies and 
Procedures 
Treatment with ERT and chaperone therapy for Fabry disease is excluded from 3 years prior to 
signing informed consent (ie, study enrollment at Screening) through the Week 48 study visit. 
Treatment with cytotoxic or immunosuppressive agents is excluded from 60 days prior to signing 
informed consent (ie, study enrollment) through the Week 48 study visit; the one exception is 
treatment with cytotoxic or immunosuppressive agents required per protocol for stem cell 
transplant. Vaccinations post-transplant may be administered in accordance with standard of 
care. Treatment with anticoagulants (warfarin, dabigatran, or other oral anticoagulant; or 
heparin) is excluded from 30 days prior to signing informed consent (ie, study enrollment) 
through the Week 48 study visit due to bleeding risks and contraindications associated with study 
procedures, in particular, kidney biopsy. Use of antiplatelet agents are permitted, however should 
be withheld in the presence of bleeding or platelet counts <50 x 109/L. 
Certain medications must be discontinued temporarily prior to obtaining skin and renal biopsy 
samples. Aspirin, other platelet inhibitors, and anticoagulants must be discontinued at least 
10 days prior to the biopsies, and non-steroidal anti-inflammatory drugs must be discontinued at 
least 3 days prior to the procedure. Full details for collecting biopsy samples are contained in the 
Laboratory Manual.   
Subjects are prohibited from undergoing bone marrow transplant and/or solid organ transplant 
through the Week 48 study visit. 


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9. 
STUDY ASSESSMENTS  
An overview of required assessments for the study (including the timing of each) can be found in 
Section 14.1 (Schedule of Assessments from Screening through Investigational Product 
Preparation and Testing for Release in the Pre-Transplant Period), Section 14.2 (Schedule of 
Assessments from the Pre-Transplant Conditioning Period through Transplant [Day 0]), and 
Section 14.3 (Schedule of Assessments for the Post-Transplant Follow-up Period [Study Week 1 
(Day 1) through Study Week 48 (Day 336)]). 
9.1. 
Efficacy Measures  
9.1.1. 
Primary Efficacy Measure: Globotriaosylceramide (Gb3) Inclusions in 
Peritubular Capillaries (PTC) on Kidney Biopsy 
Kidney biopsies will be collected at the times shown in the Schedule of Assessments 
(Sections 14.1 and 14.3).  
Electron microscopic images of kidney biopsy samples will be taken and read centrally by two 
independent renal pathologists. The renal pathologists will score the average number of Gb3 
inclusions (ie, myelinosomes) per kidney PTC per subject using a quantification method similar 
to the Barisoni Lipid Inclusion Scoring System (BLISS) previously described for light 
microscopy (Barisoni 2012).  
Details on collection, processing, and shipment of kidney biopsy samples will be included in the 
Laboratory Manual.  
9.1.2. 
Secondary Efficacy Measures 
The following secondary efficacy measures will be collected at the times shown in the Schedule 
of Assessments (Sections 14.1, 14.2, and 14.3): 
 AGA enzyme activity in plasma and peripheral blood leukocytes: AGA activity will be 
measured in plasma and peripheral blood leukocytes using standard methods in an 
accredited central laboratory. 
 Biomarkers for Fabry disease (ie, Gb3 and its deacylated form, lyso-Gb3) in plasma and 
urine: Gb3 and lyso-Gb3 will be measured in plasma and urine using tandem mass 
spectrometry (MS/MS) analyses as described in the Laboratory Manual. Urine samples 
must be obtained from a second or third morning void. 
 Biomarkers for Fabry disease (ie, Gb3) in skin biopsy samples: Gb3 will be measured in 
skin from biopsy samples using MS/MS analyses. Details for collecting biopsy samples 
can be found in the Laboratory Manual. 
 Clinical laboratory measures of renal function: 
 mGFR: The mGFR will be determined using plasma clearance of iohexol 
(Delanaye, 2016a; Delanaye, 2016b). 
 eGFR: The eGFR will be determined using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation for adults (Levey, 2009), using 
serum creatinine collected with serum chemistry, normalized for age. 


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 Urine protein/albumin: Urine protein and albumin will be determined using 
samples from an overnight void. 
 Cardiac structure assessed by LVMI on cardiac MRI. 
 GI symptoms assessed by the DIBSS-D: The DIBSS-D is an event-driven, daily diary 
developed to measure changes in the severity of symptoms experienced by patients with 
diarrhea-predominant irritable bowel syndrome (IBS). This scale includes measures of 
bowel function (stool frequency, consistency, urgency) and abdominal symptoms 
(abdominal pain, discomfort, bloating, and cramping). Stool consistency and abdominal 
pain will be evaluated as secondary endpoints. 
 Pain assessed by the BPI-SF questionnaire: The BPI-SF is a 9-item self-administered 
e impact of this pain 
-point scale. 
 Functional status assessed by the SF-36: The SF-36 is a 36-item, patient-reported 
measure yielding eight subscale scores (Vitality, Physical Functioning, Bodily Pain, 
General Health Perceptions, Physical Role Functioning, Emotional Role Functioning, 
Social Role Functioning, and Mental Health) and two component summary scores 
(Physical Functioning and Mental Functioning). The secondary efficacy measure will be 
the component scores (ie, Physical Functioning and Mental Functioning). 
 Engraftment: Engraftment of gene-augmented HSCs will be assessed by determining 
average VCN in peripheral blood leukocytes and bone marrow stem and progenitor cells 
using qPCR and/or ddPCR analysis. Only peripheral blood leukocytes with an average 
, suggesting 
 of the sampled 
blood cells are vector positive, with an average of 1 copy per diploid genome (c/dg), will 
undergo ISA at the times specified in the Schedule of Assessments. 
9.1.3. 
Exploratory Efficacy Measures 
The following exploratory efficacy measures will be collected at the times shown in the Schedule 
of Assessments (Sections 14.1, 14.2, and 14.3): 
 Microscopic findings on kidney biopsy: Kidney biopsy samples will be evaluated for 
microscopic findings (eg, total number of globally sclerotic glomeruli, morphological 
finding in glomeruli, degree of tubular atrophy and interstitial fibrosis [scale of 0 to 3], 
and vascular intimal fibrosis [scale of 0 to 3]). 
 AGA enzyme activity in skin and kidney from biopsy samples: AGA activity will be 
measured in skin and kidney using standard methods in an accredited central laboratory. 
Details for collecting biopsy samples can be found in the Laboratory Manual. 
 Podocytes in urine: The number of podocytes per mL of urine, and per gram of urine 
creatinine, will be determined using immunofluorescence techniques on samples obtained 
from a second morning void. 
 GI symptoms assessed by the DIBSS-D: Stool frequency, recurrent bowel movements, 
urgency, and the abdominal symptom subscale score (abdominal pain, discomfort, 
bloating, and cramping) will be evaluated. 


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 Functional status assessed by the SF-36: The exploratory efficacy measure will be the 
eight subscale scores (Vitality, Physical Functioning, Bodily Pain, General Health 
Perceptions, Physical Role Functioning, Emotional Role Functioning, Social Role 
Functioning, and Mental Health). 
 To assess reconstitution dynamics, immunophenotyping of the fluorescence-activated 
cell-sorted peripheral blood subpopulation, as well as scRNAseq, will be performed, with 
the following subpopulations analyzed: T cells (CD3+), NK cells (CD56+), B cells 
(CD19+), granulocytes (CD15+), and monocytes (CD14+). Immunophenotyping and 
scRNAseq of the fluorescence-activated bone marrow CD34+ subpopulation will also be 
performed, with the following populations analyzed: HSCs (HSC CD34+CD38-
CD90+CD45RA-) and multipotent progenitors (MPP CD34+CD38-CD90-CD45RA-), 
multilymphoid progenitors (MLP CD34+CD38-CD90-CD45RA+), common myeloid 
progenitors (CMP CD34+CD38+CD7-CD10-CD135+CD45RA-), 
granulocytes/monocytes progenitors (GMP CD34+CD38+CD7-CD10-
CD135+CD45RA+), megakaryocyte/erythroid progenitors (MEP CD34+CD38+CD7-
CD10-CD135-CD45RA-), and Pre-B/NK progenitors (CD34+CD38+CD7-CD10+) cells. 
No whole genome sequencing will be performed. Details on peripheral blood and bone 
marrow sample collection, processing, and shipment will be included in the Laboratory 
Manual for the study. 
 To assess engraftment dynamics, average VCN will be determined, and ISA performed, 
on fluorescence-activated cell-sorted peripheral blood subpopulations and bone marrow 
CD34+ subpopulations, with the following analyzed for peripheral blood: T cells 
(CD3+), NK cells (CD56+), B cells (CD19+), granulocytes (CD15+), and monocytes 
(CD14+). For bone marrow, the following will be analyzed: HSCs (HSC CD34+CD38-
CD90+CD45RA-) and multipotent progenitors (MPP CD34+CD38-CD90-CD45RA-), 
multilymphoid progenitors (MLP CD34+CD38-CD90-CD45RA+), common myeloid 
progenitors (CMP CD34+CD38+CD7-CD10-CD135+CD45RA-), 
granulocytes/monocytes progenitors (GMP CD34+CD38+CD7-CD10-
CD135+CD45RA+), megakaryocyte/erythroid progenitors (MEP CD34+CD38+CD7-
CD10-CD135-CD45RA-), and Pre-B/NK progenitors (CD34+CD38+CD7-CD10+) cells. 
Details on peripheral blood and bone marrow sample collection, processing, and 
shipment will be included in the Laboratory Manual for the study. 
 Subject-reported (and caregiver- or other subject observer-reported) experience with 
AVR-RD-01 treatment and Fabry disease burden and quality of life assessed by 
qualitative interviews: With separate written informed consent, subjects will complete a 
series of qualitative interviews intended to collect direct feedback about their experience 
in the study, particularly with respect to AVR-RD-01 treatment and perception of 
changes in Fabry disease burden (eg, pain [including general and chronic pain, and pain 
crises]; gastrointestinal symptoms; fatigue; hearing loss and inner ear-related symptoms; 
cognitive, neurological and mood-related disease manifestations) and quality of life. With 
separate consent, caregivers or other individuals (observers) familiar enough with the 
daily life of participating subjects will also be asked to complete the same series of 
interviews. Casimir (Plymouth, MA, USA), an organization specializing in the capture of 
patient- and caregiver-reported data, will schedule and conduct the interviews. Interviews 


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will be conducted using a secure, web-based conferencing system, and only Casimir staff 
trained in qualitative research methods will conduct the interviews. Interviews will be 
conducted with a semi-structured interview guide, recorded and transcribed for analysis. 
Baseline interviews will assess disease-related burden and quality of life experience over 
the month preceding the interview, while Follow-up interviews will assess disease-related 
burden and quality of life experience since the preceding interview, as well as perceptions 
of change in their disease burden and quality of life. In addition, Follow-up interviews 
also assess subject experience with pre-treatment conditioning. Each interview takes 
approximately 60 minutes to complete. 
 Exploratory biomarkers for Fabry disease in plasma and urine: With separate subject 
consent (Optional Genetic Biomarker Research ICF), samples will be collected in plasma 
and urine for assessment of biomarkers for Fabry disease that may become available 
during or after the study. Samples obtained will be labele
may withdraw consent for use of biorepository samples at any time, as described in the 
Optional Genetic Biomarker Research ICF. Biorepository samples will be used only for 
this specific analysis, and will be destroyed 5 years after the Clinical Study Report (CSR) 
is finalized. 
9.2. 
Safety Assessments 
9.2.1. 
Physical Examinations 
A physical examination will be performed at the times specified in Sections 14.1, 14.2, and 14.3. 
Each examination will include the following assessments: general appearance; skin; head, ears, 
eyes, nose, and throat; neck; lymph nodes; chest; heart; abdomen; neurologic examination; and 
musculoskeletal system.  
If clinically significant changes from screening are noted, the changes will be documented as 
AEs in the AE electronic case report form (eCRF). Conditions present at the time informed 
consent is signed will be documented in the Medical History eCRF. Clinical significance is 
defined as any variation in physical findings that has medical relevance and may result in an 
alteration in medical care. The Investigator will continue to monitor the subject until the 
parameter returns to baseline or until the Investigator determines that follow-up is no longer 
medically necessary. 
9.2.2. 
Vital Signs 
The following vital signs will be recorded at the times specified in Sections 14.1, 14.2, and 14.3: 
heart rate (beats/minute), systolic and diastolic blood pressure (mmHg), respiratory rate 
(breaths/minute), and temperature (°C or °F). Vital signs will be obtained after the subject has 
been supine or seated. On Days 6 and 7 of the Apheresis phase of the Pre-transplant Period, vital 
signs must be taken prior to apheresis. On Day 0 of the Transplant Period (ie, the day of 
AVR-RD-01 infusion), vital signs must be taken pre-infusion (window -10 minutes) and 
post-infusion (window +10 minutes). Additional vital signs may be taken if clinically indicated 
and/or mandated per local institution practice for transplantation. 
If clinically significant vital sign changes as compared to screening are noted, the changes will 
be documented as AEs in the AE eCRF. Conditions present at the time informed consent is 


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signed will be documented in the Medical History eCRF. Clinical significance is defined as any 
variation in vital signs that has medical relevance and may result in an alteration in medical care. 
The Investigator will continue to monitor the subject until the parameter returns to baseline or 
until the Investigator determines that follow-up is no longer medically necessary. 
9.2.3. 
Serum Chemistry, Hematology, and Urinalysis 
Serum chemistry, hematology, and urinalysis will be performed at the times specified in 
Sections 14.1, 14.2, and 14.3. In particular, safety laboratory assessments will be performed daily 
for the first 7 days post-transplant (see Section 8.1.3). 
Serum chemistry includes AST, ALT, gamma-glutamyl transferase, amylase, alkaline 
phosphatase, lipase dehydrogenase, bilirubin, calcium, albumin, phosphate, magnesium, uric 
acid, and glucose. Electrolytes include sodium, potassium, chloride, and bicarbonate. 
Hematology includes hematocrit, hemoglobin, platelet count, WBC count (total and differential), 
RBC count, ANC, and flow cytometric analysis of peripheral blood lymphocyte subsets (CD3, 
CD4, CD8, CD19, and CD16/56). Urinalysis includes blood, glucose, protein, specific gravity, 
and microscopic examination (if clinically indicated). 
Laboratory assessments for safety will be tested at local laboratories. 
It is anticipated that some laboratory values may be outside of the normal value range due to the 
underlying disease or procedures associated with AVR-RD-01 transplant. As in routine practice, 
the Investigators should use their medical judgment when assessing clinical significance. Clinical 
significance is defined as any variation in laboratory measurements which has medical relevance 
and which results in a change in medical care. If clinically significant laboratory changes from 
the time informed consent is signed are noted, the changes will be documented as AEs in the AE 
eCRF. Any Grade 3 or higher platelet count, grade 3 or higher WBC count, and grade 2 or higher 
neutrophil count (grade determined by Common Terminology Criteria for Adverse Events 
[CTCAE] v4.03; see Section 9.3.1.2) must also be documented as an AE in the AE eCRF, 
regardless of whether considered clinically significant by Investigator report (see Section 9.3.1). 
For all clinically significant out-of-range values (and Grade 3 or higher platelet count, grade 3 or 
higher WBC count, and grade 2 or higher neutrophil count) documented as AEs, the Investigator 
will assess the relationship to study treatment (see Section 9.3.1.3). The Investigator will also 
continue to monitor the subject with additional laboratory assessments until (1) values have 
reached normal range and/or baseline, or (2) in the judgment of the Investigator, the values are 
not related to the administration of study drug or other protocol-specific procedures. 
9.2.4. 
Electrocardiograms 
For each subject, 12-lead digital ECGs will be collected according to the Schedule of 
Assessments (Sections 14.1, 14.2, and 14.3) as single ECGs for over-read. Subjects must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection. 
ECGs may be obtained at additional times, when deemed clinically necessary. Collection of 
more ECGs than expected at a given time point is allowed when needed to ensure high quality 
records. 


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ECGs will be interpreted by a qualified physician (the Investigator or qualified designee) at the 
site as soon after the time of ECG collection as possible, and ideally while the subject is still 
present, to determine whether the subject meets entry criteria and for immediate subject 
management, should any clinically relevant findings be identified. 
9.2.5. 
Pulmonary Function 
Spirometry will be performed according to the Schedule of Assessments (Sections 14.1, 14.2, 
and 14.3) per American Thoracic Society (ATS)/European Respiratory Society (ERS) Standards, 
using the National Health and Nutrition Examination Survey (NHANES) III reference standard. 
FEV1, FVC, and FEV1/FVC ratio will be collected; diffusing capacity of the lung for carbon 
dioxide (DLCO) must also be collected if FEV1 is not available. Actual values and percent 
predicted values will be recorded. 
9.2.6. 
Chest X-ray 
Standard chest x-rays will be performed according to the Schedule of Assessments 
(Sections 14.1, 14.2, and 14.3). 
9.2.7. 
Immunogenicity 
Blood samples for immunogenicity testing will be collected at the times specified in the 
Schedule of Assessments (Sections 14.1, 14.2, and 14.3) to assess for the presence of anti-AGA 
antibodies. Immunogenicity will be assessed using a qualified assay designed to detect anti-AGA 
antibodies. 
9.2.8. 
Testing for Replication Competent Lentivirus 
Peripheral blood samples will be collected for RCL testing at the times specified in the Schedule 
of Assessments (Sections 14.1, 14.2, and 14.3) to determine infection of non-target cells. Testing 
will be performed by qPCR; possible future serology testing may also be performed. 
Blood samples for qPCR will be tested centrally. Blood samples for possible future serology 
testing will be centrally stored. Details on blood sample collection, processing, and shipment will 
be included in the Laboratory Manual. 
9.2.9. 
Reproductive Potential 
Sperm samples for volume, sperm count, sperm concentration, total motility, progressive 
motility, and morphology will be collected at the times specified in the Schedule of Assessments 
(Sections 14.1, 14.2, and 14.3). Samples should be collected after at least 2 to 3 days of 
abstinence. Samples will be tested locally. For samples that yield abnormal results, an additional 
sample must be collected and tested to confirm the initial results. If test results indicate reduced 
fertility (eg, oligospermia or azoospermia, decreased sperm motility, and/or abnormal sperm 
morphology), investigational sites should follow institutional guidelines for further evaluation. 
For subjects continuing in the AVRO-RD-01-LTF01 study with reduced fertility at Week 48, 
sperm samples must also continue to be collected in that study until the subject demonstrates 
recovery. 


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9.2.10. 
Samples to be Archived for Possible Future Testing 
Peripheral blood and bone marrow aspirate samples will be collected at Baseline, as specified in 
the Schedule of Assessments (Section 14.1), and archived for possible future testing should a 
subject develop hematologic cancer. 
Details on sample collection, processing, and shipment will be included in the Laboratory 
Manual. 
9.3. 
Safety Monitoring 
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting the Sponsor or its designee to any event that seems unusual, even if the event 
may be considered an unanticipated benefit to the subject. 
The Investigator is responsible for the appropriate medical care of subjects during the study. 
The Investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study treatment or the study, and that caused the 
subject to discontinue before completing the study. The subject should be followed for 30 days 
or until the event is resolved, whichever is longer. Frequency of follow-up evaluation is left to 
the discretion of the Investigator. 
The Medical Monitor will monitor safety data throughout the course of the study. 
The Sponsor or designee will review SAEs within time frames mandated by company 
procedures. The Medical Monitor will, as appropriate, periodically review: 
 Trends in safety data 
 Laboratory analytes 
 Adverse events, including monitoring of infections and malignancies 
If a subject experiences elevated ALT or AST >3X ULN or elevated total bilirubin >2X ULN, 
clinical and laboratory monitoring should be initiated by the Investigator. Details for hepatic 
monitoring depend upon the severity and persistence of observed laboratory test abnormalities. 
To ensure subject safety and comply with regulatory guidance, the Investigator is to consult with 
al Monitor regarding collection of specific recommended clinical 
information and follow-up laboratory tests. 
9.3.1. 
Adverse Events 
An AE is any untoward medical occurrence in a clinical study subject who has been 
administered a medicinal product and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable or unintended sign (for example, an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to this medicinal product. 
For the purposes of this study, the definition of an AE also covers: 
 Medication errors and uses outside what is foreseen in the protocol, including 
accidental overdose, if an AE results from the error. 


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 Any Grade 3 or higher platelet count, grade 3 or higher WBC count, and grade 2 or 
higher neutrophil count (grade determined by CTCAE v4.03; see Section 9.3.1.2), 
regardless of whether considered clinically significant by Investigator report. 
The Sponsor has standards for reporting AEs that are to be followed, regardless of applicable 
regulatory requirements that may be less stringent.  
Cases of pregnancy that occur during paternal exposures to study treatment are to be reported 
(see Section 9.3.2). Data on fetal outcome are collected for regulatory reporting and drug safety 
evaluation. 
Study site personnel will record the occurrence and 
condition(s), including clinically significant signs and symptoms of the disease under treatment 
in the study. After the ICF is signed, site personnel will record any change in the condition(s) 
and the occurrence and nature of any AEs. Exceptions to this requirement are outlined in 
Section 9.3.1.1. 
9.3.1.1. 
Exemptions to Adverse Event Recording/Reporting 
For the purposes of this study, the following will not be considered AEs: 
 Situations where an untoward medical occurrence did not occur (eg, social and/or 
convenience admission to a hospital, inpatient busulfan conditioning and 
management), and anticipated day-to-day fluctuations of pre-existing disease(s) or 
condition(s) present or detected at the start of the study that do not worsen over the 
course of the study. 
 Lack of drug effect (because one of the objectives of this study is to establish the 
effect of AVR-RD-01 transplant). 
 Individual Fabry disease-related signs and symptoms assessed during the periodic 
visits for the study, which include physical examinations and laboratory studies. The 
physical examination content is outlined in Section 9.2.1. Key Fabry disease signs 
and symptoms will also be evaluated through the efficacy endpoints outlined in 
Section 9.1, which include patient-reported outcome measures for key Fabry disease 
symptoms such as pain, gastrointestinal abnormalities, and mental and physical 
functioning. 
9.3.1.2. 
Severity Assessment 
Adverse event severity will be graded using the CTCAE v4.03. The CTCAE is a descriptive 
terminology utilized for AE reporting. A grading (severity) scale is provided for each AE term 
(each CTCAE v4.03 term is a Medical Dictionary for Regulatory Activities [MedDRA] Lowest 
Level Term).  
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5, with unique 
clinical descriptions of severity for each AE based on this general guideline: 


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Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).a 
Grade 3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL.b 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
a Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
b Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.  
Change in severity of an AE should be documented based on specific guidelines in the eCRF 
completion guidelines. 
Severity and seriousness must be differentiated: severity describes the intensity of an AE, while 
the term seriousness refers to an AE that has met the criteria for an SAE (see Section 9.3.1.5). 
9.3.1.3. 
Causality Assessment 
Investigators will be instructed to report to the Sponsor or its designee their assessment of the 
potential relatedness of each AE (both serious and non-serious) to protocol procedures and/or 
study treatment. Causality assessments will be provided on the eCRF (and any additional forms, 
as appropriate). Causality relationship will be classified according to the definitions in Table 2. 




