A Phase I/II, Multicenter, Non-randomized, Open Label, Adaptive Design, 5-year Follow-up, Single Dose-escalation Study of VTX-801 in Adult Patients With Wilson's Disease
Phase: PHASE1
Conditions: Wilson's Disease
Sponsor: Vivet Therapeutics SAS

Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023 
Author: Aixial Group CRO 
MSSOP002/F1; Version 1.0 01NOV2016 
  CONFIDENTIAL   
  Page 1 of 223 
Clinical Study Protocol 
A Phase I/II, Multicenter, Non-randomized, Open Label, Adaptive Design, 5-year Follow-
up, Single Dose-escalation Study of VTX-801 in Adult Patients with Wilson’s Disease 
Study / IND Sponsor: 
Vivet Therapeutics, SAS 
Investigational Product: 
VTX-801 (Adeno-associated viral vector serotype 
3B encoding shortened human ATP7B) 
Indication: 
Wilson’s Disease 
Protocol Number: 
VTX-801_CLN_001 
International 
Coordinating 
Investigator: 
Prof. Michael Schilsky, MD 
Medical Monitoring: 
Aixial Group CRO (formerly Cmed) 
Final Version Number: 
9 
Final Version Date: 
07 Aug 2023 
EudraCT number 
2020-000963-22 
IND number 
026173 
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property of the Sponsor 
of this study, Vivet Therapeutics. It is therefore provided to you in confidence as an Investigator, potential 
Investigator, or consultant, for review by you, your staff, and an Ethics Committee/institutional Review 
Board. It is understood that this information will not be disclosed to others without written authorization 
from Vivet Therapeutics, except to the extent necessary to obtain informed consent from those persons 
to whom the study product may be administered. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 2 of 223 
COMPLIANCE STATEMENT  
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
• 
International Conference on Harmonization (ICH) Guideline on GCP E6; 62 Federal Register 
25691 (May 9, 1997) 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
• 
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of Good Clinical Practice in the conduct of clinical trials on 
medicinal products for human use 
• 
Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed 
guidelines for Good Clinical Practice as regards investigational medicinal products for human 
use, as well as the requirements for authorization of the manufacturing or importation of such 
products  
• 
Regulation (EU) no 536/2014 of the European Parliament and of the Council of 16 April 2014 
on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 3 of 223 
PROTOCOL SIGNATURES 
Sponsor’s Chief Medical Officer: 
Name: 
 
Date:  
 
Position: 
 
Signature: 
 
Clinical