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 Not Recovered/Not Resolved: the event has not improved, or the subject has not 
recuperated 
 Fatal: termination of life as a result of an AE.  There should be only one AE marked 
with this outcome 
 Unknown: not known, not observed, not recorded, or refused 
Additional details can be found in the eCRF completion guidelines. 
9.3.1.5. 
Serious Adverse Events 
Serious adverse event collection begins after the subject has signed informed consent. Planned 
surgeries and/or hospitalizations should not be reported as SAEs unless the underlying medical 
condition has worsened during the course of the study. 
Study site personnel must alert the Sponsor or its designee of any SAE within 24 hours of 
Investigator awareness of the event via a Sponsor-approved method. This 24-hour notification 
requirement refers to the initial SAE information.  
An SAE is any AE from this study that results in 1 or more of the following outcomes: 
 Results in death  
 Requires or prolongs hospitalization 
 Is life threatening (that is, immediate risk of dying) 
 Persistent or significant disability/incapacity 
 Congenital anomaly or birth defect 
 Other medically important serious event 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
in the study has ended (including any protocol-required post-treatment follow-up), the 
causation. For subjects consenting and meeting eligibility for participation in the long-term 
follow-up study to AVRO-RD-01-201 (ie, Study AVRO-RD-01-LTF01), SAEs occurring after 
AVRO-RD-01-201 study completion should be reported in the AVRO-RD-01-LTF01 study.  
Information on SAEs expected in the study population independent of study treatment, and that 
will be assessed by the Sponsor in aggregate periodically during the course of the study, may be 
 


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9.3.1.6. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the associated 
detailed guidances or national regulatory requirements in participating countries require the 
reporting of SUSARs. The Sponsor has procedures that will be followed for the recording and 
expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances. 
9.3.1.7. 
Reporting Adverse Events 
All non-serious AEs must be recorded in the eCRF upon awareness.  
All SAEs must be reported to the Sponsor or designee, via the SAE contact in the Safety 
Management Plan, within 24 hours of the Investigator or their staff becoming aware of them. 
The Investigator must complete, sign, and date the SAE pages; verify the accuracy of the 
information recorded on the SAE pages with the corresponding source documents; and send a 
copy via electronic submission to the safety database or email. Facsimile transmission may be 
used in the event of electronic submission or email failure. 
When further information becomes available, the SAE Form should be updated with the new 
information and reported immediately via the same methods as the initial information.  
Additional follow-up information, if required or available, should be reported to the Sponsor or 
designee within 24 hours of the Investigator or their staff becoming aware of this additional 
information via the same manner as above.  
These timelines for reporting information to the Sponsor must be followed for all initial SAE 
reports and for all follow-up versions of the initial reports.  
SAE Forms should be kept within the appropriate section of the study files. SAEs should be 
reported to your local REB/HREC/IRB per institutional guidelines (see Section 9.3.1.9). 
All SAEs (related and unrelated) will be recorded from the signing of informed consent until the 
Week 48 (or Early Termination) Visit.  
For all SAEs the Investigator must provide the following: 
 Appropriate and requested follow-up information in the time frame detailed above
 Causality of the SAE(s) 
 Outcome of the SAE(s) 
 Redacted medical records and laboratory/diagnostic information 
9.3.1.8. 
Sponsor Reporting Requirements 
The Sponsor or its legal representative is responsible for notifying the relevant regulatory 
authorities of SAEs meeting the reporting criteria. This protocol will use the current 
criteria of an SAE will be determined by the Sponsor from the Reference Safety Document. 


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9.3.1.9. 
Investigator Reporting Requirements 
The Investigator must fulfill all local regulatory obligations required for study Investigators. It is 
ibility to notify the REB/HREC/IRB of all SAEs that 
occur at his or her site. Investigators will also be notified of all SUSAR events that occur during 
the clinical study. Each site is responsible for notifying its REB/HREC/IRB of these additional 
SAEs according to local requirements.  
9.3.2. 
Exposure During Pregnancy  
Pregnancy data will be collected during this study for all subjects. Should it occur, exposure 
during pregnancy (also referred to as exposure in-utero [EIU]) for this study would result from 
transmission of any study treatments via semen following paternal exposure. 
submit a pregnancy form to the Sponsor or designee via the same method as SAE reporting (see 
Section 9.3.1.7). When the outcome of the pregnancy becomes known (ie, spontaneous 
miscarriage, elective termination, normal birth, or congenital abnormality), the pregnancy form 
must be completed and returned to the Sponsor or designee. If additional follow-up is required, 
the Investigator will be requested to provide the information. 
For any partner pregnancies reported during the study, the pregnancy must be followed until the 
outcome of the pregnancy is known, even if the subject discontinues from the study. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that study treatment may 
have interfered with the effectiveness of a contraceptive medication. However, complications of 
pregnancy and abnormal outcomes of pregnancy are AEs, and many may meet criteria for an 
SAE (such as ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, 
or congenital anomaly). Elective abortions without complications should not be reported as AEs
9.4. 
Appropriateness of Measurements 
Efficacy and safety measures chosen for this study have been commonly used to measure 
treatment effects in trials of ERT for Fabry disease (van Breemen, 2011; Germain, 2007; Eng, 
2001; Schiffmann, 2001; Ries, 2006; Ramaswami, 2007). The following were considered in 
choosing efficacy and safety endpoints, and the timing of related assessments: 
 The natural history of Fabry disease, and the clinical progression of sign/symptoms 
known to impact morbidity and mortality in patients with the disease.  
 Regulatory guidelines for follow-up of subjects receiving gene therapy products (ie, 
United States Department of Health and Human Services, FDA, CBER, Guidance for 
Industry, Long Term Follow-Up After Administration of Human Gene Therapy 
Products, January 2020; United States Department of Health and Human Services, 
FDA, CBER, Guidance for Industry, Testing of Retroviral Vector-Based Human 
Gene Therapy Products for Replication Competent Retrovirus During Product 
Manufacture and Patient Follow-up, January 2020; EMA, Guideline on Follow-up of 
Patients Administered with Gene Therapy Medicinal Products, October 2009).  
 


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10. 
DATA QUALITY ASSURANCE 
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following: 
 Provide instructional material to the study sites, as appropriate 
 Provide start-up training to instruct the Investigators and study coordinators. This 
training will give instruction on the protocol, the completion of the eCRFs, and study 
procedures. 
 Make periodic visits to the study site 
 Be available for consultation and stay in contact with the study site personnel by 
email, telephone, and/or fax 
 Review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection 
 Conduct a quality review of the database 
In addition, the Sponsor or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site. The study may be audited by the Sponsor or 
its representatives, and/or regulatory agencies at any time. Investigators will be given notice 
before an audit occurs. 
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the study. If requested, the 
Investigator will provide the Sponsor, applicable regulatory agencies, and applicable 
REBs/HRECs/IRBs with direct access to original source documents. 
10.1. 
Data Collection and Storage 
All clinical raw data will be recorded promptly, accurately, and legibly, either directly into a data 
capture system as e-source data, or indelibly on paper (eg, ECG readings). A detailed list of the 
type (electronic or paper) and location for all source data will be included in the Trial Master 
File. When recorded electronically, CRFs will be electronically generated. All raw data will be 
preserved in order to maintain data integrity. The Investigator or designee will assume the 
responsibility of ensuring the completeness, accuracy, and timeliness of the clinical data 
recording. 
At each scheduled monitoring visit, the Investigator or designee will cooperate with the 
and completeness of data capture. 
The Investigator or designee will prepare and maintain adequate and accurate study documents 
(medical records, ECGs, AE and concomitant medication reporting, raw data collection forms) 
designed to record all observations and other pertinent data for each subject. 
The Investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors, and the REB/HREC/IRB to have direct access to all documents pertaining 
to the study. 


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11. 
STATISTICAL METHODS AND PLANNED ANALYSES 
11.1. 
General Considerations 
Prior to the analysis of the study data, a detailed SAP will be written describing all analyses to be 
performed. The SAP will contain any modifications to the analysis plan described below. Any 
changes to the statistical plans will be described and justified in the CSR. 
The study aims to explore the possibility of any indications of an efficacy response signal, as 
well as to assess safety and tolerability of AVR-RD-01. As such, all continuous efficacy, safety 
and tolerability endpoints will be summarized descriptively at each protocol-scheduled time 
point and as change from baseline. Continuous data will be summarized using descriptive 
summary statistics (number of non-missing observations, mean, standard deviation [SD], 
minimum, and maximum). Categorical data will be summarized as frequency counts and 
percentages at each protocol-scheduled time point. 
For all safety endpoints, baseline will be defined as the last available, non-missing observation 
prior to first study treatment administration, unless specifically mentioned otherwise. For all 
efficacy endpoints, baseline will be defined as the last available, non-missing observation prior 
to AVR-RD-01 administration. In general, Unknown, Not Done, Not Applicable, and other 
classifications of missing data will not be considered when calculating baseline observations. 
However, valid categorical observations will be considered for baseline calculations. In addition, 
non-missing results from unscheduled assessments prior to first study drug administration may 
also be considered in the calculation of baseline observations. 
Only data from nominal protocol-scheduled visits will be included in summary tables. Data from 
unscheduled visits will not be included in the summary tables but will be included in figures and 
listings. 
No formal hypothesis tests or statistical models are planned. 
11.2. 
Determination of Sample Size 
The sample size of 8 to 12 subjects chosen for this study was selected without statistical 
considerations, but was determined to be adequate to meet the study objectives. 
11.3. 
Analysis Sets 
Subject inclusion into each population defined below will be determined after database lock and 
prior to commencing the analysis. 
All Subjects Population 
The All Subjects population will consist of all enrolled subjects. The All Subjects population will 
be used for the summaries of all disposition and demographic and baseline data. In addition, all 
listings will also be produced using the All Subjects population. 
Safety Population 
The Safety population will consist of all enrolled subjects who receive any amount of study 
treatment. The Safety population will be used for the summaries of all safety data. 


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Efficacy Population 
The Efficacy population will consist of all enrolled subjects who received AVR-RD-01 
transplant, have no major protocol deviations, and have efficacy data both at baseline and at least 
one post-baseline assessment. The Efficacy population will be used for the summaries of all 
efficacy endpoints. 
11.4. 
Demographics and Baseline Characteristics 
Demographic (age, race, ethnicity, height, weight, and body mass index) and baseline data, 
including disease history and characteristics, will be summarized. Medical and surgical history 
will be coded using the most current MedDRA and summarized by System Organ Class and 
Preferred Term. All other data recorded at the screening assessment will be listed only. 
11.5. 
Subject Disposition 
The total number of subjects enrolled, treated, and included in each analysis population will be 
summarized. The number of subjects discontinuing the study early, along with the reason for 
early study discontinuation, will also be summarized. 
11.6. 
Concomitant Medications and Non-Pharmacologic Therapies and 
Procedures  
Medications used in this study will be coded using the most current World Health Organization 
Drug Dictionary Enhanced (WHO). 
The start dates of medications will be used to assign medications into the following categories:
 Prior medication: any medication that started before initial dosing of study treatment, 
regardless of when it ended 
 Concomitant medication: medication continued or newly received at or after initial 
dosing of study treatment  
Medications will be classified as a prior medication and/or a concomitant medication. If a 
medication has a missing or partial missing start/end date or time, and it cannot be determined 
whether it was taken before initial treatment or concomitantly, it will be considered as prior and 
concomitant. Prior and concomitant medications will be summarized by Anatomical Therapeutic 
Chemical (ATC) classification and drug preferred term; the summary tables will show the 
number and percentage of subjects taking each medication by ATC and preferred term. For 
subjects who take the same medication (in terms of the ATC and preferred term) more than once, 
the subject will be counted only once for that medication. 
Prior medication and concomitant medication will be listed and summarized separately. 
11.7. 
Treatment Compliance  
All study treatment administration data will be listed. As all study treatment will be administered 
at the investigational site, treatment compliance will not be determined for this study. 


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11.8. 
Efficacy Analyses  
All efficacy analyses will be conducted on the Efficacy Population. All raw and derived efficacy 
data will be listed. 
11.8.1. 
Primary Efficacy Analysis 
As previously reported (see Section 9.1.1), electron microscopic images of kidney biopsy 
samples will be read centrally by two independent renal pathologists. The renal pathologists will 
score the average number of Gb3 inclusions (ie, myelinosomes) per kidney PTC per subject 
using a quantification method similar to the BLISS previously described for light microscopy 
(Barisoni, 2012). 
The average number of Gb3 inclusions (ie, myelinosomes) per kidney PTC per subject at 
Baseline and Week 48 will be summarized using descriptive statistics. Observed values and 
changes from baseline will be summarized at each protocol-scheduled time point. 
Additional details on statistical analysis will be included in the SAP for the study. 
11.8.2. 
Secondary Efficacy Analyses 
Observed values and changes from baseline will be summarized at each protocol-scheduled time 
point. For questionnaire data, the appropriate scores will be calculated, and data will be 
summarized overall and for each domain, where relevant. 
11.8.3. 
Exploratory Efficacy Analyses  
For quantitative exploratory efficacy data collected, observed values and changes from baseline 
will be summarized at each protocol-scheduled time point. 
Descriptive summaries of average VCN and ISA results at each timepoint in each population 
analyzed will be provided by-subject for qualitative exploratory efficacy and safety assessment. 
For qualitative interviews conducted, thematic analysis will be performed to assess perception of 
changes over time in Fabry disease burden and quality of life, including impact of pre-treatment 
conditioning on participating subjects, to augment other clinical data collected in the study. 
11.9. 
Safety Analyses  
All safety analyses will be conducted on the Safety Population. 
11.9.1. 
Physical Examination and Vital Signs 
All individual vital signs results will be presented in data listings. Observed vital signs parameter 
values and changes from baseline will be summarized at each protocol-scheduled time point. 
Physical examination data will be listed only. 
11.9.2. 
Serum Chemistry, Hematology, and Urinalysis 
For serum chemistry, hematology (including peripheral blood lymphocyte subsets [CD3, CD4, 
CD8, CD19, and CD16/56]), and urinalysis, all individual clinical laboratory results will be 


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presented in data listings. Values outside the laboratory reference range will be flagged (low-L, 
high-H). 
Observed values and changes from baseline in clinical laboratory data will be summarized at 
each protocol-scheduled time point. Frequency tabulations of the number of normal and 
abnormal (low and high) records, as well as the number of clinically significant (CS) and not 
clinically significant (NCS) records, will also be summarized at each protocol-scheduled time 
point. Urinalysis results will be summarized at each protocol-scheduled time point, using 
frequency tabulations, and any available microscopic urinalysis results will be listed. 
In addition, shift tables presenting the number of subjects with abnormal values compared to 
baseline will be produced. 
11.9.3. 
Adverse Events 
Adverse events will be coded using MedDRA. Adverse events will be grouped by System Organ 
Class and Preferred Term and summarized. The summary tables will present the frequency and 
percentage of total subjects, by System Organ Class and Preferred Term. 
For the summaries of AEs, subjects who experience the same AE (in terms of the MedDRA 
Preferred Term) more than once will be counted only once for that event in the number of 
subjects; however, all occurrences of the same event will be counted in the number of events.
Adverse event summaries will be restricted to treatment-emergent AEs (TEAEs) only. Treatment 
emergent events are defined as AEs that commence on or after the time of first study treatment 
administration. Adverse events without an onset date or time will be defined as treatment 
emergent except where an incomplete date (eg, month and year) clearly indicates that the event 
started prior to the start of first study treatment administration, or the AE stop date indicates that 
the event started and/or stopped prior to the start of first study treatment administration. Adverse 
events will be summarized by study period (ie, Pre-transplant [Mobilization, Apheresis, or 
Conditioning], Transplant, or Post-transplant Follow-up). 
Incidence of AEs, as well as the duration, severity, relationship to study treatment, outcome, and 
actions taken, will be listed for each subject. In addition, listings of AEs leading to 
discontinuation of the study, SAEs, and deaths will be provided if applicable. 
The following AE summaries will be provided: 
 Overall summary of TEAEs: 
 Any TEAE 
 
 
 Any TEAE considered as related to any study treatment (assessed by the 
Investigator as being possibly related, probably related, or definitely related) 
 Any TEAE leading to discontinuation from the study 
 Any serious TEAE 
 Any life-threatening TEAE 
 Any TEAE leading to death 


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 TEAEs overall and by System Organ Class and Preferred Term 
 TEAEs related to any study treatment, overall and by System Organ Class and Preferred 
Term (a TEAE related to study treatment is defined as any TEAE assessed by the 
Investigator as being possibly related, probably related, or definitely related to any study 
treatment) 
 TEAEs by severity/CTCAE Grade, overall and by System Organ Class and Preferred 
Term 
 TEAEs leading to study discontinuation, overall and by System Organ Class and 
Preferred Term 
 Serious TEAEs, overall and by System Organ Class and Preferred Term 
In the summary tables, AEs will be presented by decreasing frequency across all subjects. 
11.9.4. 
Reproductive Potential 
Reproductive potential will be evaluated based on sperm count, morphology, and motility.  
All individual results collected will be presented in data listings. Values outside the laboratory 
reference range will be flagged (low-L, high-H), where applicable. 
Observed values and changes from baseline in reproductive endpoints will be summarized at 
each protocol-scheduled time point. Frequency tabulations of the number of normal and 
abnormal (low and high) records, as well as the number of CS and NCS records, will also be 
summarized at each protocol-scheduled time point. 
11.9.5. 
Other Safety Assessments  
All individual ECG parameter results and the clinical assessment of the ECG will be presented in 
data listings. Observed ECG parameter values and changes from baseline will be summarized at 
each protocol-scheduled time point. Clinical assessment of the ECG (Normal, Abnormal NCS, 
Abnormal CS) will be summarized using frequency tabulations. 
Anti-AGA antibody data will also be summarized.  
All other safety data, including results of vector ISA and testing for presence of RCL, will be 
listed only. 
11.10. 
Subgroup Analyses  
No subgroups are defined for this study. 
11.11. 
Other Statistical Issues 
11.11.1. 
Significance Levels 
Due to the small sample size, no formal statistical testing will be conducted. 
11.11.2. 
Missing or Invalid Data 
For subjects who are withdrawn from the study prior to study completion, all data compiled up to 
the point of discontinuation will be used for analysis. All withdrawals will be included in all 


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analyses up to the time of withdrawal. There will be no imputation for missing data, unless 
otherwise stated. 
11.12. 
Interim Analyses  
In this open-label study, after AVR-RD-01 transplant, measures of engraftment, clinical 
response, and safety are analyzed for each individual subject on an ongoing basis. Considering 
this, a discrete interim analysis of data collected in this study will not be performed. Final 
statistical analysis for the study will be performed after all enrolled subjects complete the Week 
48 assessments (or prematurely discontinue the study). Full analytical details for the study will 
be outlined in the SAP. 


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12. 
INFORMED CONSENT, ETHICAL REVIEW, AND 
REGULATORY CONSIDERATIONS 
12.1. 
Informed Consent 
The Investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study (including participating in the optional qualitative 
interviews and genetic biomarker research outlined in Section 9.1.3), including answering any 
questions the subject may have throughout the study, and sharing in a timely manner any new 
information tha
in the study and optional qualitative interviews and genetic biomarker research. 
Three ICFs, one for the study, one for the optional qualitative interviews, and one for the 
optional genetic biomarker research, will be used to explain the potential risks and benefits of 
study and optional qualitative interview and genetic biomarker research participation to the 
subject in simple terms before the subject is entered into the study, and to document that the 
subject is satisfied with his or her understanding of the risks and benefits of participating in the 
study and optional qualitative interviews and genetic biomarker research, and desires to 
participate.  
The Investigator is responsible for ensuring that informed consent is given by each subject or 
legal representative. This includes obtaining the appropriate signatures and dates on the ICF(s) 
prior to the performance of any protocol procedures and prior to the administration of 
investigational product. 
A legal representative must give informed consent for a minor to participate in this study. In 
addition to informed consent given by the legal representative, the minor may be required to give 
documented assent. 
For any caregivers or other qualified observers of subjects who opt to participate in qualitative 
interviews being conducted for the study, written informed consent will also be obtained for 
participation.  
consent and assent given by 
subjects or their legal representatives, as well any caregivers or other qualified observers of 
subjects who opt to participate in the qualitative interviews for the study. 
12.2. 
Data Monitoring Committee  
An independent DMC has been established for the study. The DMC will consist of clinical trial 
experts in stem cell transplantation, gene therapy, and Fabry disease independent of the study. 
The DMC will monitor the safety aspects of the trial, including review of safety data (including 
all SAEs) after subjects complete the Week 4 follow-up visit in accordance with the schedule 
outlined in Section 6.1. The DMC will also convene for a safety review if stopping rules for the 
study are met (see Section 7.4.4). Additional meetings may be scheduled as necessary. 
The specific responsibilities of the DMC are described in the DMC Charter, which is maintained 
as a separate document. 


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12.3. 
Ethical Review 
The Sponsor or its representatives must approve all ICFs before they are used at investigative 
sites(s). All ICFs must be compliant with the International Council for Harmonisation (ICH) 
guideline on GCP.  
Documentation of REB/HREC/IRB approval of the protocol and the ICF must be provided to the 
Sponsor before the study may begin at the investigative site(s). The REBs/HRECs/IRBs will 
review the protocol as required. 
 
 The current Inv
-RD-01 
 ICF 
 Relevant curricula vitae 
12.4. 
Regulatory Considerations 
This study will be conducted in accordance with: 
1. Consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
2. The ICH GCP Guideline (E6) 
3. Applicable laws and regulations 
The Investigator or designee will promptly submit the protocol to applicable 
REBs/HRECs/IRBs. 
Some of the obligations of the Sponsor will be assigned to a Third Party Organization. 
-related data. 
12.4.1. 
Investigator Information 
One PI will oversee the trial at each investigative site. The PI undertakes to perform the study in 
accordance with this clinical trial protocol, ICH GCP Guidelines, and the applicable national 
regulations and local REB/HREC/IRB requirements. 
The PI may appoint other individuals as he/she deems appropriate to assist in the conduct of the 
study. All appointed designees will be listed in the site delegation log. The appointed designates 
will be supervised by and under the responsibility of the PI. 
12.4.2. 
Protocol Signatures 
of her knowledge, the protocol accurately describes the planned design and conduct of the study.
After reading the protocol, each PI will sign the protocol signature page and send a copy of the 
signed page to a Sponsor representative. 


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12.4.3. 
Final Report Signature 
The CSR coordinating Investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.  
and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study. 
12.5. 
Publication Policy 
The full terms for publication are included in the clinical trial agreement between the Sponsor 
and the Investigator. 


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13. 
LIST OF REFERENCES 
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with phenytoin for the prevention of intravenous busulfan-induced seizures in hematopoietic 
cell transplantation recipients. Cancer Chemother Pharmacol. 2018 Oct;82(4):717-721. 
Baiamonte E, Barone R, Di Stefano R, Iacono ML, Spina B, Contino F, et al. Hematopoietic 
stem cell mobilization for gene therapy: the combination of G-CSF+plerixafor in patients with 
Beta-Thalassemia Major provides high yields of CD34+ cells with primitive signatures. Blood 
2015;126:4412. 
Barisoni L, Jennette JC, Colvin R, Sitaraman S, Bragat A, Castelli J, et al. Novel quantitative 
method to evaluate globotriaosylceramide inclusions in renal peritubular capillaries by virtual 
microscopy in patients with fabry disease. Arch Pathol Lab Med. 2012 Jul;136(7):816-24. 
Bartelink IH, Boelens JJ, Bredius RG, Egberts AC, Wang C, Bierings MB, et al. Body weight-
dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation 
patients: towards individualized dosing. Clin Pharmacokinet. 2012 May 1;51(5):331-45. 
Bartelink IH, Lalmohamed A, van Reij EM, Dvorak CC, Savic RM, Zwaveling J, et al. 
Association of busulfan exposure with survival and toxicity after haemopoietic cell 
transplantation in children and young adults: a multicentre, retrospective cohort analysis. 
Lancet Haematol. 2016 Nov;3(11):e526-e536. 
Benjamin ER, Della Valle MC, Wu X, Katz E, Pruthi F, Bond S, et al. The validation of 
pharmacogenetics for the identification of Fabry patients to be treated with migalastat. Genet 
Med 2017 Apr;19(4):430-438. doi: 10.1038/gim.2016.122. Epub 2016 Sep 22. 
Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, et al. Lentiviral hematopoietic 
stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013 Aug 
23;341(6148):1233158. 
Biffi A. Gene therapy for lysosomal storage disorders: a good start. Hum Mol Genet 2016 
Apr 15;25(R1):R65-75. 
Busulfan Prescribing Information: SAGENT Pharmaceuticals, Schaumburg, IL; 2018. Available 
at: https://www.sagentpharma.com/wp-content/uploads/2018/11/Busulfan_PI-Update-1.pdf.
Busulfan Product Monograph: BC Cancer Drug Manual; 2018. Available at: 
http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Busulfan%20monograph.pdf.
Busulfan SmPC: Accord Healthcare Limited, North Harrow, Middlesex, UK; 2018. Available at: 
https://www.medicines.org.uk/emc/product/2160/smpc. 
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, 
Version 4.0, DCTD, NCI, NIH, DHHS. 2009. Publish date: 29 May 2009. 
Davis JM, Ivanova A, Chung Y, Shaw JR, Rao K, Sharf JP, et al. Evaluation of a test dose 
strategy for pharmacokinetically guided busulfan dosing for hematopoietic stem cell 
transplantation. Biol Blood Marrow Transplant. 2018 Sep 19. pii: S1083-8791(18)30574-3. 
doi: 10.1016/j.bbmt.2018.09.017. [Epub ahead of print] 


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Delanaye P, Ebert N, Melsom T, Gaspari F, Mariat C, Cavalier E, et al. Iohexol plasma clearance 
for measuring glomerular filtration rate in clinical practice and research: a review. Part 1: 
How to measure glomerular filtration rate with iohexol? Clin Kidney J 2016a;9(5):682-99.
Delanaye P, Melsom T, Ebert N, Sten-Erik B, Mariat C, Cavalier E, et al. Iohexol plasma 
clearance for measuring glomerular filtration rate in clinical practice and research: a review. 
Part 2: Why to measure glomerular filtration rate with iohexol? Clin Kidney J 
2016b;9(5):700-4. 
EMA, Guideline on Follow-up of Patients Administered with Gene Therapy Medicinal Products, 
October 2009. 
Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldeck S, Caplan L, Linthorst GE, 
-galactosidase A - replacement 
-16. 
Eng CM, Fletcher J, Wilcox WR, Waldek S, Scott CR, Sillence DO, et al. Fabry disease: 
baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J 
Inherit Metabl Dis 2007 Apr;30(2):184-92. 
Germain DP, Waldek S, Banikazemi M, Bushinsky DA, Charrow J, Desnick RJ, Lee P, Loew T, 
Vedder AC, Abichandani R, Wilcox WR, Guffon N: Sustained, long-term renal stabilization 
after 54 months of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol 
2007;18:1547-1557. 
Germain DP. Fabry disease. Orphanet Journal of Rare Diseases. 2010; 5:30. Available from : 
http://ojrd.biomedcentral.com/articles/10.1186/1750-1172-5-30. 
Germain DP, Giugliani R, Hughes DA, Mehta A, Nicholls K, Barisoni L, et al. Safety and 
pharmacodynamic effects of a pharmacological ch
-galactosidase A activity and 
globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies. 
Orphanet J Rare Dis 2012;7:91. 
Goker H, Etgul S, Buyukasik Y. Optimizing mobilization strategies in difficult-to-mobilize 
patients; the role of plerixafor. Transfus Apher Sci 2015 Aug;53(1):23-9. 
Hughes DA, Nicholls K, Shankar SP, Sunder-Plassmann G, Koeller D, Nedd K, et al. Oral 
pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry 
disease; 18-month results from the randomised phase III ATTRACT study. J Med Genet 
2017;54:288-96. 
ICH E11 (2000) and ICH E11(R1) Addendum (2017), Clinical Investigation of Medicinal 
Products in the Pediatric Population. Available from: 
https://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html 
Kanter J, Tisdale JF, Kwiatkowski JL, Krishnamurti L, Mapara MY, Schmidt M, et al. Outcomes 
for Initial Patient Cohorts with up to 33 Months of Follow-up in the Hgb-206 Phase 1 Trial 
(Poster). American Society of Hematology Annual Meeting. 2018. Poster available at: 
https://ash.confex.com/ash/2018/webprogram/Paper113477.html. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF III, Feldman HI, et al.  A new 
equation to estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604-12. 


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Long-Boyle JR, Savic R, Yan S, Bartelink I, Musick L, French D, et al. Population 
pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic 
cell transplant: a model-based dosing algorithm for personalized therapy and implementation 
into routine clinical use. Ther Drug Monit. 2015 Apr;37(2):236-45. 
Mehta A, Hughes DA. Fabry Disease. 2002 Aug 5 [Updated 2017 Jan 5]. In: Pagon RA, Adam 
MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of 
Washington, Seattle; 1993-2017. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK1292/ 
Ramaswami U, Wendt S, Pintos-Morell G, Parini R, Whybra C, Leon-Leal JA, Santus F, 
Beck M. Enzyme replacement therapy with agalsidase alfa in children with Fabry disease. 
Acta Paediatr 2007;96:122-127. 
Ries M, Clarke JT, Whybra C, Timmons M, Robinson C, Schlaggar BL, Pastores G, Lien YH, 
Kampmann C, Brady RO, Beck M, Schiffmann R. Enzyme-replacement therapy with 
agalsidase alfa in children with Fabry disease. Pediatr 2006;118:924-932. 
Schiffmann R, Kopp JB, Austin HA, Sabnis S, Moore DF, Weibel T, Balow JE, Brady RO. 
Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 
2001;285:2743-9. 
Smid BE, Rombach SM, Aerts JM, Kuiper S, Mirzaian M, Overkleeft HS, et al. Consequences of 
a global shortage of agalsidase beta in adult Dutch Fabry patients. Orphanet J Rare Dis. 2011 
Oct 31;6:69. 
Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, et al. Gene 
therapy in patients with transfusion-
-thalassemia. N Engl J Med. 2018 Apr 
19;378(16):1479-1493. 
Thurberg BL. EveryLife Foundation for Rare Diseases, Rare Disease Workshop Series, The Use 
of Pathology Surrogate Markers in Fabry Disease, 2011. Available at: 
https://everylifefoundation.org/wp-content/uploads/images/workshopseries/16-Thurberg-
Fabry-pathology-Nov-2011-compr-dc.pdf 
Tisdale JF, Kanter J, Mapara MY, Kwiatkowski JL, Krishnamurti L, Schmidt M, et al. Current 
results of lentiglobin gene therapy in patients with severe sickle cell disease treated under 
a refined protocol in the phase 1 Hgb-206 study. Presented in oral presentation (and abstract 
1026) at American Society of Hematology Meeting, San Diego, CA, USA, December, 2018. 
United States Department of Health and Human Services, FDA, CBER, Guidance for Industry, 
Long Term Follow-Up After Administration of Human Gene Therapy Products, January 
2020. 
United States Department of Health and Human Services, FDA, CBER, Guidance for Industry, 
Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication 
Competent Retrovirus During Product Manufacture and Patient Follow-up, January 2020.  
van Breemen MJ, Rombach SM, Dekker N, Poorthuis BJ, Linthorst GE, Zwinderman AH, et al. 
Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease 
following enzyme replacement therapy. Biochim Biophys Acta 2011 Jan;1812(1):70-6. 


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Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death in 
males and females with Fabry disease: findings from the Fabry Registry. Genet Med 2009 
Nov;11(11):790-6. 
Weidemann F, Kramer J, Duning T, Lenders M, Canaan-Kuhl S, Krebs A, et al. Patients with 
Fabry disease after enzyme replacement therapy dose reduction versus treatment switch. J Am 
Soc Nephrol. 2014 Apr;25(4):837-49. 
Weil E, Zook F, Oxencis C, Canadeo A, Urmanski A, Waggoner M, et al. Evaluation of the 
pharmacokinetics and efficacy of a busulfan test dose in adult patients undergoing 
myeloablative hematopoietic cell transplantation. Biol Blood Marrow Transplant 2017 
Jun;23(6):952-57. 
Yannaki E, Karponi G, Zervou F, Constantinou V, Bouinta A, Tachynopoulou V, et al. 
Hematopoietic stem cell mobilization for gene therapy: superior mobilization by the 
combination of granulocyte-
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thalassemia major. Hum Gene Ther 2013 Oct;24(10):852-60. 


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14. 
APPENDICES 
 










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Footnotes: 
a 
Unless otherwise specified, Screening assessments must be performed within 8 weeks of the Baseline visit. 
b 
The Baseline visit may be conducted over the course of up to 3 days. 
c   Between the Apheresis and Conditioning phases of the Pre-transplant Period, there is an approximately 4-6 week period during which time AVR-RD-01 is tested for  
 
release for infusion. 
d 
 Assessments required for those subjects who prematurely discontinue the study after initiation of the Pre-transplant Period. Assessments should be completed as soon as 
feasible after the decision to discontinue the study has been made. 
e 
 Medical history will include retrospective collection of Fabry-disease specific medical and surgical history, including historical results of any AGA enzyme activity testing.
f 
 Documented historical results of mutation analysis from a certified laboratory will be recorded if available. Mutation analysis must also be performed at Screening, regardless 
of the availability of historical results. 
g 
 Transmittable disease testing includes serological analysis for HIV Ag/Ab, HIV nucleic acid-amplification testing (NAT), HBsAg, anti-HBc, HBV NAT, anti-HCV antibody, 
HCV NAT, syphilis test (VDRL, CMIA, or EIA test), cytomegalovirus (CMV) IgG Ab, CMV IgM Ab, HTLV-1 Ab, HTLV-2 Ab, HSV-1 IgG Ab, and, if applicable, VSV IgG 
Ab. If applicable, testing for West Nile virus by PCR must also be performed. Testing is performed for study eligibility determination and/or AVR-RD-01 manufacturing 
purposes. Transmittable disease testing will be performed locally. Subjects who test positive for HBV, HCV, HIV (type 1 or 2), HTLV-1, HTLV-2, and/or syphilis on VDRL, 
CMIA, or EIA test will be discontinued from the study. 
h 
 Blood or urine sample(s) will be tested centrally. Details on collection, processing, and shipment will be included in the Laboratory Manual.  
i 
Sample collection for biomarkers for Fabry disease (ie, Gb3 and its deacylated form, lyso-Gb3) in urine must be the second or third morning void. 
j  For consenting subjects, samples will be collected in plasma and urine for assessment of biomarkers for Fabry disease that may become available during or after the study. 
Samples obtained will be labeled for 
years after the 
Clinical Study Report (CSR) is finalized. 
k 
Skin and renal biopsies will ideally be the last assessment performed at Screening, and will be analyzed centrally for substrate (ie, Gb3) and AGA activity. Renal biopsy will 
also be analyzed centrally to exclude other renal disease. Details on collection, processing, and shipment will be included in the Laboratory Manual.  
l 
Urine for podocytes and creatinine should be second morning void. 
m  Cardiac MRI will be analyzed centrally. 
n  Baseline DIBSS-D diary data will be collected for two consecutive weeks during the Screening period.  
o 
BPI-SF questionnaire and SF-36 should be completed prior to any other required assessments at the study visit. 
p 
 Interviews will be scheduled and conducted by Casimir for both subjects and caregivers, or other qualified observers, of subjects who opt to participate, provide written 
informed consent is obtained. 
q  
d by the central laboratory
the sampled blood cells are vector positive, with an average of 1 c/dg. At Baseline only, a peripheral blood sample will be archived for possible future testing should a subject 
develop hematologic cancer. 
r  At Baseline only, a bone marrow sample will be archived for possible future testing should a subject develop hematologic cancer. 
s 
Vital signs include heart rate, blood pressure, respiratory rate, and temperature. Vital signs will be obtained with the subject supine or seated. On Days 1 and 2 of the Apheresis 
phase of the Pre-transplant Period, vital signs must be taken prior to apheresis. Additional vital signs may be taken if clinically indicated and/or mandated per local institution 
practice. 
t 
 Pulmonary function tests include FEV1, FVC, and FEV1/FVC ratio; DLCO must also be collected if FEV1 is not available. Both results and percent predicted results should be 
recorded. A 50% predicted value (corrected for hemoglobin) for one or more of the following at Screening is an exclusion criterion for the study: FEV1, FVC, and DLCO. 
PFT at Baseline is only required if there is a change in physical examination or new onset pulmonary or other medical condition relevant to testing since the Screening PFT.
u 
 CBC with differential includes the following: hematocrit, hemoglobin, platelet count, WBC count (total and differential), RBC count, and ANC count. Samples will be tested 
locally.


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v 
Assessment will also include routine flow cytometric analysis of peripheral blood lymphocyte subsets. Panel will include: CD3, CD4, CD8, CD19, and CD16/56. Samples will 
be tested locally. 
w Serum chemistry includes AST, ALT, GGT, amylase, ALP, LDH, bilirubin, calcium, albumin, phosphate, magnesium, uric acid, and glucose. Samples will be tested locally. 
x 
Electrolytes include sodium, potassium, chloride, and bicarbonate. Samples will be tested locally. 
y 
Urinalysis includes blood, glucose, protein, specific gravity, and microscopic examination (if clinically indicated). Samples will be tested locally. 
z 
Blood sample collection for immunogenicity testing must be collected for all subjects at Screening, regardless of whether or not they have received previous treatment with 
enzyme replacement therapy. 
aa  Samples will be collected for RCL testing to determine infection of non-target cells. Testing will be performed by qPCR; possible future serology testing may also be 
performed. Blood samples for possible future serology testing will be centrally stored. 
bb Sperm samples for volume, sperm count, sperm concentration, total motility, progressive motility, and morphology will be collected. Samples should be collected after at least 
2 to 3 days of abstinence. Samples will be tested locally. For samples that yield abnormal results, an additional sample must be collected and tested to confirm the initial results. 
If test results indicate reduced fertility (eg, oligospermia or azoospermia, decreased sperm motility, and/or abnormal sperm morphology), investigational sites should follow 
institutional guidelines for further evaluation. 
cc On Mobilization Days 1 through 4 of the Pre-transplant Period, a daily G-CSF dose of 10 µg/kg body weight will be administered (for sites with only prefilled syringes, a 
G-CSF daily dose from 10 µg/kg body weight up to 12 µg/kg body weight, administered in either a single or divided twice a day (BID) dose, may be administered). The G-CSF 
dose may be administered IV or SC. The 'G-CSF Diary' should be completed by subjects self-administering. 
dd On the evening of Mobilization Day 4 and on the evening of Apheresis Day 1, plerixafor (0.24 mg/kg) will be administered SC.  
ee On the morning of Apheresis Day 1 (ie, between 10 and 12 hours after plerixafor administration on Mobilization Day 4), cells 
blood; this apheresis unit will be shipped to the manufacturing site for cell transduction and processing. On the morning of Apheresis Day 2 (ie between 10 and 12 hours after 
plerixafor administration on Apheresis Day 1), an additional harvest of cells will occur; cells harvested from this apheresis (nontransduced cells) will be retained and stored at 
the investigational site for use as rescue treatment (if needed). Standard institutional procedures at the participating investigational study site will be used for both apheresis 
procedures. 
ff Prior and concomitant medications and therapies will be recorded from the time of signing of informed consent until completion of the Week 48 assessments for the study. 
gg All AEs (including SAEs) will be recorded from the time of signing of informed consent until completion of the Week 48 assessments for the study. 
 








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h 
Vital signs include heart rate, blood pressure, respiratory rate, and temperature. Vital signs will be obtained with the subject supine or seated. On Day 0 of the Transplant Period 
(ie, the day of AVR-RD-01 infusion), vital signs must be taken pre-infusion (window -10 minutes) and post-infusion (window +10 minutes). Additional vital signs may be 
taken if clinically indicated and/or mandated per local institution practice for transplantation.  
i 
 Pulmonary function tests include FEV1, FVC, and FEV1/FVC ratio; DLCO must also be collected if FEV1 is not available. Both results and percent predicted results should be 
recorded. 
j 
 CBC with differential includes the following: hematocrit, hemoglobin, platelet count, WBC count (total and differential), RBC count, and ANC count. During the Conditioning 
washout period, testing should be performed daily. Samples will be tested locally. 
k 
Assessment will also include routine flow cytometric analysis of peripheral blood lymphocyte subsets. Panel will include: CD3, CD4, CD8, CD19, and CD16/56. Samples will 
be tested locally. 
l 
Serum chemistry includes AST, ALT, GGT, amylase, ALP, LDH, bilirubin, calcium, albumin, phosphate, magnesium, uric acid, and glucose. During the Conditioning washout 
period, testing should be performed daily. Samples will be tested locally. 
m Electrolytes include sodium, potassium, chloride, and bicarbonate. During the Conditioning washout period, testing should be performed daily. Samples will be tested locally.
n 
Urinalysis includes blood, glucose, protein, specific gravity, and microscopic examination (if clinically indicated). Samples will be tested locally. 
o  Samples will be collected for RCL testing to determine infection of non-target cells. Testing will be performed by qPCR; possible future serology testing may also be 
performed. Blood samples for possible future serology testing will be centrally stored. 
p 
Sperm samples for volume, sperm count, sperm concentration, total motility, progressive motility, and morphology will be collected. Samples should be collected after at least 
2 to 3 days of abstinence. Samples will be tested locally. For samples that yield abnormal results, an additional sample must be collected and tested to confirm the initial results. 
If test results indicate reduced fertility (eg, oligospermia or azoospermia, decreased sperm motility, and/or abnormal sperm morphology), investigational sites should follow 
institutional guidelines for further evaluation. 
q 
A conditioning regimen of IV busulfan, including a test dose of 0.8 mg/kg on Day -6, will be administered. The Day -4 and Day -3 busulfan dose will be PK- and 
weight-guided based on the test dose and the respective calculated AUC using a web-based dose simulation program. The busulfan doses for Days -2 and -1 of Conditioning 
will be based on an AUC calculation generated from a web-based dose simulation program that will use measurements of busulfan in serial blood samples drawn over several 
-6 (test dose), -4 (for the Day -2 dose), and -3 (for the Day -1 dose). If the AUC previous dose is outside of +/- 0% of the AUCtarget
determined by the program, the busulfan dose will be adjusted accordingly. See Section 8.1.1.3 (and the Study Treatment Manual) for further details on busulfan dose 
determination. 
r  Blood samples will be collected 1, 3, 5, and 7 hours post-
Blood samples will be 
collected 1, 3, and 5 hours post-busulfan dose administration on Days -4, -3, -2, and -1 for busulfan TDM for dose determination (ie, Days -2 and -1) and actual cumulative 
AUC calculations (ie, Days -4, -3, -2 and -
Laboratories performing TDM must use validated methods to quantify busulfan in plasma according to 
Good Laboratory Practice. 
s 
Levetiracetam will be administered at a dosage of 1000 mg per day beginning two days prior to administration of the busulfan test dose (ie, on Conditioning Day -8), and 
continuing until one day after administration of the 4-day busulfan conditioning regimen (ie, until one day into the Conditioning washout period). For subjects with 
contraindication to levetiracetam, an alternative anticonvulsant medication (eg, benzodiazepines or valproic acid) may be used. Details on medication administered must be 
captured in the eCRF. 
t 
A minimum of 48 up to a maximum of 72 hour busulfan washout period is required before administration of the AVR-RD-01 infusion. 
u 
Prior and concomitant medications and therapies will be recorded from the time of signing of informed consent until completion of the Week 48 assessments for the study. 
v  All AEs (including SAEs) will be recorded from the time of signing of informed consent until completion of the Week 48 assessments for the study. 








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e Blood or urine sample(s) will be tested centrally. Details on collection, processing, and shipment will be included in the Laboratory Manual.  
f Sample collection for biomarkers for Fabry disease (ie, Gb3 and its deacylated form, lyso-Gb3) in urine must be second or third morning void. Samples will be tested centrally.
g For consenting subjects, samples will be collected in plasma and urine for assessment of biomarkers for Fabry disease that may become available during or after the study. 
ars after the 
Clinical Study Report (CSR) is finalized. 
h Skin and renal biopsies will be analyzed centrally for substrate (ie, Gb3) and AGA activity. Details on collection, processing, and shipment will be included in the Laboratory 
Manual. 
i  Urine for podocytes and creatinine should be second morning void. 
j Cardiac MRI will be analyzed centrally. 
k DIBSS-D diary data will be collected over the 2 weeks following the site visit, except at the Week 48 visit when the DIBSS-D diary data will be collected over the 2 weeks prior 
to the site visit. 
l BPI-SF questionnaire and SF-36 should be completed prior to any other required assessments at the study visit.  
m Interviews will be scheduled and conducted by Casimir for both subjects and caregivers, or other qualified observers, of subjects who opt to participate, provide written informed 
consent is obtained. For subjects who enrolled and received AVR-RD-01 treatment in the study prior to approval of Amendment 4, the first interview will take place upon 
Amendment 4 approval, unless the subject is within one month of the next regularly scheduled interview. 
n Integration site analysis will 
the sampled blood cells are vector positive, with an average of 1 c/dg. 
o At a minimum, physical examinations, vital signs collection, and blood sample collection for CBC with differential and electrolytes must occur daily through a minimum of 
7 days post-transplantation (ie, until Day 7 of the Post-transplant Follow-up Period). If clinically indicated and/or mandated per local institution practice post-transplantation, 
additional physical examinations, vital signs collection, and blood sample collection for CBC with differential and electrolytes should also take place.  
p Vital signs include heart rate, blood pressure, respiratory rate, and temperature. Vital signs will be obtained with the subject supine or seated.  
q  Pulmonary function tests include FEV1, FVC, and FEV1/FVC ratio (both results and percent predicted results should be collected). 
r CBC with differential includes the following: hematocrit, hemoglobin, platelet count, WBC count (total and differential), RBC 
9/L on 
Day 5 of the Post-transplant Follow-up Period, blood sample for ANC should continue to be collected (and G-CSF injection administered [see footnote s]) until the subject 
achieves an ANC >1.5 x 109/L. Samples will be tested locally. 
s G-CSF injection of 5 µg/kg body weight (for sites with only prefilled syringes, a G-CSF dose from 4 µg/kg body weight up to 6 µg/kg body weight, administered in either a 
single or divided twice a day (BID) dose, may be administered) will be administered every morning from Day 5 post-transplant until the subject achieves an ANC >1.5 x 109/L. 
The 'G-CSF Diary' should be completed by subjects self-administering.  
t Assessment will also include routine flow cytometric analysis of peripheral blood lymphocyte subsets. Panel will include: CD3, CD4, CD8, CD19, and CD16/56. Samples will 
be tested locally. 
u Serum chemistry includes AST, ALT, GGT, amylase, ALP, LDH, bilirubin, calcium, albumin, phosphate, magnesium, uric acid, and glucose. Samples will be tested locally.  
v Electrolytes include sodium, potassium, chloride, and bicarbonate. Samples will be tested locally.  
w Urinalysis includes blood, glucose, protein, specific gravity, and microscopic examination (if clinically indicated). Samples will be tested locally. 
x Samples will be collected for RCL testing to determine infection of non-target cells. Testing will be performed by qPCR; possible future serology testing may also be performed. 
Blood samples for possible future serology testing will be centrally stored. 
y Sperm samples for volume, sperm count, sperm concentration, total motility, progressive motility, and morphology will be collected. Samples should be collected after at least 2 
to 3 days of abstinence. Samples will be tested locally. For samples that yield abnormal results, an additional sample must be collected and tested to confirm the initial results. If 
test results indicate reduced fertility (eg, oligospermia or azoospermia, decreased sperm motility, and/or abnormal sperm morphology), investigational sites should follow 
institutional guidelines for further evaluation. For subjects continuing in the AVRO-RD-01-LTF01 study with reduced fertility at Week 48, sperm samples for volume, sperm 
count, sperm concentration, total motility, progressive motility, and morphology must also continue to be collected in that study until the subject demonstrates recovery.
z Prior and concomitant medications and therapies will be recorded from the time of signing of informed consent until completion of the Week 48 assessments for the study.


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aa All AEs (including SAEs) will be recorded from the time of signing of informed consent until completion of the Week 48 assessments for the study. 

SAP_003.pdf: 




Protocol AVRO-RD-01-201                                                                             July 26, 2023 
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Page 3 of 77 
 
 
 
  
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................... 15 
2. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ..................................... 16 
2.1. 
Study Objective(s) ................................................................................... 16 
2.1.1. 
Primary Objectives .................................................................................. 16 
2.1.2. 
Secondary Objectives .............................................................................. 16 
2.1.3. 
Exploratory Objectives ............................................................................ 17 
2.2. 
Study Endpoints ....................................................................................... 17 
2.2.1. 
Efficacy Endpoints ................................................................................... 17 
2.2.1.1. 
Primary Efficacy Endpoints ..................................................................... 17 
2.2.1.2. 
Secondary Efficacy Endpoints ................................................................. 18 
2.2.1.3. 
Exploratory Efficacy Endpoints .............................................................. 18 
2.2.2. 
Safety Endpoints ...................................................................................... 19 
2.3. 
Statistical Hypotheses .............................................................................. 20 
2.4. 
Pharmacokinetic (PK) and PK/Pharmacodynamic (PD) Hypotheses ..... 20 
3. 
STUDY DESIGN .................................................................................... 21 
3.1. 
Definition of Study Treatment ................................................................. 22 
3.2. 
Sample Size Considerations .................................................................... 22 
3.2.1. 
Sample Size Justifications ....................................................................... 22 
3.2.2. 
Sample Size Re-estimation ...................................................................... 22 
3.3. 
Randomization ......................................................................................... 22 
3.4. 
Clinical Assessments ............................................................................... 23 
4. 
PLANNED ANALYSES ......................................................................... 24 
4.1. 
Interim Analysis ....................................................................................... 24 
4.2. 
Final Analysis .......................................................................................... 24 
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ............................................................................................ 25 
5.1. 
General Summary Table and Individual Subject Data Listing 
Considerations ......................................................................................... 25 
5.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ............................................................................. 26 
5.3. 
Data Management .................................................................................... 26 
5.4. 
Data Presentation Conventions ................................................................ 29 
5.5. 
Analysis Populations ............................................................................... 32 
5.5.1. 
All Subjects Population ........................................................................... 32 
5.5.2. 
Safety Population ..................................................................................... 32 


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5.5.3. 
Infused Population ................................................................................... 32 
5.6. 
Baseline Definition .................................................................................. 32 
5.7. 
Derived and Transformed Data ............................................................... 33 
5.7.1. 
Screening Age .......................................................................................... 33 
5.7.2. 
Body Mass Index ..................................................................................... 33 
5.7.3. 
Study Day ................................................................................................ 33 
5.7.4. 
Time since AVR-RD-01 Infusion ............................................................ 33 
5.7.5. 
Age at enrollment .................................................................................... 33 
5.7.6. 
Age at AVR-RD-01 infusion ................................................................... 34 
5.7.7. 
Adverse event onset time relative to AVR-RD-01 infusion .................... 34 
5.7.8. 
Duration of Adverse Events..................................................................... 34 
5.7.9. 
Change from Baseline .............................................................................. 34 
5.7.10. 
Observed Cases (OC) and Last Observation Carried Forward (LOCF) 
and Outliers .............................................................................................. 35 
5.7.11. 
Completers ............................................................................................... 35 
5.7.12. 
Treatment Compliance ............................................................................. 35 
5.7.13. 
Kidney Biopsy ......................................................................................... 35 
5.7.14. 
Diary for Irritable Bowel Syndrome (DIBSS-D) ..................................... 35 
5.7.15. 
BPI-SF ..................................................................................................... 35 
5.7.16. 
SF-36........................................................................................................ 35 
5.7.17. 
Estimated GFR ......................................................................................... 36 
5.7.18. 
Measured GFR ......................................................................................... 36 
5.7.19. 
Derivations for Adverse Events ............................................................... 38 
6. 
TREATMENT COMPARISONS ............................................................ 41 
6.1. 
Data Display Treatment and Other Sub-Group Descriptors .................... 41 
7. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ................ 42 
7.1. 
Multicenter Studies .................................................................................. 42 
7.2. 
Other Strata and Covariates ..................................................................... 42 
7.3. 
Examination of Subgroups ...................................................................... 42 
7.4. 
Multiple Comparisons and Multiplicity................................................... 42 
7.5. 
Data handling conventions ...................................................................... 42 
7.5.1. 
Premature Withdrawal and Dropouts ...................................................... 42 
7.5.2. 
Additional/Unscheduled Assessments ..................................................... 42 
7.5.3. 
Assessment Windows .............................................................................. 43 
7.5.4. 
Visit/Study Period Mapping and Labels .................................................. 44 


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7.6. 
Derived and Transformed Data ............................................................... 46 
8. 
STUDY POPULATION .......................................................................... 47 
8.1. 
Disposition of Subjects ............................................................................ 47 
8.2. 
Protocol Deviations ................................................................................. 47 
8.3. 
Demographic and Baseline Characteristics ............................................. 48 
8.4. 
Medical History and Medical Conditions Present at Entry ..................... 48 
8.5. 
Treatment Compliance ............................................................................. 49 
8.6. 
Prior and Concomitant Medications ........................................................ 49 
9. 
EFFICACY ANALYSES ........................................................................ 53 
9.1. 
Primary Efficacy Analysis ....................................................................... 53 
9.2. 
Secondary Efficacy Analyses .................................................................. 53 
9.2.1. 
AGA Enzyme Activity ............................................................................ 53 
9.2.2. 
Biomarkers ............................................................................................... 54 
9.2.3. 
Skin Biopsies ........................................................................................... 54 
9.2.4. 
mGFR ...................................................................................................... 54 
9.2.5. 
eGFR ........................................................................................................ 54 
9.2.6. 
Urine Protein/Albumin Excretion ............................................................ 55 
9.2.7. 
Cardiac MRI ............................................................................................ 55 
9.2.8. 
DIBSS-D .................................................................................................. 55 
9.2.9. 
BPI-SF ..................................................................................................... 55 
9.2.10. 
SF-36........................................................................................................ 55 
9.2.11. 
VCN in Peripheral Blood ......................................................................... 55 
9.2.12. 
VCN in Bone Marrow Aspirate ............................................................... 56 
9.3. 
Exploratory Efficacy Analyses ................................................................ 57 
9.3.1. 
Light Microscopic Findings on Kidney Biopsies .................................... 57 
9.3.2. 
AGA Enzyme Activity in Skin and Kidney Biopsies .............................. 57 
9.3.3. 
Podocyturia .............................................................................................. 57 
9.3.4. 
DIBSS-D .................................................................................................. 57 
9.3.5. 
SF-36........................................................................................................ 58 
9.3.6. 
Exploratory Biomarkers for Fabry Disease ............................................. 58 
9.3.7. 
Peripheral Blood Cell Subpopulations and Bone Marrow CD34+ 
Subtypes ................................................................................................... 58 
9.3.8. 
Average VCN and ISA in Peripheral Blood Cell Subpopulations and 
Bone Marrow CD34+ Subtypes............................................................... 59 
9.3.9. 
Perception of changes in disease burden and quality of life, assessed by 
qualitative interview ................................................................................ 59 


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10. 
SAFETY ANALYSES ............................................................................ 60 
10.1. 
Extent of Exposure .................................................................................. 60 
10.2. 
Adverse Events ........................................................................................ 61 
10.2.1. 
Treatment-emergent Adverse Events ...................................................... 61 
10.2.2. 
Serious Adverse Events ........................................................................... 62 
10.2.3. 
Adverse Drug Reaction or Adverse Reaction .......................................... 62 
10.2.4. 
Unexpected Adverse Reaction ................................................................. 62 
10.2.5. 
Adverse Event Severity ........................................................................... 62 
10.2.6. 
Adverse Event Relationship .................................................................... 63 
10.2.7. 
Adverse Event Tabulations ...................................................................... 64 
10.3. 
Pregnancies .............................................................................................. 68 
10.4. 
Clinical Laboratory Evaluations .............................................................. 68 
10.5. 
Vital Signs Evaluations ............................................................................ 70 
10.6. 
ECG Evaluations ..................................................................................... 70 
10.7. 
Pulmonary Function Test ......................................................................... 70 
10.8. 
Chest X-Ray ............................................................................................. 70 
10.9. 
Immunogenicity ....................................................................................... 70 
10.10. 
Physical Examination .............................................................................. 71 
10.11. 
Rescue Medication ................................................................................... 71 
10.12. 
Reproductive Potential ............................................................................. 71 
10.13. 
Achievement of Hematological Reconstitution ....................................... 71 
10.14. 
Presence of Replication Competent Lentivirus (RCL) ............................ 71 
10.15. 
Identification of mononuclear cells with integration site profiles 
suggestive of aberrant clonal expansion(s) .............................................. 71 
10.16. 
Other Safety Measures ............................................................................. 72 
11. 
REFERENCES ........................................................................................ 73 
APPENDIX 1 .............................................................................................................. 74 
 


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LIST OF TABLES 
Table 1. Laboratory Data Vendors.................................................................................................27 
Table 2. Algorithm for Treatment Emergent Adverse Events .......................................................38 
Table 3. Visit Window Assignment ...............................................................................................43 
Table 4. Algorithm for assignment of timing for medication use..................................................50 


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List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
AGA 
Alpha-galactosidase A 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutical Chemical (classification) 
BMI 
Body mass index 
BPI-SF 
Brief Pain Inventory-Short Form 
BSFS 
Bristol Stool Form Scale 
CABG 
Coronary artery bypass grafting 
CAD 
Coronary artery disease 
cDNA 
Complementary deoxyribonucleic acid 
CKD 
Chronic kidney disease 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically significant 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DIBSS-D 
Diary for Irritable Bowel Syndrome Symptoms-Diarrhea 
DLCO 
Diffusing capacity of the lung for carbon dioxide 
DMC 
Data Monitoring Committee 
DP 
Drug Product 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ERT 
Enzyme replacement therapy 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
Gb3 
Globotriaosylceramide 
G-CSF 
Granulocyte-colony stimulating factor 




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Abbreviation 
Term 
SD 
Standard Deviation 
SF-36 
Short Form 36 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure  
TIA 
Transient ischemic attack 
VCN 
Vector copy number 
VDRL 
Venereal Disease Research Laboratory 
WBC 
White blood cell 
WHO 
World Health Organization 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 
 


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SAP Updates from Version 1 to 2
The SAP is updated from version 1 to version 2 with the following updates: 
 The version 1 of the SAP was based on protocol amendment 2, dated May 01, 2018. The 
version 2 of the SAP is based on protocol amendment 5, dated April 01, 2022.  
 Study objectives were updated according to protocol amendment 5. [Note:  Protocol 
amendment 6 was submitted to the Food and Drug Administration; however, this protocol 
version was not implemented for this study] 
 The following protocol terminology has been updated as follows: 
o 
-RD-
replaces 
.  
o 
-RD-
replaces to 
.  
o 
-AVR-RD-
replaces 
-
 
o 
-AVR-RD-01 Infusion Follow-U
replaces Post-transplant Follow-U
 
o 
Preparatory medications  refers to G-CSF, plerixafor, busulfan/melphalan, or anti-
 
 Extra exploratory efficacy endpoints and their associated descriptive analyses were added:  
 Changes from baseline in peripheral blood cell subpopulations (i.e., T cells [CD3+], 
natural killer [NK] cells [CD56+], B cells [CD19+], granulocytes [CD15+], and 
monocytes [CD14+]) and bone marrow CD34+ subtypes (i.e., hematopoietic stem cells 
[HSCs] [HSC CD34+CD38-CD90+CD45RA-] and multipotent progenitors [MPP 
CD34+CD38-CD90-CD45RA-], multilymphoid progenitors [MLP CD34+CD38-CD90-
CD45RA+], common myeloid progenitors [CMP CD34+CD38+CD7-CD10-
CD135+CD45RA-], granulocytes/monocytes progenitors [GMP CD34+CD38+CD7-
CD10-CD135+CD45RA+], megakaryocyte/erythroid progenitors [MEP 
CD34+CD38+CD7-CD10-CD135-CD45RA-], and Pre-B/NK progenitors 
[CD34+CD38+CD7-CD10+] cells) analyzed by immunophenotyping and scRNAseq 
over time  
 Average VCN and ISA results in both peripheral blood cell subpopulations (i.e., T cells 
[CD3+], NK cells [CD56+], B cells [CD19+], granulocytes [CD15+], and monocytes 
[CD14+]) and bone marrow CD34+ subtypes (i.e., HSCs [HSC CD34+CD38-
CD90+CD45RA-] and multipotent progenitors [MPP CD34+CD38-CD90-CD45RA-], 
multilymphoid progenitors [MLP CD34+CD38-CD90-CD45RA+], common myeloid 
progenitors [CMP CD34+CD38+CD7-CD10-CD135+CD45RA-], 
granulocytes/monocytes progenitors [GMP CD34+CD38+CD7-CD10-
CD135+CD45RA+], megakaryocyte/erythroid progenitors [MEP CD34+CD38+CD7-
CD10-CD135-CD45RA-], and Pre-B/NK progenitors [CD34+CD38+CD7-CD10+] 
cells) over time  
 Some extra wordings are added/updated to clarify the context. 


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Compared with SAP version 1, the version 2 of SAP has been updated for the sections 
related to statistical summaries:
Extra statements were added in Section 
to clarify the study background.
Extra statements were added in Section  5 to clarify the general descriptive analysis 
methods.
Infusion analysis population was added in Section 5.5.3. It was defined to accommodate 
the analyses for efficacy endpoints. Instead, Efficacy analysis population from SAP 
version 1 has been removed.
In Section 5.7.17, steps and formulas to calculate eGFR were added.
In Section 5.7.18, steps and formulas to calculate mGFR were added.
In Section 5.7.19, details of assigning AEs into different study periods were added.
In Section 6.1, details of displaying outputs by study periods were updated. Accordingly, 
all mock-up shells for tables were updated to a different format from those in version 1. 
The data analyses are still descriptive in nature in SAP version 2.
In Section 7.5.3, visit windows were added for applicable analyses. In Section 7.5.4, 
visit labels were added.
In Section 8.6, analyses for concomitant medications were updated. The data were to be 
summarized by study period.
In Section 10.1, summaries of AVR-RD-01 infusion drug product characteristics were
added. 
In Section 10.2.7, summaries of AEs by study period were updated according to the 
updated definitions for study period. 
Various other exploratory summary analyses and data plots related to efficacy and safety 
endpoints were added by the sponsor.


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SAP Updates from Version 2 to 3 
The SAP is updated from version 2 to version 3 with the following updates: 
 The version 1 of the SAP was based on protocol amendment 2, dated May 01, 2018. The 
versions 2 and 3 of the SAP is based on protocol amendment 5, dated April 01, 2022.  
 For evaluating subject experience with respect to AVR-RD-01 treatment and perception of 
changes in Fabry disease burden and quality of life by qualitative interview (for subjects, 
and caregivers or other qualified observers of subjects, who provide separate written 
informed consent), no data were captured as the 
 qualitative interviews were not 
validated in Fabry disease. The listing was removed. 
 
Listings will present all visits and Baseline (Derived), however, figures and tables will only 
include Baseline (Derived) and post-AVR-RD-01 visits (for efficacy) and post-baseline 
visits (for safety).  
 The All Subjects population will consist of all subjects who consented, i.e. were enrolled.  
o This was changed from enrolled subjects who consented, were confirmed eligible, 
and entered the baseline period in order to present the total who were enrolled, who 
were screen failures, and who were rescreened.  
 Subject 101-103 is to be reported as a screen failure. 
 101-103 was rescreened as 101-105. Where the same data are 
captured for both subjects, this will only be presented once in listings, 
tables and figures. 
 For subject 101-106, who received Mobilization and Apheresis twice: 
o The study period between the end of the first apheresis and the start of Mobilization 
#2 will be captured as Post-Apheresis 
o The study period between the start of the second Mobilization until the start of the 
second apheresis will be captured as Mobilization #2 
o The study period between the start of the second apheresis until the end of the 
second apheresis will be captured as Apheresis #2 
o The study period between the end of the second apheresis and the first dosing of 
anti-convulsant medication (levetiracetam or others [benzodiazepines or valproic 
acid]) given for prophylaxis ahead of busulfan will be captured as Post-Apheresis #2 
 For subjects 503-102 and 504-101, who had Mobilization but did not proceed to receive 
conditioning or AVR-RD-01, the study period after the end of Apheresis will be captured as 
Post-Apheresis. 
 Where data are captured on separate individual days during conditioning, e.g., Conditioning 
(Day 1) etc., subjects who received melphalan (Subjects 101-101, 102-102, and 101-102), 
busulfan (short washout, Subject 102-104) and busulfan (long washout, Subjects 101-104, 


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101-105, 102-105, 101-106, and 101-107) will be grouped separately for derivation of 
summary statistics on all tables and figures. 
 The listing of melphalan will include the dose administered, percentage difference between 
expected and actual dose, the start and end times, total dose (mg), body surface area (m2) 
and total dose/BSA (mg/m2). 
 The listing of busulfan will include the dose administered each day, percentage dose 
increased/decreased vs. the previous dose, percentage difference between expected and 
actual dose, the start and end times, total dose (mg), body surface area (m2), total dose/BSA 
(mg/m2), AUC and Total AUC. 
 The tabulations of AEs by Onset and by TEAEs by Causal Relationship were simplified to 
include only the tabulation of (TE)AEs by SOC, PT. 
 Plots of CFB in ANC and Platelets changed to present absolute values between study 
day -50 and study day 100, with a line for each subject, and vertical reference lines at study 
day 1 (solid, black), 35 (dashed, red), 42 (solid, red) and 49 (dashed, red).  
o In order to include the reference lines, the Infused Population will be used. 
o Stacked panel plot of ANC values with 
 replaced 
by the panel plot of ANC between study day -50 and study day 100. 
 General language on inclusion of horizontal reference line(s) for the LLOQ, LLN and ULN, 
as appropriate, on figures was replaced by endpoint dependent detail of inclusion of 
horizontal reference line(s). 
o Similarly, endpoint dependent detail was added for when L or H flags are needed on 
listings.  
 Details of LLOQ, LLN and ULN added for AGA enzyme in peripheral leukocytes and in 
plasma. 
 Immunogenicity data will be listed only. 
 RCL data will be listed only. 
 The frequency table for achievement of hematological reconstitution was removed. 
 On the listings of ANC and of platelets, removed requirement for G-CSF and platelet 
transfusions (will be captured on their own individual listings instead). 
o Added a listing of platelet transfusions. 
 Removed panel plots of cumulative AEs for individual subjects. 
 Palm provided LLOQ, LLN and ULN for AGA enzyme in peripheral leukocytes and AGA 
enzyme in plasma. 
o Details added to specify the LLN and ULN to be presented as reference lines on 
Figures, and the LLN and ULN to be used for L/H flags on Listings. 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) for study AVRO-RD-01-201 is developed based on Amendment 
5 of the protocol dated April 01, 2020.  The purpose of this SAP is to ensure that the data listings 
and summary tables which will be produced, and the statistical methodologies that will be used, are 
comprehensive and appropriate for the analysis of the study objectives specified in the protocol.  
Any amendments to the SAP will be made prior to database lock. Any additional analyses not 
described in the final SAP or deviation from the final SAP (e.g., change in the population used, 
change from statistical method/assumption listed, transformation of data type [e.g., continuous data 
transformed to categorical], exclusion of planned analysis, etc.) will be documented (and justified) 
in the clinical study report (CSR). The reason for the changes and the datasets and outputs that are 
affected will also be documented on a form which is reviewed by the reviewers of this SAP and 
signed off by the author of the SAP, the Head of Biostatistics (or designated designee) and Clinical 
Lead. 
This SAP supersedes the protocol in all specifications associated with data analyses and statistical 
methodologies. 
Fabry disease is a rare lysosomal storage disorder (LSD) associated with significant morbidity and 
early mortality caused by deficiency of the alpha-galactosidase A (AGA) enzyme activity due to 
mutations in the AGA (GLA) gene (MIM 301500). This deficiency in enzyme activity leads to 
accumulation of glycosphingolipids (e.g., globotriaosylceramide [Gb3] and its deacylated form, 
globotriaosylsphingosine [lyso-Gb3]), resulting in multi-organ damage. Fabry disease is a chronic, 
progressive disorder that ultimately leads to end-organ damage in the kidneys (end-stage renal 
disease), heart (hypertrophic cardiomyopathy, diastolic heart failure and arrhythmias) and brain 
(vascular stroke). Due to end-stage renal disease and other life-threatening complications associated 
with the disease, average life expectancy in affected males is reduced to approximately 50 years of 
age. 
Study AVRO-RD-01-201 is a multinational, open-label study to assess the efficacy and safety of 
AVR-RD-01 in approximately 8 to 12 male subjects 16  (and post-pubertal) to 50 years of age 
with a confirmed diagnosis of classic Fabry disease based on deficient AGA enzyme activity who 
have received no enzyme replacement therapy (ERT) and/or chaperone therapy for Fabry disease 
within 3 years of Screening. It has five study periods: Screening, Baseline, Pre-AVR-RD-01 
Infusion, AVR-RD-01 Infusion, and Post-AVR-RD-01 Infusion Follow-Up. Data Monitoring 
Committee (DMC) will review safety information that may preclude continued study enrollment 
and/or necessitate changes to the protocol.  
The study was prematurely discontinued.  
 will perform all efficacy and safety statistical analyses. 
 


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2. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) 
2.1. 
Study Objective(s) 
2.1.1. 
Primary Objectives 
The primary objectives of this study are to: 
 Evaluate the effect of AVR-RD-01 on substrate (i.e., globotriaosylceramide [Gb3]) in 
kidney biopsies 
 Evaluate the safety and tolerability of AVR-RD-01 including, but not limited to:  
 Evaluation of adverse events (AEs)/serious adverse events (SAEs)  
 Evaluation of immunogenicity of AVR-RD-01  
 Testing for the presence of replication competent lentivirus (RCL)  
 Performance of integration site analysis (ISA) to assess for potential aberrant clonal 
expansion(s)  
 
2.1.2. 
Secondary Objectives 
The secondary objectives of the study are to: 
 Evaluate AGA enzyme activity in plasma and peripheral leukocytes 
 Evaluate the effect of AVR-RD-01 on biomarkers for Fabry disease (i.e., Gb3 and its 
deacylated form, globotriaosylsphingosine [lyso-Gb3]) in plasma and urine 
 Evaluate the effect of AVR-RD-01 on substrate (i.e., Gb3) in skin biopsies 
 Evaluate the effect of AVR-RD-01 on other clinical indices of Fabry disease, including: 
 Clinical laboratory measures of renal function, including measured glomerular 
filtration rate (mGFR), estimated glomerular filtration rate (eGFR) and urine total 
protein and albumin excretion 
 Cardiac structure assessed by left ventricular mass index (LVMI) on cardiac 
magnetic resonance imaging (MRI) 
 Abdominal pain and stool consistency assessed by the Diary for Irritable Bowel 
Syndrome Symptoms-Diarrhea (DIBSS-D) 
 Pain assessed by the Brief Pain Inventory Short Form (BPI-SF) questionnaire 
 Functional status assessed by the Physical Component Summary (PCS) and Mental 
Component Summary (MCS) scores of the 36-Item Short Form Health Survey (SF-
36) 
 Assess measures of engraftment of gene-augmented hematopoietic stem cells by 
determining average vector copy number (VCN) in peripheral blood leukocytes and 


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bone marrow stem and progenitor cells using quantitative polymerase chain reaction 
(qPCR) and/or droplet digital polymerase chain reaction (ddPCR) analysis  
2.1.3. 
Exploratory Objectives 
The exploratory objectives of the study are to: 
 Evaluate the effect of AVR-RD-01 on: 
 Microscopic findings on kidney biopsy  
 AGA enzyme activity in skin and kidney biopsies 
 Podocyturia (shedding of podocytes into urine) 
 Other gastrointestinal (GI) symptoms associated with Fabry assessed by the DIBSS-
D, including stool frequency, urgency, recurrent bowel movements, and the 
abdominal symptom subscale 
 Functional status assessed by the eight subscale scores (i.e., Vitality, Physical 
Functioning, Bodily Pain, General Health Perceptions, Physical Role Functioning, 
Emotional Role Functioning, Social Role Functioning and Mental Health) of the SF-
36 
 Exploratory biomarkers for Fabry disease in plasma and urine (for subjects with 
written informed consent to optional genetic biomarker research) [Note: Samples 
were not tested by the end of study] 
 Assess reconstitution dynamics by immunophenotyping the fluorescence-activated 
peripheral blood subpopulation and bone marrow CD34+ subpopulations, and by 
studying changes in cell populations composition by single-cell RNA sequencing 
(scRNAseq) 
 Assess engraftment dynamics by determining average VCN, and performing ISA, on 
fluorescence-activated cell-sorted peripheral blood subpopulations and bone marrow 
CD34+ subpopulations 
 Evaluate subject experience with respect to AVR-RD-01 treatment and perception of 
changes in Fabry disease burden and quality of life by qualitative interview (for subjects, 
and caregivers or other qualified observers of subjects, who provide separate written 
informed consent). [Note: No data captured as the 
 qualitative interviews were 
not validated in Fabry disease] 
 Assess the impact of the conditioning regimen on reproductive potential 
2.2. 
Study Endpoints 
2.2.1. 
Efficacy Endpoints 
2.2.1.1. 
Primary Efficacy Endpoints 
The primary efficacy endpoint is the change from baseline in the average number of Gb3 inclusions 
(i.e., myelinosomes) per kidney peritubular capillary (PTC) per subject at Week 48. 


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2.2.1.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following: 
 Change from baseline in AGA enzyme activity level in plasma and peripheral 
leukocytes at Weeks 24 and 48 
 Change from baseline in biomarkers for Fabry disease (i.e., Gb3 and its deacylated form, 
lyso-Gb3) in plasma and urine at Weeks 24 and 48 
 Change from baseline in substrate (i.e., Gb3) in skin biopsy (at Weeks 24 and 48)  
 Change from baseline in mGFR at Week 48 
 Change from baseline in eGFR and urine total protein and albumin at Weeks 24 and 48 
 Change from baseline in LVMI assessed by cardiac MRI at Week 48 
 Change from baseline in abdominal pain and stool consistency assessed by the DIBSS-D 
at Weeks 24 and 48 
 Change from baseline in BPI-SF questionnaire scores at Weeks 24 and 48 
 Change from baseline in physical and mental functioning assessed by the SF-36 PCS 
and MCS scores at Weeks 24 and 48 
 Average VCN in peripheral blood leukocytes assessed by qPCR and/or ddPCR at Weeks 
24 and 48  
 Average VCN in bone marrow stem and progenitor cells assessed by qPCR and/or 
ddPCR at Week 48  
2.2.1.3. 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include the following: 
 Change from baseline in light microscopic findings on kidney biopsy at Week 48 
 Change from baseline in AGA enzyme activity in skin biopsy (Weeks 24 and 48) and 
kidney biopsy (Week 48) 
 Change from baseline in the number of podocytes shed into the urine (podocyturia) at 
Weeks 24 and 48  
 Change from baseline in other GI symptoms associated with Fabry disease assessed by 
the DIBSS-D, including stool frequency, urgency, recurrent bowel movements and the 
abdominal symptom subscale at Weeks 24 and 48 
 Change from baseline in physical and mental functioning assessed by the eight SF-36 
subscale scores (i.e., Vitality, Physical Functioning, Bodily Pain, General Health 
Perceptions, Physical Role Functioning, Emotional Role Functioning, Social Role 
Functioning and Mental Health) at Weeks 24 and 48 
 Change from baseline in exploratory biomarkers for Fabry disease in plasma and urine 
at Weeks 24 and 48 (for subjects with written informed consent to optional genetic 


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biomarker research for consenting subjects) [Note: Samples were not tested by the end 
of study] 
 Changes from baseline in peripheral blood cell subpopulations (i.e., T cells [CD3+], 
natural killer [NK] cells [CD56+], B cells [CD19+], granulocytes [CD15+], and 
monocytes [CD14+]) and bone marrow CD34+ subtypes (i.e., hematopoietic stem cells 
[HSCs] [HSC CD34+CD38-CD90+CD45RA-] and multipotent progenitors [MPP 
CD34+CD38-CD90-CD45RA-], multilymphoid progenitors [MLP CD34+CD38-CD90-
CD45RA+], common myeloid progenitors [CMP CD34+CD38+CD7-CD10-
CD135+CD45RA-], granulocytes/monocytes progenitors [GMP CD34+CD38+CD7-
CD10-CD135+CD45RA+], megakaryocyte/erythroid progenitors [MEP 
CD34+CD38+CD7-CD10-CD135-CD45RA-], and Pre-B/NK progenitors 
[CD34+CD38+CD7-CD10+] cells) analyzed by immunophenotyping and scRNAseq 
over time  
 Average VCN and ISA results in both peripheral blood cell subpopulations (i.e., T cells 
[CD3+], NK cells [CD56+], B cells [CD19+], granulocytes [CD15+], and monocytes 
[CD14+]) and bone marrow CD34+ subtypes (i.e., HSCs [HSC CD34+CD38-
CD90+CD45RA-] and multipotent progenitors [MPP CD34+CD38-CD90-CD45RA-], 
multilymphoid progenitors [MLP CD34+CD38-CD90-CD45RA+], common myeloid 
progenitors [CMP CD34+CD38+CD7-CD10-CD135+CD45RA-], 
granulocytes/monocytes progenitors [GMP CD34+CD38+CD7-CD10-
CD135+CD45RA+], megakaryocyte/erythroid progenitors [MEP CD34+CD38+CD7-
CD10-CD135-CD45RA-], and Pre-B/NK progenitors [CD34+CD38+CD7-CD10+] 
cells) over time  
 Change from baseline in Fabry disease burden and quality of life, including exploration 
of the impact of pre-treatment conditioning on participating subjects and perception of 
changes in disease burden and quality of life, assessed by qualitative interview 
conducted at Weeks 12, 24, and 48 (for subjects, and caregivers or other qualified 
observers of subjects, who provide separate written informed consent) [Note: No data 
captured as the 
 qualitative interviews were not validated in Fabry disease] 
2.2.2. 
Safety Endpoints 
Primary 
Primary safety endpoints include the following: 
 Incidence and severity of AEs and serious adverse events (SAEs) 
 Change from baseline in clinical laboratory values relevant to safety 
 Abnormal clinical laboratory values relevant to safety 
 Change from baseline in vital signs 
 Change from baseline in electrocardiogram (ECG) findings 
 Presence of anti-AGA antibodies 
 Presence of RCL  


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 Identification of mononuclear cells with integration site profiles suggestive of aberrant 
clonal expansion(s)  
Exploratory 
 The exploratory safety endpoint is change from baseline in sperm count, sperm motility, 
and sperm morphology. 
2.3. 
Statistical Hypotheses 
No formal hypothesis tests or statistical models are planned. 
2.4. 
Pharmacokinetic (PK) and PK/Pharmacodynamic (PD) Hypotheses 
Not applicable for this study. 
 


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3. 
STUDY DESIGN 
This is a multinational, open-label study to assess the efficacy and safety of AVR-RD-01 in 
approximately 8 to 12 adults 
post-pubertal, where permitted by region) male subjects up to 50 years of age with a confirmed 
diagnosis of classic Fabry disease based on deficient AGA enzyme activity who are treatment-
naïve. For this study, treatment-naïve is defined as having received no enzyme replacement therapy 
(ERT) and/or chaperone therapy for Fabry disease within 3 years of Screening. 
Five study periods (Screening, Baseline, Pre-AVR-RD-01 Infusion, AVR-RD-01 Infusion and Post-
AVR-RD-01 Infusion Follow-Up) comprise the study. During the Screening Period (approximately 
8 weeks), written informed consent (and assent, if applicable) will be obtained and the subject will 
complete other Screening procedures to confirm study eligibility. Once study eligibility is 
confirmed, subjects will enter the Baseline Period (up to 3 days) during which time assessments 
will be performed to establish a pre-AVR-RD-01 infusion baseline. Once baseline assessments are 
complete, the subject will enter the Pre-AVR-RD-01 Infusion Period (approximately 6 to 8 weeks) 
during which time mobilization, apheresis, AVR-RD-01 Drug Product preparation and testing for 
release and conditioning regimen administration to achieve partial myeloablation will take place. 
Following completion of the Pre-AVR-RD-01 Infusion Period, the subject will enter the AVR-RD-
01 Infusion Period (1 day) during which time AVR-RD-01 infusion will take place. After AVR-
RD-01 infusion, the subject will enter the Post-AVR-RD-01 Infusion Follow-Up Period 
(approximately 48 weeks) during which time periodic safety and efficacy assessments will be 
performed to assess measures of engraftment, clinical response and safety post-infusion. Post-AVR-
RD-01 infusion follow-up will occur at the following time points: Week 1 (Days 1 through 7), 
Week 2 (Days 10 and 14), Week 4 (Day 28), Week 8 (Day 56), Week 12 (Day 84), Week 24 (Day 
168), Week 36 (Day 252) and Week 48 (Day 336). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be re-
screened once upon discussion between the Investigator and Medical Monitor. Subjects who 
discontinue from the study prior to infusion of AVR-RD-01 will be replaced. 
An independent Data Monitoring Committee (DMC) will be established for the study to review 
safety information during the Pre-AVR-RD-01 Infusion, AVR-RD-01 Infusion, and Post-AVR-RD-
01 Infusion Follow-Up Periods to assess for signals that may preclude continued study enrollment 
and/or necessitate changes to the protocol. A safety review meeting will take place to review the 
infusion and completed the Week 4 
follow-up visit. Once the DMC has reviewed these Week 4 data and determined that there are no 
significant clinical safety events (serious adverse events [SAEs] related to AVR-RD-01 infusion), 
the next 2 subjects can begin the mobilization phase of the study. The DMC will meet again after 
these 2 subjects have completed the Week 4 follow-up visit. Once the DMC has reviewed the Week 
4 data from subjects 2 and 3 and determined that there are no significant clinical safety events 
(serious adverse events [SAEs] related to AVR-RD-01 infusion), any currently enrolled subjects 
that have completed the baseline assessments can begin the mobilization phase of the study, and the 
study will be opened to enrollment. After the 6th subject has completed the Week 4 follow-up visit, 
the DMC will review all available safety data (i.e., accumulated safety data available from subjects 
1 through 6) to assess for signals that may preclude continued study enrollment and/or necessitate 
changes to the protocol, as well as make recommendations on the timing of any future periodic 
DMC meetings. Ad-hoc safety review meetings will also take place if stopping rules for the study 


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are met, or for any other safety reason(s), at the discretion of the DMC. Further details on the DMC, 
including its composition and responsibilities, will be outlined in the DMC Charter for the study. 
Final statistical analysis for the study will be performed after all enrolled subjects complete the 
Week 48 assessments (or prematurely discontinue the study). 
After study completion, consenting subjects will continue periodic safety and efficacy assessments 
for approximately 14 years (for a total of 15 years post-infusion follow-up) in a long-term follow-
up study to AVRO-RD-01-201. 
3.1. 
Definition of Study Treatment 
The Sponsor identifier for the study drug product is AVR-RD-01. The active substance in AVR-
RD-01 is autologous CD34+ enriched cell fraction transduced with LV/AGA that encodes for the 
human AGA cDNA sequence. The finished drug product is presented as a cryopreserved cell 
solution which is thawed immediately prior to use. The drug product is intended for one time IV 
infusion of between 3 and 20 x 106/kg body weight autologous CD34+ transduced cells. 
In addition to AVR-RD-01, in this study subjects will receive the following preparatory 
medications:  
 Four to eight G-CSF and two plerixafor injections for HSC mobilization prior to AVR-
RD-01 infusion 
 Anti-convulsant medication administration (levetiracetam or others [benzodiazepines or 
valproic acid]), concurrent with busulfan administration, for seizure prophylaxis 
 Five IV infusions of busulfan, one test dose to inform the conditioning dose and four for 
myeloablative conditioning, prior to AVR-RD-01 infusion 
o In prior versions of the protocol, melphalan was used. 
It should be noted that these preparatory medications are not considered IMP. 
3.2. 
Sample Size Considerations 
3.2.1. 
Sample Size Justifications 
The sample size of 8 to 12 subjects chosen for this study was selected without statistical 
considerations but was determined to be adequate to meet the study objectives. 
3.2.2. 
Sample Size Re-estimation 
Not applicable for this study. 
3.3. 
Randomization 
Not applicable for this study. 
 
 


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3.4. 
Clinical Assessments 
Screening 
Demography (date of birth, age, race and ethnicity, height, weight, body mass index (BMI)), 
medical and surgical history, Fabry diagnosis, historical mutation analysis, mutation analysis, 
echocardiogram (ECHO) and transmittable disease testing (including HIV). 
Efficacy 
Globotriaosylceramide (Gb3) and Globotriaosylsphingosine (lyso-Gb3) in plasma and urine, AGA 
enzyme activity in plasma, serum and peripheral leukocytes, biomarkers for Fabry disease (i.e., 
Gb3) in skin biopsy and kidney biopsy samples, clinical laboratory measures of renal function 
(mGFR, eGFR and urine protein/albumin), cardiac function assessed by LVMI on cardiac MRI, GI 
symptoms assessed by the DIBSS-D, pain assessed by the BPI-SF questionnaire, functional status 
assessed by the SF-36, engraftment, AGA enzyme activity in skin and kidney from biopsy samples, 
podocytes in urine and exploratory biomarkers for Fabry disease in plasma and urine (not tested). 
Safety 
Adverse events and serious adverse events, vital signs (heart rate, systolic and diastolic blood 
pressure, respiratory rate and temperature), physical examination, 12-lead electrocardiogram 
(ECG), laboratory assessments (serum chemistry, hematology and urinalysis), pulmonary function 
test by spirometry, chest x-ray, cardiac MRI, immunogenicity, measures of reproductive potential 
and concomitant medications. 


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4. 
PLANNED ANALYSES 
4.1. 
Interim Analysis 
In this open-label study, after AVR-RD-01 infusion, measures of engraftment, clinical response, 
and safety are analyzed for each individual subject on an ongoing basis. Considering this, a discrete 
interim analysis of data collected in this study will not be performed.  
4.2. 
Final Analysis 
The final database lock will occur when all subjects have completed the study (i.e., the final follow-
up visit at Week 48 [or prematurely discontinued the study]) and all data are collected and cleaned. 
 


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5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
5.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Summary tables and listings will be prepared according to ICH Guideline E3. 
The All Subjects population will be used for specific outputs, as defined below. Safety data will be 
summarized using the Safety population, and Efficacy data will be summarized using the Infused 
population. 
Summary tables for any concomitant medications will be coded according to the World Health 
Organization (WHO) Drug dictionary Version of WHODrug Global B3 March 2022. Adverse event 
preferred terms and body/organ systems and medical history conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA®) dictionary Version 25.0.  
Missing data will be reported as follows: 
 
presented as such in the Listings 
 
Missing data and will be displayed as follows in Listings: 
 
ted/assessment 
was not performed (as per EDC) 
 
Result
 was collected/assessment 
was performed (as per EDC) but no result is available. 
 
not 
required/expected for that subject/visit, e.g., where a result would only be 
expected after a protocol amendment but not prior to that amendment. 
 
no result can be derived, e.g., 
standard deviation is NC when n<3, or change from baseline (CFB) is NC 
when no baseline or post-baseline result is available. 
 
If all data for a specific visit are missing the data are included in the table with N=0. 
 
i.e., below the lower limit of 
quantifi
i.e., above the upper limit of quantification) will be 
 
 
If the calculated mean at a sampling time point is BLQ then the mean value 
calculated (NC) in the summary. Similarly, any calculated BLQ values for 
in the summary. 
Imputed dates and times will NOT be presented in the listings. Completely missing start or end 
dates/times will remain missing, with no imputation applied. Consequently, time to onset and 
duration of such events will be missing. Partial dates/times will be displayed as captured in subject 
listing displays.  


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5.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations 
The tables and listings will be numbered using a decimal system to reflect main levels of unique 
tables and listings and sub-levels of replicate tables and listings with two digits per level (e.g., 
 
1. 
The first level number will be consistent with the corresponding Clinical Study Report 
(CSR) appendix in which the tables or listings will appear. For example, the post text tables will 
appear in Appendix 14 (and will be numbered 14.XX.YY) and the individual subject data listings 
will appear in Appendix 16 (and will be numbered 16.XX.YY). The subject disposition table will 
be first in the first section of the report and will be numbered Table 14.1. The supportive subject 
data listing will be Listing 16.1. Any subset table will have the number Table 14.1.2, etc. 
2. 
Table numbering will follow ICH E3. Subject disposition, baseline and demography and 
prior and concomitant medications tables should appear as the second level number (Table 14.1 
series). Efficacy tables will occupy the next sub-level (Table 14.2 series). Safety tables will follow 
next (Table 14.3 series). Similar conventions will be applied to the subject data listings. 
3. 
Each table and figure title will be complete, accurate and concise. The last line of the title 
will provide the analysis population being summarized/presented. 
4. 
All analysis and summary tables will include the analysis population sample size (i.e., 
number of subjects). 
5. 
Each listing title will be complete, accurate and concise. Inclusion in each analysis 
population will be presented as a flag on selected listings. 
6. 
If possible, variables being summarized and statistics reported will appear in the left most 
column of a table. 
5.3. 
Data Management 
All data will be recorded by the site in individual source documents. An eCRF will be created by 
the data management group for recording of the required data in the study database. All eCRF 
information is to be filled in by site staff. If an item is not available or is not applicable, this fact 
should be indicated. Blank spaces should not be present unless otherwise directed. 
All information recorded in the eCRFs for this study must be consistent with the 
source documentation for the study participants. The investigative site will make available source 
documents to any personnel monitoring the study. The study monitor will verify consent of all 
subjects to participate in the study and will perform 100% source data verification (SDV) of data 
entered into the eCRF and raise queries for correction by the site. The data entered into the eCRF 
will be subject to data validation checks for consistency and completeness by the data management 
group. Data queries will then be generated and sent to the investigational site for response before 
the database is locked and released for statistical analysis. 
Data from any screen failures might be entered into the clinical database. If screen failure data is 
entered in the clinical database this data might not be cleaned. In order to describe the 
representativeness of the study, this data should be presented including the reasons for screen 
failures (failure of individual inclusion/exclusion criteria could be presented if appropriate).  








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using the same precision as the value(s) from which they were derived. For the reporting 
of descriptive statistics, the mean, median, standard deviation and CV% will be reported 
to 1 decimal place more than the source data; the minimum and the maximum values 
will be presented to the same precision as the source data. 
 For categorical/discrete variables, the frequency count and the percentage (of available 
data) for each category of the variable will be presented and will be displayed in the 
form XX (XX.X%) where the percentage is in the parentheses. The denominator for all 
percentages will be the number of subjects with non-missing data within the analysis 
population of interest, unless otherwise stated. Otherwise, percentages (for example for 
AEs and Concomitant Medications) will be calculated based on the population total. If 
the analysis population is not stated in the title then a footnote will clarify the 
account for dropouts and missing values. 
 All percentages will be rounded to one decimal place. In the case the numerator is equal 
to the denominator, the percentage should be presented as (100) instead of (100.0). In 
the case the numerator is equal to 0, the percentage will not be presented. 
 Date variables will be formatted as YYYY-MM-DD for presentation. Time will be 
formatted in military time as HH:MM for presentation. 
 Unscheduled assessments will be considered when applying visit windows and derived 
study periods and will also contribute to the end of study value, or best/worst case value 
where required (e.g., shift table).  
 When deriving a subject level statistic (e.g., maximum value post-baseline), all values 
should be included regardless of whether they appear in a corresponding visit-based 
summary. 
 All listings will be sorted for presentation in order of subject, parameter, and date/time 
of procedure or event.  
 Individuals who do not meet the criteria for participation in this study (screen failure) 
may be re-screened once upon discussion between the Investigator and Medical 
Monitor. 
o Where a re-screened subject is present in the clinical database under two 
different identifiers, data will be combined for Tables and Figures, and the 
identifiers will be concatenated for Listings with a footnote included to describe 
the details of re-screening. This is for subject numbers 101-103 and 101-105. 
 101-103 is to be reported as a screen failure. 
 For medical/surgical history and AEs, frequency ordering will be used for the summary 
table presentation (i.e., order by the overall grouping in descending frequency, and then 
alphabetical order in the case of equal frequency, for each System Organ Class (SOC) 
and also for each Preferred Term (PT) within each SOC). Columns that are used for 
grouping in descending frequency will be specified in the footnote. 


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 Outputs will define Lower Limit of Quantification (LLOQ) values, including the units, if 
applicable; 
o Values below the LLOQ (BLQ), or not detected or not quantifiable, will be 
imputed as the LLOQ (where available) or as 0.01 for figures and for summary 
statistics, and n imp, the number of imputed values, will be reported; 
o Imputed values will be used for Tables and Figures, but Listings will present the 
original values 
 Outputs will define Lower Limit of Detection (LLOD) values, including the units, if 
applicable; 
 Outputs will include reference ranges and Normal Ranges, including the units, if 
applicable; 
 Outputs will include units, if applicable; 
 On all plots, the subjects who received melphalan (Subjects 101-101, 102-102, and 101-
102), busulfan (short washout, Subject 102-104) and busulfan (long washout, Subjects 
101-104, 101-105, 102-105, 101-106, and 101-107) will be identified as follows (a 
legend will describe the conditioning regime associated with each color): 
o Subjects conditioned with melphalan will be presented in red, with a different 
symbol (eg, square, circle, triangle) per subject; 
o Subjects conditioned with busulfan with a washout period of 20h (short washout) 
will be presented in blue, with a symbol (eg, square, circle, triangle)  
o Subjects conditioned with busulfan with a washout period of 68-70h (long 
washout) will be presented in green, with a different symbol (eg, square, circle, 
triangle) per subject; 
o Where a mean line is included on plots, a dashed black line (thickness greater 
than the red/blue/green individual subject lines) will be used; 
 A mean line will be included even when n<3 
 Where data are captured on separate individual days during conditioning, e.g., 
Conditioning (Day 1) etc., subjects who received melphalan (Subjects 101-101, 102-
102, and 101-102), busulfan (short washout, Subject 102-104) and busulfan (long 
washout, Subjects 101-104, 101-105, 102-105, 101-106, and 101-107) will be grouped 
separately for derivation of summary statistics on all tables and figures; 
 A month is counted as 30.4375 days and a year is counted as 365.25 days (30.4375 days 
× 12 months); 
 Summary statistics: 
o Summary statistics for efficacy data (absolute values) will include N, n, 
geometric mean, coefficient of variation between subjects (CV%), median, 


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minimum, and maximum will be reported (where n<3, only mean, median, 
minimum and maximum will be presented); 
 Geometric Mean will be presented when at least 3 values (including 
imputed values) are available; 
 %GeoCV will be calculated as: 
; 
o Summary statistics for safety data, and for changes from baseline, will include N, 
n, mean, SD, minimum, median, and maximum will be reported (where n<3, 
only mean, median, minimum and maximum will be presented); 
 For plots of log-normal data, the y-axis may be presented on the log-scale, as required; 
Outputs will be delivered as pdf and rtf format. 
5.5. 
Analysis Populations 
Subject inclusion into each population will be determined before database lock and prior to 
commencing the final analysis. 
5.5.1. 
All Subjects Population 
The All Subjects population will consist of all subjects who consented, i.e. were enrolled. The All 
Subjects population will be used for all listings and for summaries of all disposition, demographic, 
and baseline data.  
5.5.2. 
Safety Population 
The Safety population will consist of all enrolled subjects who received any preparatory medication 
(G-CSF for Mobilization, plerixafor, busulfan/melphalan, or anti-convulsant). This population will 
be used for the summaries of all safety data, demographic, baseline characteristics and medical 
history. 
5.5.3. 
Infused Population 
The Infused population will consist of all enrolled subjects who received all preparatory 
medications and AVR-RD-01. This population will be used for the summaries of all efficacy data, 
and selected summaries of safety data. 
5.6. 
Baseline Definition 
For all safety and efficacy endpoints, Baseline (Derived) will be defined as the last available, non-
missing observation prior to first administration of a preparatory medication (G-CSF for 
Mobilization, plerixafor, busulfan/melphalan, or anti-convulsant), unless specifically mentioned 
otherwise. 
Non-numeric (i.e., categorical) observations will be considered for baseline calculations, where 
applicable. In addition, non-missing results from unscheduled assessments prior to first 
administration of a preparatory medication may also be considered in the calculation of baseline 
observations. 


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If more than one assessment is collected before first administration of a preparatory medication and 
it is not possible to determine which is the closest then the mean of the assessments will be used as 
Baseline (Derived).  
Where baseline values are at or below the LLOQ (BLQ), or not detected or not quantifiable, these 
will be imputed as the LLOQ (where available) or as 0.01 for figures and for summary statistics. 
Baseline (Derived) will be defined in a footnote on each applicable output. 
Listings will present all visits and Baseline (Derived), however, figures and tables will only include 
Baseline (Derived) and post-AVR-RD-01 visits (for efficacy) and post-baseline visits (for safety).  
5.7. 
Derived and Transformed Data 
5.7.1. 
Screening Age 
Age, in completed years, at screening will be defined as: 
Age (years) = integer value ((Date (first) signed Informed Consent  Date of Birth + 1) / 365.25) 
5.7.2. 
Body Mass Index 
Body Mass Index (kg/m2, to one decimal place) = Body Weight (kg) / (Height x Height (m)) 
5.7.3. 
Study Day 
Study Day will be defined as: 
Study Day = Date of Assessment  Date of AVR-RD-01 infusion (if date of assessment is 
before Date of AVR-RD-01 infusion) 
 
Otherwise, 
Study Day = (Date of Assessment  Date of AVR-RD-01 infusion) + 1 
For any population which includes subjects who may not have received AVR-RD-01, e.g., the 
Safety population, the Study Day will not be derived, except where the SAP indicates date of (first) 
signing of informed consent is used. 
5.7.4. 
Time since AVR-RD-01 Infusion 
Time since AVR-RD-01 infusion will be calculated as: 
 
 
5.7.5. 
Age at enrollment 
Age at enrollment will be calculated as: 
 
 


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5.7.6. 
Age at AVR-RD-01 infusion 
Age at AVR-RD-01 infusion will be calculated as:  
 
 
 
5.7.7. 
Adverse event onset time relative to AVR-RD-01 infusion 
Adverse event onset time relative to AVR-RD-01 infusion will be calculated as: 
Adverse event onset time relative to AVR-RD-01 infusion = Onset Date and Time of AE  
AVR-RD-01 infusion Date and Time, if onset date of AE is before Date of AVR-RD-01 
infusion 
Otherwise, Adverse event onset time relative to AVR-RD-01 infusion = (Onset Date and 
Time of AE  AVR-RD-01 infusion Date and Time) + 1 
 
Where time is missing, only dates will be used. Refer to Section 5.7.19 for handling of incomplete 
dates. 
5.7.8. 
Duration of Adverse Events 
Duration of Adverse Events (in days) will be calculated as: 
Duration of Adverse Event = (Resolution Date and Time)  (Onset Date and Time) 
 
Where time is missing, only dates will be used. If a resolution or onset date is missing or 
incomplete, no duration will be derived. 
5.7.9. 
Change from Baseline 
For efficacy, CFB will be calculated as (post-AVR-RD-01 result  baseline result). 
For safety, CFB will be calculated as (post-baseline result  baseline result). 
Changes from baseline will use Baseline (Derived), including where Baseline (Derived) uses the 
imputed LLOQ value.  
Change from baseline comparisons for categorical variables will use Baseline (Derived) and will be 
displayed using shift-tables that display the frequency and percentage of subjects within each 
category at baseline and at any specified time points. 
If Baseline (Derived) is missing then the CFB will also be set to missing, unless otherwise stated. 
Only subjects with a value at both the Baseline (Derived) visit and the specific post-baseline visit 
will be presented. 


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5.7.10. 
Observed Cases (OC) and Last Observation Carried Forward (LOCF) and 
Outliers 
Not applicable for this study. Missing data will not be imputed.  
Outliers will be included in all outputs. 
5.7.11. 
Completers 
Not applicable for this study. 
5.7.12. 
Treatment Compliance 
Not applicable for this study (as AVR-RD-01 is administered once, treatment compliance is not 
pertinent). 
5.7.13. 
Kidney Biopsy 
The number of myelinosomes per kidney peritubular capillary (PTC) per subject will be evaluated 
by two independent renal pathologists. The renal pathologists will score the average number of Gb3 
inclusions (i.e., myelinosomes) per kidney PTC per subject, based on electron microscopic images 
of kidney biopsy samples. The primary efficacy measure will be based on the mean of the average 
number of Gb3 inclusions (i.e., myelinosomes) per kidney PTC, across the two independent 
reviewers. 
5.7.14. 
Diary for Irritable Bowel Syndrome (DIBSS-D) 
The DIBSS-D produces item-level scores across 2 domains (bowel movements and abdominal 
completed to calculate a weekly score for either the bowel movements (BM) or the abdominal 
symptom items. 
Scores for bowel movements (stool consistency, stool frequency, and urgency), for abdominal 
symptoms (abdominal pain, abdominal discomfort, abdominal bloating, and abdominal cramping), 
and for the abdominal symptoms domain score, will be obtained at each protocol scheduled time 
point. 
5.7.15. 
BPI-SF 
Two scores are calculated from the Brief Pain Inventory.   
The pain severity score is calculated as the mean of the non-missing values for questions 3 (worst 
pain), 4 (least pain), 5 (average pain) and 6 (current pain).  
The pain interference score is calculated as the mean of the non-missing values for questions 9a, b, 
c, d, e, f and g, which represent pain interference with general activity, mood, walking ability, 
normal work, relations with other people, sleep, and enjoyment of life. Subjects who answer fewer 
than four questions will not have a pain interference score derived.   
5.7.16. 
SF-36 
SF-36 version 2 will be used in the study. There are eight health domains (Vitality, Physical 
Functioning, Bodily Pain, General Health Perceptions, Physical Role Functioning, Emotional Role 


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Functioning, Social Role Functioning and Mental Health) and psychometrically-based physical 
component summary (PCS) and mental component summary (MCS) scores. Scoring will be 
undertaken using the commercial software by QualityMetric. The scores provided by QualityMetric 
will be used for the data summary.   
5.7.17. 
Estimated GFR 
Estimated GFR (eGFR), used to estimate how well the kidneys are filtering certain agents produced 
by the body, will be calculated using the CKD-EPI Creatinine Equation as follows:  
 
5.7.18. 
Measured GFR 
Measured GFR (mGFR), a measurement of how well the kidneys are filtering certain agents not 
produced by the body, will be assessed using Iohexol clearance following the process described by 
Brøchner Mortensen correction, 
(Brøchner-Mortensen & Jødal, 2009), shown in formula 3 below. The JBM-corrected mGFR values 
will be used for the analysis.  
 
Definitions: 
CIo = Dose of Iohexol in mg 
A = Intercept of measurements [ln concentration vs. time] [mcg * min / mL] 
mL] 
CLIo = Clearance of Iohexol 
Cor_CLIo = Corrected clearance of Iohexol 
BSA = Body Surface Area 








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 For subjects 503-102 and 504-101, who had Mobilization but did not 
proceed to receive conditioning or AVR-RD-01, the study period after the 
end of Apheresis will be captured as Post-Apheresis 
o Conditioning: started (or worsened) on or after first dosing of melphalan (for 
subjects conditioned with melphalan) or first dosing of anti-convulsant 
medication (levetiracetam or others [benzodiazepines or valproic acid]) given for 
prophylaxis ahead of busulfan (for subjects conditioned with busulfan) and before 
infusion of AVR-RD-01 
 AVR-RD-01 Infusion: started (or worsened) on or after the start of infusion of AVR-RD-
01 
 Post-AVR-RD-01 Infusion Follow-Up: started (or worsened) after the end of AVR-RD-
01 infusion 
The date and time of AEs are captured, as well as date and time for G-CSF, plerixafor, apheresis, 
levetiracetam or others [benzodiazepines or valproic acid], busulfan/melphalan and AVR-RD-01 
infusion. Therefore, when assigning AEs to a study period, the time (HH:MM) of the onset (or 
worsening) of the AE will be compared to the time of the preparatory medication or AVR-RD-
01, e.g., on Day 1, an AE with onset time prior to the start time of AVR-RD-01 infusion will be 
assigned to the Conditioning study period. Where time is missing or incomplete, the AE will be 
assigned to the study period using the date alone, e.g., on Day 1, an AE on Day 1 with onset time 
missing will be assigned to the AVR-RD-01 infusion study period. 
If an adverse event continues into subsequent study periods it will only be counted in the study 
period in which it first occurred, in order to avoid double counting.  
 


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6. 
TREATMENT COMPARISONS 
6.1. 
Data Display Treatment and Other Sub-Group Descriptors 
The Analysis Population used will be presented on all tabulations. 
Adverse Events will be summarized by System Organ Class (SOC) and Preferred Term (PT). 
Additionally, AEs will be summarized by study period (Pre-Mobilization, Preparatory 
Medications, AVR-RD-01 Infusion, and Post-AVR-RD-01 Infusion Follow-Up). The Preparatory 
Medications study period will be further broken down into Mobilization, Apheresis, Post-
Apheresis, and Conditioning. The following labels for study period will be used on applicable AE 
tabulations: 
 All Adverse Events 
 Pre-Mobilization 
 Preparatory Medications 
 Mobilization 
i. 
Mobilization #2 (for 101-106) 
 Apheresis 
i. 
Apheresis #2 (for 101-106) 
 Post-Apheresis 
i. 
Post-Apheresis #2 (for 101-106) 
 Conditioning 
 AVR-RD-01 Infusion 
 Post-AVR-RD-01 Infusion Follow-Up 


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7. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
The listings and summary tables for the disposition, safety and efficacy data will be the 
responsibility of the study Biostatistician. 
The currently supported version of SAS® software will be used to perform all data analyses. The 
actual SAS® version used will be presented in the Clinical Study Report. 
All data in the database will be presented in the data listings. Unless otherwise stated, all listings 
will be sorted by subject number and assessment date/time. In the listings, subject number will 
be of the format 101-001, etc. 
The study aims to explore the possibility of any indications of an efficacy response signal, as 
well as to assess safety and tolerability of AVR-RD-01. As such, all continuous efficacy 
endpoints will be summarized descriptively at each protocol-scheduled time point and as change 
from baseline at each post-AVR-RD-01 time point, and all continuous safety and tolerability 
endpoints will be summarized descriptively at each protocol-scheduled time point and as change 
from baseline at each post-baseline time point. 
7.1. 
Multicenter Studies 
Data from all participating sites will be pooled. 
7.2. 
Other Strata and Covariates 
Not applicable for this study. 
7.3. 
Examination of Subgroups 
Due to protocol amendments regarding the conditioning regimen, safety data will be presented 
overall and by the three subgroups of i) subjects who received melphalan, ii) subjects who 
received busulfan, and iii) subjects who received busulfan (long washout). 
7.4. 
Multiple Comparisons and Multiplicity 
Not applicable for this study. 
7.5. 
Data handling conventions 
7.5.1. 
Premature Withdrawal and Dropouts 
For subjects who are withdrawn or dropout from the study prior to study completion, all data 
collected will be listed and included in data summaries. Early termination data will be mapped 
using visit windows. 
7.5.2. 
Additional/Unscheduled Assessments 
Generally, missing dates/times will not be imputed. Adverse events with missing or partial dates 
will be handled such that in the absence of contradictory information an AE is classified based 
on the study period closest to the AE onset. Adverse events will be assigned to each study period 
according to Section 5.7.19  


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Unscheduled assessments will be considered when applying visit windows and for derived study 
periods and will also contribute to the end of study value, or best/worst case value where 
required (e.g., shift table).  
When deriving a subject level statistic (e.g., maximum value post-baseline), all values should be 
included (including scheduled, unscheduled, retest and early discontinuation data) regardless of 
whether they appear in a corresponding visit-based summary. 
Listings will include scheduled, unscheduled, retest and early discontinuation data.  
7.5.3. 
Assessment Windows 
For by-visit summaries, visit windows as defined below will be applied:  
Table 3. Visit Window Assignment 
Assigned Study Day (Inclusive) 
Visit Assigned 
Target Study 
Day 
From 
To 
 
 
1 
1 
Day 0 (AVR-RD-01)
1 
2 
2 
Day 1 (W1) 
2 
3 
3 
Day 2 (W1) 
3 
4 
4 
Day 3 (W1) 
4 
5 
5 
Day 4 (W1) 
5 
6 
6 
Day 5 (W1) 
6 
7 
7 
Day 6 (W1) 
7 
8 
9 
Day 7 (W1) 
8 
10 
12 
Day 10 (W2) 
11 
13 
21 
Day 14 (W2) 
15 
22 
42 
Day 28 (W4) 
29 
43 
70 
Day 56 (W8) 
57 
71 
126 
Day 84 (W12) 
85 
127 
210 
Day 168 (W24) 
169 
211 
294 
Day 252 (W36) 
253 
295 
379 
Day 336 (W48) 
337 
 
In the case where two or more measurements fall within the same visit window, the available 
measurement closest to the planned visit date will be used. If two measurements are equidistant 
from the planned visit date then the earlier value will be used. If multiple measurements occurred 
on the same date, and the time (HH:MM) of each assessment is available, then these will be 
reviewed on a case-by-case basis. If time is unavailable, the mean of the measurements will be 
taken. In the case of a retest where there is clear evidence to suggest that the retest was done due 
to erroneous data, then the retest value will be used. Otherwise, the mean of the measurements 
will be used.  
Scheduled, unscheduled, retest and early discontinuation data will be included when mapping to 
visit windows. 


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7.5.4. 
Visit/Study Period Mapping and Labels 
Within Tables, Figures and Listings, the mapping and derived visit labels in Table 3 will be 
used from date of AVR-RD-01 infusion onwards.  
Prior to the date of AVR-RD-01 infusion, the below mapping and derived study period labels 
will be used in Listings: 
 Pre-Mobilization: date is before first dosing of G-CSF for Mobilization 
 Mobilization:  
o Date is on or after first dosing of G-CSF for Mobilization and before start of 
apheresis 
 For subject 101-106, the study period between the start of the second 
Mobilization until the start of the second apheresis will be captured as 
Mobilization #2 
 Apheresis: 
o Date is on or after start of apheresis until the end date of the last apheresis 
 For subject 101-106, the study period between the start of the second 
apheresis until the end of the second apheresis will be captured as 
Apheresis #2 
 Post-Apheresis: date is after the end of the last apheresis and before date of first dosing of 
melphalan (for subjects conditioned with melphalan) or first dosing of anti-convulsant 
medication (levetiracetam or others [benzodiazepines or valproic acid]) given for 
prophylaxis ahead of busulfan (for subjects conditioned with busulfan) 
o For subject 101-106, the study period between the end of the first apheresis and 
the start of Mobilization #2 will be captured as Post-Apheresis 
 The study period between the end of the second apheresis and the first 
dosing of anti-convulsant medication (levetiracetam or others 
[benzodiazepines or valproic acid]) given for prophylaxis ahead of 
busulfan will be captured as Post-Apheresis #2 
o For subjects 503-102 and 504-101, who had Mobilization but did not proceed to 
receive conditioning or AVR-RD-01, the study period after the end of Apheresis 
will be captured as Post-Apheresis 
 Conditioning: date is on or after first dosing of melphalan (for subjects conditioned with 
melphalan) or first dosing of anti-convulsant medication (levetiracetam or others 
[benzodiazepines or valproic acid]) given for prophylaxis ahead of busulfan (for subjects 
conditioned with busulfan) and before date of infusion of AVR-RD-01 
Listings will present both protocol visit/study day and also derived study period/study day. 
Baseline (Derived) will also be included. Unscheduled, retest and early discontinuation data prior 
to the day of AVR-RD-01 infusion will be included when mapping to the above study period 
labels for Listings. 


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In Tables and Figures, the following mapping and study period labels will again be used prior to 
the day of AVR-RD-01 infusion:  
 Pre-Mobilization: date is before first dosing of G-CSF for Mobilization 
 Mobilization:  
o Date is on or after first dosing of G-CSF for Mobilization and before start of 
apheresis 
 For subject 101-106, the study period between the start of the second 
Mobilization until the start of the second apheresis will be captured as 
Mobilization #2 
 Apheresis: 
o Date is on or after start of apheresis until the end date of the last apheresis 
 For subject 101-106, the study period between the start of the second 
apheresis until the end of the second apheresis will be captured as 
Apheresis #2 
 Post-Apheresis: date is after the end of the last apheresis and before date of first dosing of 
melphalan (for subjects conditioned with melphalan) or first dosing of anti-convulsant 
medication (levetiracetam or others [benzodiazepines or valproic acid]) given for 
prophylaxis ahead of busulfan (for subjects conditioned with busulfan) 
o For subject 101-106, the study period between the end of the first apheresis and 
the start of Mobilization #2 will be captured as Post-Apheresis 
 The study period between the end of the second apheresis and the first 
dosing of anti-convulsant medication (levetiracetam or others 
[benzodiazepines or valproic acid]) given for prophylaxis ahead of 
busulfan will be captured as Post-Apheresis #2 
o For subjects 503-102 and 504-101, who had Mobilization but did not proceed to 
receive conditioning or AVR-RD-01, the study period after the end of Apheresis 
will be captured as Post-Apheresis 
 Conditioning: date is on or after first dosing of melphalan (for subjects conditioned with 
melphalan) or first dosing of anti-convulsant medication (levetiracetam or others 
[benzodiazepines or valproic acid]) given for prophylaxis ahead of busulfan (for subjects 
conditioned with busulfan) and before date of infusion of AVR-RD-01 
o Where data are captured on separate individual days during conditioning, e.g., 
Conditioning (Day 1) etc., subjects who received melphalan (Subjects 101-101, 
102-102, and 101-102), busulfan (short washout, Subject 102-104) and busulfan 
(long washout, Subjects 101-104, 101-105, 102-105, 101-106, and 101-107) will 
be grouped separately 
For Tables and Figures, scheduled, unscheduled, retest and early discontinuation data will be 
included when mapping to study periods. In the case where daily measurements were not 
scheduled per protocol, but two or more measurements still fall within the same study period, 


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then these will be reviewed on a case-by-case basis. In the case of a retest where there is clear 
evidence to suggest that the retest was done due to erroneous data, then the retest value will be 
used.  
In the case where daily measurements were scheduled per protocol, e.g., daily measurements 
during Mobilization, Apheresis or Conditioning, then each individual scheduled assessment will 
be included separately in Tables and Figures under the appropriate study period label, e.g. 
Mobilization (Day 1). 
For subjects who are withdrawn or dropout from the study prior to study completion, all data 
collected will be listed and included in data summaries. Early termination data will be mapped 
using visit windows to the derived visits in Table 3 or to the derived study periods described 
above. 
7.6. 
Derived and Transformed Data 
The required endpoints and variables will be derived by the statistical programmers at 
 
 using the derivations specified in Section 5.7 of this SAP. 


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8. 
STUDY POPULATION 
All disposition, baseline and demographic data will be summarized using the All Subjects 
population. Baseline and demographic data will also be summarized using the Safety population 
and Infused population. 
8.1. 
Disposition of Subjects 
A disposition listing will present date of informed consent, date of enrollment, date of study 
completion or early termination, the primary reason for early discontinuation, if applicable and 
whether included in each population and reasons for exclusion, for each subject. 
A listing of whether or not all inclusion and exclusion criteria were met and if not, which criteria 
were not met, by subject, will also be presented. 
The following will be summarized: 
 Number of subjects enrolled 
 Number of subjects treated with each preparatory medication (G-CSF for 
Mobilization, plerixafor, melphalan, anti-convulsant, or busulfan) or AVR-RD-01 
 8 subjects had mobilization/apheresis once and received AVR-RD-01 
 1 subject (101-106) had mobilization/apheresis twice (due to suboptimal CD34+ 
cells for making IP) and received AVR-RD-01 
 2 subjects had mobilization/apheresis once and did not receive AVR-RD-01, 
namely 503-102 (the second planned mobilization/apheresis did not happen due to 
study closure) and 504-101 (did not receive AVR-RD-01 due to study closure) 
 Number of subjects completing the study 
 Number of subjects withdrawn and reason for withdrawal 
 Number of subjects in each analysis population 
 Duration of follow-up (using Time since AVR-RD-01 infusion) 
8.2. 
Protocol Deviations 
A protocol deviation is any divergence from the protocol. Protocol deviations should be defined 
of 
defined as a subset of protocol deviations that may significantly affect the completeness, 
accuracy, and/or reliability of the study data or that may significantly affect a subject s rights, 
safety, or well-being, and include: 
 
subject and prevent the good conduct of the clinical trial; 
 Protocol violation that could compromise the quality of study data such as: use of 
erythropoietin, use of biological agents potentially modifying erythropoiesis, enrolment 
into interventional clinical trials, bone marrow transplantation; 


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 Occurrence of new diseases that could influence the treatment efficacy, for which 
AVRO-RD-01 is contraindicated or that are treated with a medication that is not 
permitted as a concomitant medication.   
The process of identifying protocol deviations as well identification of IPDs are specified in the 
Monitoring Plan. 
Protocol deviations will be reviewed on an ongoing basis and the final review and classification 
of protocol deviations will be performed prior to database lock. 
The need for any supplementary analyses resulting from protocol deviations will be determined 
following review of the protocol deviations ahead of database lock and will be documented prior 
to the primary analysis being conducted. 
All protocol deviations will be listed. The type of protocol deviation, the description, and the 
date it occurred will be included. The potential impact of notable protocol deviations deemed 
important by the study team will be discussed in the CSR. 
A frequency table will present the number of protocol deviations and IPDs per subject and per 
site, with percentages included to capture the proportion of the total numbers of PDs or IPDs.  
8.3. 
Demographic and Baseline Characteristics 
All baseline and demographic data recorded at screening and prior to dosing will be listed. 
Subject demographic and baseline variables (age at enrollment, age at AVR-RD-01 infusion, 
gender, race, ethnicity, height, body weight, BMI, Gb3 in plasma, lyso-Gb3 in plasma, AGA 
enzyme in peripheral leukocytes, and average number of Gb3 inclusions (ie, myelinosomes) per 
kidney PTC) will be summarized. 
Disease diagnosis (age at time of diagnosis and age at onset of symptoms) will be listed and 
summarized. 
Historical mutation analysis, mutation analysis, transmittable disease testing and ECHO will be 
listed only. 
8.4. 
Medical History and Medical Conditions Present at Entry 
All medical history (MH) conditions, concomitant diseases and surgical procedures will be 
classified by system organ class (SOC) and preferred term (PT) using MedDRA® v25.0 . The 
version will be labelled in the applicable outputs.  
The number and percentage of subjects with each medical history condition, concomitant disease 
and surgical procedure will be presented by SOC and PT. 
Past and current medical conditions will be listed, including whether the subject has experienced 
any past concomitant diseases or surgeries, start date, end date or whether it is ongoing, the 
disease or symptom, the SOC and PT, the maximum CTCAE Grade, and whether it resulted in 
hospitalization. 


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8.5. 
Treatment Compliance 
All preparatory medication administration data (G-CSF for Mobilization, plerixafor, melphalan, 
anti-convulsant and busulfan) and AVR-RD-01 infusion will be listed. Apheresis data (e.g., total 
cell count, CD34+ cell count) will also be listed. 
The listing of melphalan will include the dose administered, percentage difference between 
expected and actual dose, the start and end times, total dose (mg), body surface area (m2) and 
total dose/BSA (mg/m2). 
The listing of busulfan will include the dose administered each day, percentage dose 
increased/decreased vs. the previous dose, percentage difference between expected and actual 
dose, the start and end times, total dose (mg), body surface area (m2), total dose/BSA (mg/m2), 
AUC and Total AUC. 
The listing of AVR-RD-01 infusion will include start date and time of infusion, end date and 
time of infusion, subject weight (kg), total volume infused (mL) and date of initial hospital 
discharge. If more than one batch of gene therapy was manufactured and administered to the 
subject, then the sum will also be presented for total volume infused (mL). 
A listing will include the dates and derived study day of: 
 G-CSF for Mobilization 
o Excludes any G-CSF administered for hematological reconstitution due to 
neutrophils < 1.5 (109/L), which will be listed separately 
 Plerixafor 
 Apheresis 
 Anti-convulsant medication (levetiracetam or others [benzodiazepines or valproic acid]) 
given for prophylaxis ahead of busulfan (for subjects conditioned with busulfan)  
 Conditioning with melphalan or busulfan 
 AVR-RD-01 infusion 
Since all the above-mentioned administrations will be done at the investigational site, treatment 
compliance will not be determined for this study. 
8.6. 
Prior and Concomitant Medications 
The end dates of medications will be used to assign medications into different categories: 
 Prior medication: Prior medications are defined as any medication where the use was 
stopped prior to the first administration of G-CSF for Mobilization.  
 Concomitant medication: Concomitant medications are defined as any medication (other 
than the preparatory medications and AVR-RD-01) that was used at least once after the 
first administration of G-CSF for Mobilization. Medications that were stopped on the 
same date as G-CSF for Mobilization will be defined as concomitant medications. The 
consideration to determine if a medication is classed as concomitant. 




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The start dates and end dates of prior and concomitant medications will be used to further split 
prior and concomitant medications into the following study periods: 
 Pre-Mobilization: ended before first dosing of G-CSF for Mobilization 
 Preparatory Medications:  
 Mobilization:  
o Date is on or after first dosing of G-CSF for Mobilization and before start of 
apheresis 
 For subject 101-106, the study period between the start of the second 
Mobilization until the start of the second apheresis will be captured as 
Mobilization #2 
 Apheresis: 
o Date is on or after start of apheresis until the end date of the last apheresis 
 For subject 101-106, the study period between the start of the second 
apheresis until the end of the second apheresis will be captured as 
Apheresis #2 
 Post-Apheresis: date is after the end of the last apheresis and before date of first dosing of 
melphalan (for subjects conditioned with melphalan) or first dosing of anti-convulsant 
medication (levetiracetam or others [benzodiazepines or valproic acid]) given for 
prophylaxis ahead of busulfan (for subjects conditioned with busulfan) 
o For subject 101-106, the study period between the end of the first apheresis and 
the start of Mobilization #2 will be captured as Post-Apheresis 
 The study period between the end of the second apheresis and the first 
dosing of anti-convulsant medication (levetiracetam or others 
[benzodiazepines or valproic acid]) given for prophylaxis ahead of 
busulfan will be captured as Post-Apheresis #2 
o For subjects 503-102 and 504-101, who had Mobilization but did not proceed to 
receive conditioning or AVR-RD-01, the study period after the end of Apheresis 
will be captured as Post-Apheresis 
 Conditioning: started on or after first dosing of melphalan (for subjects conditioned with 
melphalan) or first dosing of anti-convulsant medication (levetiracetam or others 
[benzodiazepines or valproic acid]) given for prophylaxis ahead of busulfan (for subjects 
conditioned with busulfan) and before date of AVR-RD-01 infusion 
 AVR-RD-01 Infusion: started on or after the start of infusion of AVR-RD-01 
 Post-AVR-RD-01 Infusion Follow-Up: started after the end of AVR-RD-01 infusion 
Note since only dates are captured for medications, and not times, that the start/end dates will be 
used to assign medications to a study period, e.g., a medication starting on Study Day 1 will be 
assigned to the AVR-RD-01 infusion study period because it is not known if the medication 
started before or after the start time of the AVR-RD-01 infusion on Day 1. 


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Medications will be classified as a prior medication and/or a concomitant medication. The prior 
and concomitant medications are exclusive with each other. The same concomitant medication, 
however, could appear in multiple study periods of Mobilization, Apheresis, Post-Apheresis, 
Conditioning, AVR-RD-01 Infusion, and Post-AVR-RD-01 Infusion Follow-Up, if it was used in 
two or more of those study periods. 
Concomitant medications do not include G-CSF for Mobilization, plerixafor, 
busulfan/melphalan, and anti-convulsant medications for seizure prophylaxis. However, any 
G-CSF administered for hematological reconstitution due to neutrophils < 1.5 (109/L) will be 
listed separately. 
Similarly, any platelet transfusions will be listed separately. 
Prior and concomitant medications will be coded by WHODrug Global B3 March 2022.  
Data will be summarized by Anatomical Therapeutic Chemical (ATC) system (Level 4) and drug 
preferred name. The summary tables will show the number and percentage of subjects taking 
each medication by ATC Level 4 and preferred name. 
Where a subject may have taken two or more medications, the subject may be counted only once 
within an ATC classification, if appropriate. Also, the same subject may contribute to two or 
more preferred terms in the same classification but will only be counted once within the 
preferred term.  
Frequency ordering will be used for the table presentation (i.e., order by the overall grouping in 
descending frequency for each ATC, and additionally for each preferred term within each ATC; 
in each case where there are equal frequencies items would be ordered alphabetically). 
Summary tables will be presented for concomitant medications over the course of the study for 
each study period (Pre-Mobilization, Preparatory Medications, AVR-RD-01 Infusion, and Post-
AVR-RD-01 Infusion Follow-Up). The Preparatory Medications study period will be further 
broken down into Mobilization, Apheresis, Post-Apheresis, and Conditioning. Summary tables 
will be produced for the Safety Population and for the Infused Population. 
Prior medications and concomitant medications will be listed and summarized, separately.  The 
study period and within study period study day for medication start and stop and all study 
periods where the medication has been used will be provided. For concomitant medications, 
medication name, product name, start dates and end dates, dose, dose unit, frequency, route, and 
indication (including details of any associated MH or AE) will be presented. Concomitant 
preparatory medication will be flagged.  
The preparatory medication (G-CSF for Mobilization, plerixafor, melphalan, anti-convulsant and 
busulfan) will be listed separately (see Section 8.6). 
Listings will be sorted by subject identification number and start date. If the start date is 
completely missing, then these events will be presented first. If the onset date is missing a month 
or a day then partial dates for medications will be imputed as per Table 4 to allow medications to 
be sorted appropriately. Imputed dates will not be listed. 


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9. 
EFFICACY ANALYSES 
All efficacy analyses will be conducted on the Infused population.  
Absolute values and CFB will be listed. 
9.1. 
Primary Efficacy Analysis 
The primary efficacy measure is globotriaosylceramide (Gb3) inclusions in peritubular 
capillaries on kidney biopsy.  Electron microscopic images of kidney biopsy samples will be 
read centrally by two independent renal pathologists. The renal pathologists will score the 
average number of Gb3 inclusions (i.e., myelinosomes) per kidney PTC per subject.  
The primary efficacy endpoint will be the change from baseline in the average number of Gb3 
inclusions (i.e., myelinosomes) per kidney PTC at Week 48 (the mean from two independent 
reviewers will be used when deriving CFB). This efficacy measure will also be summarized at 
the other protocol-scheduled time points. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  
9.2. 
Secondary Efficacy Analyses 
9.2.1. 
AGA Enzyme Activity 
Observed values and absolute change from baseline in AGA enzyme activity level values will be 
summarized at each protocol scheduled time point, separately for plasma, serum and peripheral 
leukocytes. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  
For the figure displaying observed values of AGA enzyme in plasma, horizontal reference lines 
will be added at the LLN of 4.2 and ULN of 15 nmol/h/mL.  
For the listing of observed values of AGA enzyme in plasma, values below the LLN of 4.2 and 
above the ULN of 15 nmol/h/mL will be flagged. 
For the figure displaying observed values of AGA enzyme in serum, horizontal reference lines 
will be added at the LLN of 0.074 and ULN of 0.457 nmol/min/mL.  
For the listing of observed values of AGA enzyme in serum, values below the LLN of 0.074 and 
above the ULN of 0.457 nmol/min/mL will be flagged. 
For the figure displaying observed values of AGA enzyme in peripheral leukocytes, horizontal 
reference lines will be added at the LLN of 24 and ULN of 56 nmol/h/mg protein.  
For the listing of observed values of AGA enzyme in peripheral leukocytes, values below the 
LLN of 24 and ULN of 56 nmol/h/mg protein will be flagged. 


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9.2.2. 
Biomarkers 
All observed values and absolute changes from baseline in Gb3 and isoforms, and its deacylated 
form lyso-Gb3 and analogs, will be listed at each protocol scheduled time point, separately for 
plasma and urine. On the listing of observed values, any values above the ULN will be flagged 
(refer to Appendix 1). 
Gb3 isoforms and lyso-Gb3 analogs will not be included in summaries or plots. 
Observed values and absolute change from baseline in total Gb3 and its deacylated form, lyso-
Gb3, will be summarized at each protocol scheduled time point, separately for plasma and urine. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, in total Gb3 and its deacylated form, lyso-Gb3, will also be provided.  
Figures displaying observed values over time will include horizontal reference lines at the 
LLOD, LLOQ and ULN, as appropriate (refer to Appendix 1). 
9.2.3. 
Skin Biopsies 
Observed values and absolute change from baseline in substrate (i.e., Gb3) values will be 
summarized at each protocol scheduled time point for skin biopsies. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  
9.2.4. 
mGFR 
A listing of Iohexol injection will include date/time of Iohexol injection, volume (mL) of Iohexol 
injection, dose (mg/mL) of Iohexol injection, total dose (mg), the date/time and plasma 
concentrations (mg/mL) of the 3h and 4h samples, and the number of minutes between time of 
Iohexol injection and the time of the 3h and 4h samples. 
Observed values and absolute change from baseline in mGFR values will be summarized at each 
protocol scheduled time point. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided. On the figure displaying observed values, a horizontal reference 
line will be added at the LLN of 90 mL/min/1.73 m2. 
On the listing of mGFR, values <90 mL/min/1.73 m2 will be flagged as lower than normal. 
9.2.5. 
eGFR 
Observed values and absolute change from baseline in eGFR and calculated eGFR values will be 
summarized at each protocol scheduled time point. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided. On the figure displaying observed values, a horizontal reference 
line will be added at the LLN of 90 mL/min/1.73 m2. 
On the listing of eGFR, values <90 mL/min/1.73 m2 will be flagged as lower than normal. 


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9.2.6. 
Urine Protein/Albumin Excretion 
Observed values and absolute change from baseline in urine total protein/albumin excretion 
values will be summarized at each protocol scheduled time point. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  
9.2.7. 
Cardiac MRI 
Observed values and absolute change from baseline in LVMI values assessed by the cardiac MRI 
will be summarized at each protocol scheduled time point. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  
9.2.8. 
DIBSS-D 
Abdominal pain and stool consistency scores and change from baseline will be summarized at 
each protocol scheduled time point. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  
9.2.9. 
BPI-SF 
Observed values and absolute change from baseline in BPI-SF questionnaire scores for pain 
severity and pain interference will be summarized at each protocol scheduled time point. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  
9.2.10. 
SF-36 
Observed values and absolute change from baseline in physical and mental functioning assessed 
by the SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) 
scores will be summarized at each protocol scheduled time point. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  
9.2.11. 
VCN in Peripheral Blood 
VCN in peripheral blood leukocytes assessed by qPCR and/or ddPCR will be summarized at 
each protocol scheduled time point, using either summary statistics or frequency tabulations, as 
appropriate for the type of data. Note if values are obtained by qPCR and also ddPCR, these will 
be reported separately. 
Figures displaying observed values over time, along with arithmetic or geometric means, will 
also be provided.  


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Scatter plots will be produced for the comparison of VCN in peripheral blood leukocytes (x-axis) 
with each of the below parameters (y-axis). A log-scale for x and/or y will be considered. To be 
included, data needs to be available for a subject for x and for y at the same visit: 
 AGA enzyme in peripheral leukocytes 
o Reference lines will be added at the LLN of 24 and ULN of 56 nmol/h/mg protein 
 AGA enzyme in plasma 
o Reference lines will be added at the LLN of 4.2 and ULN of 15 nmol/h/mL 
 AGA enzyme in serum 
o Reference lines will be added at the LLN of 0.074 and ULN of 0.457 
nmol/min/mL 
 AGA enzyme in skin biopsies 
 AGA enzyme in kidney biopsies 
 Gb3 concentration in Leukocytes 
 Gb3 concentration in Plasma 
 Gb3 concentration in Urine 
 Average number of Gb3 inclusions (i.e., myelinosomes) per kidney peritubular capillary 
(PTC) 
 Lyso-Gb3 concentration in Leukocytes 
 Lyso-Gb3 concentration in Plasma 
 Lyso-Gb3 concentration in Urine 
9.2.12. 
VCN in Bone Marrow Aspirate 
VCN in bone marrow stem and progenitor cells assessed by qPCR and/or ddPCR will be 
summarized at each protocol scheduled time point, using either summary statistics or frequency 
tabulations, as appropriate for the type of data. Note if values are obtained by qPCR and also 
ddPCR, these will be reported separately. 
Figures displaying observed values over time, along with arithmetic or geometric means, will 
also be provided.  
Scatter plots will be produced for the comparison of VCN in bone marrow aspirate (x-axis) with 
each of the below parameters (y-axis). A log-scale for x and/or y will be considered. To be 
included, data needs to be available for a subject for x and for y at the same visit: 
 AGA enzyme in peripheral leukocytes 
o Reference lines will be added at the LLN of 24 and ULN of 56 nmol/h/mg protein 
 AGA enzyme in plasma 
o Reference lines will be added at the LLN of 4.2 and ULN of 15 nmol/h/mL 
 AGA enzyme in serum 
o Reference lines will be added at the LLN of 0.074 and ULN of 0.457 
nmol/min/mL 
 AGA enzyme in skin biopsies 
 AGA enzyme in kidney biopsies 
 Gb3 concentration in Leukocytes 


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 Gb3 concentration in Plasma 
 Gb3 concentration in Urine 
 Average number of Gb3 inclusions (i.e., myelinosomes) per kidney peritubular capillary 
(PTC) 
 Lyso-Gb3 concentration in Leukocytes 
 Lyso-Gb3 concentration in Plasma 
 Lyso-Gb3 concentration in Urine 
9.3. 
Exploratory Efficacy Analyses 
9.3.1. 
Light Microscopic Findings on Kidney Biopsies 
Observed values and absolute change from baseline in light microscopic findings on kidney 
biopsies will be summarized at each protocol scheduled time point.  
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  
9.3.2. 
AGA Enzyme Activity in Skin and Kidney Biopsies 
Observed values and absolute change from baseline in AGA enzyme activity values will be 
summarized at each protocol scheduled time point, separately for skin and kidney biopsies.  
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  
9.3.3. 
Podocyturia 
Observed values and absolute change from baseline in the number of podocytes shed into the 
urine (podocyturia) will be summarized at each protocol scheduled time point. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  
For the figure displaying observed values, horizontal reference lines will be included at the LLN 
of 0 podocyte/g Cr (or 0 podocyte/mg Cr), and at the ULN of 3000 podocyte/g Cr (or 
3 podocyte/mg Cr). 
On the listing of podocyturia, values below the LLN of 0 podocyte/g Cr (or 0 podocyte/mg Cr) 
and above the ULN of 3000 podocyte/g Cr (or 3 podocyte/mg Cr) will be flagged. 
9.3.4. 
DIBSS-D 
Observed values and absolute change from baseline in other GI symptoms associated with Fabry 
disease assessed by the DIBSS-D, including stool frequency, urgency, abdominal discomfort, 
abdominal bloating, abdominal cramping and the abdominal symptom domain score will be 
summarized at each protocol scheduled time point. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  


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9.3.5. 
SF-36 
Observed values and absolute change from baseline in the eight SF-36 subscale scores (i.e., 
Vitality, Physical Functioning, Bodily Pain, General Health Perceptions, Physical Role 
Functioning, Emotional Role Functioning, Social Role Functioning, and Mental Health) will be 
summarized at each protocol scheduled time point. 
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  
9.3.6. 
Exploratory Biomarkers for Fabry Disease 
A listing will include dates and times of samples for any subjects for whom written informed 
consent to optional genetic biomarker research was received. Note these samples will not be 
tested by the end of study. 
9.3.7. 
Peripheral Blood Cell Subpopulations and Bone Marrow CD34+ Subtypes   
Observed values and absolute change from baseline in peripheral blood cell subpopulations and 
bone marrow CD34+ subtypes will be summarized at each protocol scheduled time point . 
 Peripheral blood cell subpopulations 
 T cells [CD3+] 
 Natural killer [NK] cells [CD56+] 
 B cells [CD19+] 
 Granulocytes [CD15+],  
 Monocytes [CD14+]  
 Bone marrow CD34+ subtypes  
 HSCs [HSC CD34+CD38-CD90+CD45RA-]  
 Multipotent progenitors [MPP CD34+CD38-CD90-CD45RA-],  
 Multilymphoid progenitors [MLP CD34+CD38-CD90-CD45RA+],  
 Common myeloid progenitors [CMP CD34+CD38+CD7-CD10-CD135+CD45RA-] 
 Granulocytes/monocytes progenitors [GMP CD34+CD38+CD7-CD10-
CD135+CD45RA+] 
 Megakaryocyte/erythroid progenitors [MEP CD34+CD38+CD7-CD10-CD135-
CD45RA-]  
 Pre-B/NK progenitors [CD34+CD38+CD7-CD10+] cells)  
Figures displaying observed values and CFB over time, along with arithmetic or geometric 
means, will also be provided.  


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9.3.8. 
Average VCN and ISA in Peripheral Blood Cell Subpopulations and Bone 
Marrow CD34+ Subtypes   
Observed values in average VCN and ISA results in peripheral blood cell subpopulations and 
bone marrow CD34+ subtypes will be summarized at each protocol scheduled time point.  
 Peripheral blood cell subpopulations 
 T cells [CD3+] 
 Natural killer [NK] cells [CD56+] 
 B cells [CD19+] 
 Granulocytes [CD15+],  
 Monocytes [CD14+]  
 Bone marrow CD34+ subtypes  
 HSCs [HSC CD34+CD38-CD90+CD45RA-]  
 Multipotent progenitors [MPP CD34+CD38-CD90-CD45RA-],  
 Multilymphoid progenitors [MLP CD34+CD38-CD90-CD45RA+],  
 Common myeloid progenitors [CMP CD34+CD38+CD7-CD10-CD135+CD45RA-] 
 Granulocytes/monocytes progenitors [GMP CD34+CD38+CD7-CD10-
CD135+CD45RA+] 
 Megakaryocyte/erythroid progenitors [MEP CD34+CD38+CD7-CD10-CD135-
CD45RA-]  
 Pre-B/NK progenitors [CD34+CD38+CD7-CD10+] cells)  
Figures displaying observed values over time, along with arithmetic or geometric means, will 
also be provided.  
9.3.9. 
Perception of changes in disease burden and quality of life, assessed by 
qualitative interview   
No data captured as the 
 qualitative interviews were not validated in Fabry disease. 


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10. 
SAFETY ANALYSES 
All safety analyses will be conducted on the Safety population.  
No inferential statistical testing will be performed for safety variables. 
Due to protocol amendments regarding the conditioning regimen, safety data will be presented 
overall and by the three subgroups of i) subjects who received melphalan, ii) subjects who 
received busulfan, and iii) subjects who received busulfan (long washout). 
10.1. 
Extent of Exposure 
A listing of AVR-RD-01 infusion drug product characteristics will be provided and will include: 
 Total nucleated cells (x10^6) 
o Derived as Nucleated cells/kg (x10^6 cells/kg) multiplied by weight (kg) at time 
of (most recent) apheresis 
 Nucleated cells/kg (x10^6 cells/kg) 
 CD34+ cells/kg (x10^6 cells/kg) 
 CD34+ (%) 
 Number of colony-forming unit-granulocyte, monocyte (CFU-GM) cells administered 
(x10^6) 
 Transduction efficiency (colony-forming unit cell [CFU-C]) (%) 
 Total CFU (%) 
 Vector copy number (VCN/cell) 
 Percentage cell viability (%) 
 AGA (transduced) 
In addition, the following drug product characteristics will be derived: 
 CD34+ cells/kg (x10^6 cells/kg) * VCN (/cell) 
 CD34+ (%) * Total CFU (%) 
 CD34+ (%) * TE (%) 
 CD34+ (%) * VCN (/cell) 
 CD34+ (%) * TE (%) * VCN (/cell) 
Scatter plots will be produced for the comparison of each drug product characteristic and derived 
drug product characteristic (x-axis) with each of the following parameters (y-axis). A log-scale 
for x and/or y will be considered, as required: 
 VCN in peripheral blood leukocytes 
 VCN in bone marrow aspirate 


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 AGA enzyme in peripheral leukocytes 
o Reference lines will be added at the LLN of 24 and ULN of 56 nmol/h/mg protein 
 AGA enzyme in plasma 
o Reference lines will be added at the LLN of 4.2 and ULN of 15 nmol/h/mL 
 AGA enzyme in serum 
o Reference lines will be added at the LLN of 0.074 and ULN of 0.457 
nmol/min/mL 
 AGA enzyme in skin biopsies 
 AGA enzyme in kidney biopsies 
 Gb3 concentration in Leukocytes 
 Gb3 concentration in Plasma 
 Gb3 concentration in Urine 
 Average number of Gb3 inclusions (i.e., myelinosomes) per kidney peritubular capillary 
(PTC) 
 Lyso-Gb3 concentration in Leukocytes 
 Lyso-Gb3 concentration in Plasma 
 Lyso-Gb3 concentration in Urine 
 Days to neutrophil reconstitution 
 Days to platelet reconstitution 
10.2. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with the IMP. 
An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the IMP, regardless of whether the 
event is causally related to the IMP. 
The definition of an AE also covers: 
 Medication errors and uses outside what is foreseen in the protocol, including accidental 
overdose, if an AE results from the error; 
 Any Grade 3 or higher platelet count, grade 3 or higher WBC count, and grade 2 or higher 
neutrophil count (grade determined by CTCAE) regardless of whether considered clinically 
significant by Investigator report; 
 Fertility-related events, considered an AE of special interest (AESI) for the study. 
Adverse events will be coded using MedDRA® version 25.0.  
10.2.1. 
Treatment-emergent Adverse Events  
Any AE that started prior to mobilization with G-CSF is considered a pre-treatment AE and is 
listed, but not included in tabulations (except for tabulations using study periods where 
Pre-Mobilization is included). However, pre-treatment AEs that worsen/increase in severity after 
the subject started mobilization with G-CSF will be recorded as new AEs and consequently will 
be regarded as treatment-emergent and thus will be included in the tabulations. 


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10.2.2. 
Serious Adverse Events 
An SAE is any untoward medical occurrence or effect that: 
 Results in death 
 Is life threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a 
more severe form, might have caused death 
 Results of in-patient hospitalisation or a prolongation of existing hospitalisation, 
excluding admission for social or administrative reasons (see below) 
 Results in a persistent or significant disability/incapacity, where disability is a 
substantial disruption of a person s ability to conduct normal life functions 
 Results in congenital anomaly/birth defect in the offspring of a subject who received 
AVR-RD-01 
 Is an important medical event that may not result in death, be life threatening, or require 
hospitalisation, but that, based upon appropriate medical judgment, may jeopardise the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  
 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in in-patient 
hospitalisation, or the development of drug dependency or drug abuse. 
10.2.3. 
Adverse Drug Reaction or Adverse Reaction 
All untoward and unintended responses to an investigational medicinal product. The 
phrase responses to an investigational medicinal product means that a causal relationship 
between the investigational medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 
10.2.4. 
Unexpected Adverse Reaction 
An adverse reaction, the nature or severity of which is not consistent with the applicable  product 
information (e.g., investiga
AVR-RD-01 or summary of 
product characteristics for an authorized product). 
10.2.5. 
Adverse Event Severity 
The intensity or severity of AEs will be defined according to CTCAE as: 
 Grade 1 (Mild): Symptoms causing no or minimal interference with usual social & 
functional activities. 
 Grade 2 (Moderate): Symptoms causing greater than minimal interference with usual 
social & functional activities. 
 Grade 3 (Severe): Symptoms causing an inability to perform usual social & functional 
activities. 
 Grade 4 (Life threatening): Symptoms causing an inability to perform basic self-care 
functions OR medical or operative intervention indicated to prevent permanent 
impairment, persistent disability, or death. 


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 Grade 5 (Death) 
10.2.6. 
Adverse Event Relationship 
The relationship between an AE and AVR-RD-01, mobilization (G-CSF or plerixafor), 
apheresis, conditioning (busulfan/melphalan), anti-convulsant medication(s), study procedures or 
underlying disease will be assessed based on clinical experience and classified according to the 
following: 
 
 Definite 
 Event or laboratory test abnormality, with plausible time relationship to drug intake 
 Cannot be explained by disease or other drugs 
 Response to withdrawal plausible (pharmacologically, pathologically) 
 Event definitive pharmacologically or phenomenologically (i.e., an objective and 
specific medical disorder or a recognized pharmacological phenomenon) 
 Rechallenge satisfactory, if necessary 
 Probable 
 Event or laboratory test abnormality, with reasonable time relationship to drug 
intake 
 Unlikely to be attributed to disease or other drugs 
 Response to withdrawal clinically reasonable 
 Rechallenge not required 
 Possible 
 Event or laboratory test abnormality, with reasonable time relationship to drug 
intake 
 Could also be explained by disease or other drugs 
 Information on drug withdrawal may be lacking or unclear 
 Unlikely 
 Event or laboratory test abnormality, with a time to drug intake that makes a 
relationship improbable (but not impossible) 
 Disease or other drugs provide plausible explanations 
 Unrelated 
 
state, underlying disease, or the study procedure/conditions 
 Time relationship to drug intake makes a relationship unreasonable 
 Other obvious causes for event or laboratory test abnormality exist 
 Unknown 
 Report suggests an AE; however, cannot be judged at this time because information 
is insufficient or contradictory 
 More data for proper assessment is needed, or additional data is under examination 
 Not applicable  (N/A) 
 Report suggests an AE; however, the need to assess causality is not practical or of 
value, due to the event itself, or to the circumstances surrounding the event 
 
tabulations. 


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10.2.7. 
Adverse Event Tabulations 
All AEs (serious and non-serious) occurring after completion of the informed consent process 
and before the end of study will be included and classified by system organ class (SOC) and 
preferred term (PT) using MedDRA® v25.0. Date imputation algorithm from Section 5.7.19 will 
be employed to partial dates.  
A data listing of all AEs, including pre-treatment AEs (as defined in Section 5.7.19), will be 
provided including verbatim term, SOC, PT, toxicity, relationship to mobilization (G-CSF or 
plerixafor), relationship to apheresis, relationship to conditioning, relationship to AVR-RD-01, 
relationship to study procedure, relationship to underlying disease, date/time and day of onset, 
date/time and day of resolution, duration, possible co-medication, treatment given to treat the 
adverse event, the outcome, whether the event was an SAE, and whether it led to withdrawal. 
AEs prior to start of treatment (Mobilization) will be flagged on this listing. In addition, a 
separate listing of all serious AEs will be provided, with any SAEs prior to treatment 
(Mobilization) flagged. 
Deaths, if any, will be listed for subject, date/time, primary cause and autopsy finding and 
tabulated with frequency counts by SOC and PT. 
Listings will be sorted by subject identification number, onset date/time, SOC, and PT. If the 
onset date is completely missing, then these events will be presented first. If the onset date is 
missing a month or a day then partial dates for AEs will be imputed as per Error! Reference 
source not found. to allow AEs to be sorted appropriately. Imputed dates will not be listed. 
The AE tabulations, unless stated otherwise, will be based on TEAEs. Therefore, all pre-
treatment AEs will be excluded from the tabulations, unless stated otherwise. However, pre-
treatment AEs that worsen/increase in severity after the start of treatment will be recorded as 
new AEs and consequently will be regarded as treatment-emergent and thus will be included in 
the tabulations. 
Descriptive statistical methods will be used to tabulate the TEAE data including both the number 
of subjects and number of events. TEAE tables including the number of events will be presented 
in the following order: number of subjects, (percentage of subjects) and [number of events]. 
When it is necessary to calculate percentages, the denominator will be the total number of 
subjects in the analysis population, unless otherwise stated, and the numerator will be the total 
number of subjects reporting a TEAE within the relevant category.  
For tabulations by SOC and PT, when tabulating the number of subjects, if a subject has repeated 
episodes of a particular TEAE, all episodes will be counted in the tabulation, however, a subject 
with multiple events will only be counted once within each SOC and PT. A subject with more 
than one type of AE in a particular SOC will be counted only once in the total of subjects 
experiencing AEs in that particular SOC. Since a subject could have more than one type of AE 
within a particular SOC, the sum of subjects experiencing different AEs within the SOC could 
appear larger than the total number of subjects experiencing AEs in that SOC. Similarly, a 
subject who has experienced an AE in more than one SOC will be counted only once in the total 


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number of subjects experiencing AEs in all SOCs. Furthermore, SOC and PT will be presented 
in descending order of frequency (i.e., order by the overall grouping in descending frequency for 
each SOC and also for each PT within each SOC; in each case where there are equal frequencies 
items would be ordered alphabetically).  
For tabulations by severity, the maximum severity for each subject will be used. A missing 
severity will not be imputed, but a row labelle
. If a subject has 
multiple events with the same SOC or PT, they will be counted under the worst severity for the 
tabulation, but the events will be counted under the applicable severity category.  
If a subject has repeated episodes of a particular TEAE, only the most severe episode, or the 
episode with the strongest causal relationship, will be counted in the tabulations. 
Plots of cumulative AE counts over time will be produced, with study day on the x-axis 
presented relative to date of AVR-RD-01 infusion (Study Day 1) for the Infused Population and 
relative to date of (first) signing of ICF for the Safety Population. One plot will include all 
subjects with a vertical reference line at Study Day of ICF or AVR-RD-01 infusion. These 
or definitely related to busulfan/melphalan. Where a single AE is captured multiple times due to 
changing severity, each change in Grade will contribute to the cumulative number of AEs for 
that subject. If it is possible to identify such AEs, the plots will be repeated with the multiple 
events collapsed into a single AE occurrence (with the causality and maximum grade considered 
appropriately). 
 Overall Summary of TEAEs 
The summary will include number (%) subjects with: 
 At least one TEAE 
 TEAEs related* to G-CSF for Mobilization 
 TEAEs related to Plerixafor  
 TEAEs related to Apheresis 
 TEAEs related to Melphalan 
 TEAEs related to Anti-Convulsant  
o Levetiracetam or others (benzodiazepines or valproic acid) given for 
prophylaxis ahead of busulfan (for subjects conditioned with busulfan) 
 TEAEs related to Busulfan 
 TEAEs related to Preparatory Medication(s) or associated procedure 
o Combine G-CSF for Mobilization, Plerixafor, Apheresis, Melphalan, Anti-
Convulsant and Busulfan 
 TEAEs related to AVR-RD-01 infusion 
 TEAEs related to G-CSF for Hematological Reconstitution 
 TEAEs related to Study Procedures 
 TEAEs related to Underlying Disease 
 TEAEs leading to Withdrawal 
 TEAEs leading to Discontinuation of the Study 


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 TEAEs leading to Death 
 Each CTCAE Grade 
 
TEAE 
 Maximum CTCAE Grade 
 At least one Treatment-Emergent SAE (TESAE) 
 
deemed possible, probable or definite causal 
relationship 
 
 TEAEs by SOC, PT 
TEAEs will be tabulated for both SOC and PT.  
 
 TEAEs by SOC, PT and CTCAE Grade 
A tabulation of TEAEs by SOC, PT will be presented for each CTCAE Grade 1 to 5, Grade 2 
and Grade 3. The column for Grade 3 will be used to determine decreasing order of 
frequencies. 
 
Treatment-Emergent Serious Adverse Events 
TESAEs will be tabulated for both SOC and PT.  
 TEAEs by Causal Relationship 
The tabulation of AEs by SOC, PT by Onset will be repeated selecting TEAEs with possible, 
probable or definite causal relationship to each preparatory medication (G-CSF for Mobilization, 
plerixafor, melphalan, anti-convulsant or busulfan), apheresis, AVR-RD-01, or study procedure, 
i.e., the AEs by SOC, PT by Onset will be repeated once for each preparatory medication (G-
CSF for Mobilization, plerixafor, melphalan, anti-convulsant or busulfan), apheresis, AVR-RD-
01, or study procedure.  
TEAEs by Causal Relationship will be produced for the Safety Population and for the Infused 
Population. 
 AEs Related to Underlying Disease 
A tabulation of number and percentage of subjects experiencing an AE with a deemed causal 
relationship (possible, probable or definite) to underlying disease will be presented by SOC and 
PT. 
 TEAEs Related to Fertility 
Fertility-related events are considered an AE of special interest (AESI). 
A tabulation of number and percentage of subjects experiencing a TEAE with any SOC or PT 
potentially associated with fertility will be presented by SOC and PT. 


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AEs Leading to Study Discontinuation 
Incidence of AEs leading to discontinuation of the study, as well as the duration, severity, 
relationship to treatment, outcome and actions taken will be listed for each subject. 
 AEs by Onset 
The tabulation of AEs by SOC, PT will be repeated using the onset date/time of each adverse 
event to assign each AE into a study period according to Section 5.7.19. AEs by Onset will be 
produced for the Safety Population and for the Infused Population. Note since Pre-Mobilization 
is included that these tabulations include all AEs as well as TEAEs:  
 Pre-Mobilization: started before first dosing of G-CSF for Mobilization 
 Preparatory Medications:  
o Mobilization:  
 G-CSF: started (or worsened) on or after first dosing of G-CSF for 
Mobilization until start of apheresis 
 For subject 101-106, the study period between the start of the 
second Mobilization until the start of the second apheresis will be 
captured as Mobilization #2 
o Apheresis: 
 started (or worsened) on or after start of the first apheresis until the end of 
the first apheresis 
 For subject 101-106, the study period between the start of the 
second apheresis until the end of the second apheresis will be 
captured as Apheresis #2 
o Post-Apheresis: started (or worsened) after the end of the apheresis and before 
first dosing of melphalan (for subjects conditioned with melphalan) or first dosing 
of anti-convulsant medication (levetiracetam or others [benzodiazepines or 
valproic acid]) given for prophylaxis ahead of busulfan (for subjects conditioned 
with busulfan) 
 For subject 101-106, the study period between the end of the first 
apheresis and the start of Mobilization #2 will be captured as Post-
Apheresis 
 The study period between the end of the second apheresis and the 
first dosing of anti-convulsant medication (levetiracetam or others 
[benzodiazepines or valproic acid]) given for prophylaxis ahead of 
busulfan will be captured as Post-Apheresis #2 
 For subjects 503-102 and 504-101, who had Mobilization but did not 
proceed to receive conditioning or AVR-RD-01, the study period after the 
end of Apheresis will be captured as Post-Apheresis 


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o Conditioning: started (or worsened) on or after first dosing of melphalan (for 
subjects conditioned with melphalan) or first dosing of anti-convulsant 
medication (levetiracetam or others [benzodiazepines or valproic acid]) given for 
prophylaxis ahead of busulfan (for subjects conditioned with busulfan) and before 
date of AVR-RD-01 infusion 
 AVR-RD-01 Infusion: started (or worsened) on or after the start of infusion of AVR-RD-
01 
 Post-AVR-RD-01 Infusion Follow-Up: started (or worsened) after the end of AVR-RD-
01 infusion 
 AEs by Presence/Absence of anti-AGA antibodies 
If applicable, AEs will additionally be classified and tabulated by SOC, PT based on presence of 
anti-AGA antibodies, i.e., Positive result at any time post-treatment vs. Negative result at all 
post-treatment assessments. 
10.3. 
Pregnancies 
Not applicable for this study. 
10.4. 
Clinical Laboratory Evaluations 
The details of measurement of laboratory parameters are described in the study protocol. 
International System (SI) units will be used in all outputs.  
All hematology, clinical chemistry and urinalysis data including CFB will be listed. In these 
listings, sample collection data (e.g., collection times) for laboratory analysis and urinalysis data 
will be included, and observed 
are 
higher or lower than their normal ranges, respectively. 
For the listings of ALT and of AST, the following values will be flagged to indicate possible 
evidence of Drug-Induced Liver Injury: 
 ALT or AST > 8×ULN  
 ALT or AST > 5×ULN 
o In the CSR, an assessment will be made of whether ALT or AST remained above 
5×ULN for more than 2 weeks  
 ALT or AST > 3×ULN 
o In the CSR, an assessment will be made of whether ALT or AST remained above 
3×ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash, and/or eosinophilia (>5%)  
For each laboratory parameter with a defined normal range, absolute values will be defined at 
each protocol scheduled time point as low, normal, or high, and post-baseline values will be 
compared to the baseline value through shift tables. 
In addition, one flag will be derived to identify whether the parameter had at least one value 
above the normal range at any time post-treatment, and another to identify whether the parameter 


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had at least one value below the normal range at any time post-treatment. Subjects having both 
High and Low values relative to normal ranges at post-treatment visits for laboratory parameters 
will be coun
post-treatment
related summary tables.  
The denominator used in laboratory shift table summaries will only include evaluable subjects 
(i.e., those who have both a baseline and at least one post-baseline value recorded). 
For continuous parameters, absolute values and CFB will be summarized at each protocol 
scheduled time point. For any parameter where multiple laboratory normal ranges, which may 
differ by subject and/or visit, have been applied, then data from each laboratory will be 
summarized separately. 
For categorical parameters, frequency tabulations of the number of normal and abnormal (low 
and high) records will also be summarized at each protocol scheduled time point, as well as the 
number considered clinically significant (CS) and not clinically significant (NCS), if captured. 
Box plots will be presented separately for the ratio of value to LLN (Hgb, HCT, Platelets and 
Leukocytes) and for the ratio of value to ULN (ALT, ALP, AST, Bilirubin and GGT) vs. 
scheduled visit. A horizontal reference line will be added at 1 to indicate where the value equals 
the LLN or ULN. 
Individual subject data for the ratio of value to LLN for Hgb, HCT, Platelets, and Leukocytes 
will be plotted vs. study day, with a line for each parameter on the same plot and one plot for 
each subject. Vertical reference lines will be included to represent the study periods of 
Mobilization, Apheresis, Post-Apheresis and Conditioning. A horizontal reference line will be 
included at 1. 
Individual subject data for the ratio of value to ULN for ALT, ALP, AST, Bilirubin and GGT 
will be plotted vs. study day, with a line for each parameter on the same plot and one plot for 
each subject. Vertical reference lines will be included to represent the study periods of 
Mobilization, Apheresis, Post-Apheresis and Conditioning. A horizontal reference line will be 
included at 1. 
An Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will be presented at each 
scheduled visit. The ratio of Bilirubin to ULN will be plotted on the log-scale against the ratio of 
ALT to ULN on the log-
3×ULN and Bilirubin = 2×ULN.  
This eDISH plot will be repeated using AST instead of ALT, and repeated for ALT and AST 
using INR = 1.5×ULN instead of Bilirubin = 2×ULN. 
Bilirubin/INR 
 
Urinalysis results will be summarized at each protocol scheduled time point, using frequency 
tabulations. 
Any available microscopic urinalysis will be listed. 
Partial thromboplastin time (PTT) and international normalized ration (INR) will be listed. 
Blood group information, and T and B cell counts will be listed. 


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10.5. 
Vital Signs Evaluations 
Observed vital signs results (systolic blood pressure, diastolic blood pressure, heart rate, 
respiratory rate and body temperature) will be presented in data listings. 
Observed values and absolute change from baseline for vital signs parameter values will be 
summarized at each protocol scheduled time point. Change from baseline will only be derived 
when the position (e.g., sitting or supine) is the same at baseline and post-baseline. 
10.6. 
ECG Evaluations 
Observed ECG parameter results (heart rate, PR interval, RR interval, QRS interval, QT interval, 
 and the 
clinical assessment of the ECG will be presented in data listings. 
Observed values and absolute change from baseline for ECG parameter values will be 
summarized at each protocol scheduled time point. Change from baseline will only be derived 
when the position (e.g., sitting or supine) is the same at baseline and post-baseline. 
Clinical assessment of the ECG (Normal, Abnormal NCS, Abnormal CS) will be summarized at 
each protocol scheduled time point, using frequency tabulations. 
10.7. 
Pulmonary Function Test 
Observed pulmonary function test results by spirometry (FVC, FEV1, FEV1/FVC ratio, FEV1 % 
of predicted, FVC % of predicted and FEV1/FVC ratio % of predicted) will be presented in data 
listings. 
Observed values and absolute change from baseline for spirometry parameter values will be 
summarized at each protocol scheduled time point. 
10.8. 
Chest X-Ray 
All chest x-ray data will be presented in data listings. 
Interpretation of the chest x-ray (Normal, Abnormal) will be summarized at each protocol 
scheduled time point, using frequency tabulations. 
10.9. 
Immunogenicity 
Observed immunogenicity data will be presented in data listings, including the presence or 
absence of anti-AGA antibodies (and Titer results). 
In case of presence/increase of anti-AGA antibodies, any investigation of the presence of 
neutralizing anti-AGA antibodies, as well as the clinical relevance of their presence with regards 
to (i) reduction of enzyme activity in blood, plasma and cells; (ii) reduction in transduced 
progenitor cells and VCN; (iii) autoimmune-mediated cytopenias will be discussed in the CSR. 
If neutralizing anti-AGA antibodies are detected, safety and/or efficacy outputs may be presented 
separately for subjects with a Positive result at any time post-treatment vs. subjects with a 
Negative result at all post-treatment assessments. 


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10.10. 
Physical Examination 
Physical examination data will be listed. 
10.11. 
Rescue Medication 
The use of rescue medication will be listed. 
10.12. 
Reproductive Potential 
Measures of reproductive potential include sperm count, sperm motility, and sperm morphology.  
Observed values and absolute change from baseline will be summarized at each protocol 
scheduled time point. 
Figures displaying observed values and CFB over time, along with arithmetic means, will also be 
provided.  
10.13. 
Achievement of Hematological Reconstitution 
The occurrence of hematological reconstitution is defined as the first day of absolute neutrophil 
9/L) and of platelets  20 (109/L) (in the absence of platelet transfusions), 
i.e. time from date of AVR-RD-01 infusion to the first date of the three consecutive values. 
All ANC and platelet values will be listed. Flags will indicate where ANC < 0.5 (109/L) or 
platelets < 20 (109/L).  
For the Infused Population, panel plots of individual subjects will be presented for ANC (109/L) 
between study day -50 and study day 100, with study day on the x-axis. Vertical reference lines 
will be included at study day 1 (solid, black), 35 (dashed, red), 42 (solid, red) and 49 (dashed, 
red) and to represent the study periods of Mobilization, Apheresis, Post-Apheresis and 
Conditioning. A horizontal reference line will be included at 0.5 (109/L).  
For the Infused Population, panel plots of individual subjects will be presented for platelet counts 
(109/L) between study day -50 and study day 100, with study day on the x-axis. Vertical 
reference lines will be included at study day 1 (solid, black), 35 (dashed, red), 42 (solid, red) and 
49 (dashed, red) and to represent the study periods of Mobilization, Apheresis, Post-Apheresis 
and Conditioning. A horizontal reference line will be included at 20 (109/L).  
10.14. 
Presence of Replication Competent Lentivirus (RCL)  
Results of the serum and whole blood tests will be listed, with absence of RCL identified by a 
negative result. In case of confirmed positivity, any resulting RCL culture test results will be 
listed. 
10.15. 
Identification of mononuclear cells with integration site profiles 
suggestive of aberrant clonal expansion(s)  
Monitoring for aberrant clonal expansion (ACE) requires the clinical review of multiple datasets 
(e.g., routine clinical and laboratory surveillance, repertoire study, bone marrow examination, 
integration site analysis). Therefore, no summary tables focused solely on ACE will be produced. 


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The results of the manual clinical review for ACE will be described in the summary documents 
with cross-reference to the relevant study listings and a separate integration site analysis report. 
10.16. 
Other Safety Measures 
All other safety data will be listed. 


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11. 
REFERENCES 
Bröchner-Mortensen, J. (1972). A Simple Method for the Determination of Glomerular 
Filtration Rate. Scandinavian Journal of Clinical and Laboratory Investigation, 30(3), 
271 274. https://doi.org/10.3109/00365517209084290 
Brøchner-Mortensen, J., & Jødal, L. (2009). Reassessment of a classical single injection 
51Cr-EDTA clearance method for determination of renal function in children and adults. 
Part II: Empirically determined relationships between total and one-pool clearance. 
Scandinavian Journal of Clinical and Laboratory Investigation, 69(3), 314 322. 
https://doi.org/10.1080/00365510802653680 
Du Bois D, Du Bois EF (Jun 1916). A formula to estimate the approximate surface area if 
height and weight be known. Archives of Internal Medicine 17 (6): 863-71. PMID 
2520314, cited at https://www.calculator.net/body-surface-area-calculator.html, retrieved 
June 18, 2022. 
 
 
 


Protocol AVRO-RD-01-201                                                                             July 26, 2023 
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Page 74 of 77 
 
 
 
  
 
APPENDIX 1 
 
Reference ranges - 
 in Clinical Mass 
Spectrometry  
 
 
 
 
 
 
 
 
 
AbbreviaƟons:  
 
 
 
 
ULN: Upper limit of normal. It is deﬁned as the 95th percenƟle of the healthy control analysis and as the 
reference value between normal and elevated levels of analytes. 
 
 
 
LLN: Lower limit of normal. It is not applicable, because the lower limit of normal is "Not detected". 
 
 
LLOD: Lower limit of detecƟon of the analyte in the UPLC-MS/MS methodology developed 
 
 
 
 
LLOQ: Lower limit of quanƟﬁcaƟon of the analyte in the UPLC-MS/MS methodology developed  
 
 
 
N/A: Not applicable 
 
 
 
 
ND: Not detected 
 
Important note: In the Final Excel results sent, all values between the LLOD and LLOQ are marked in red.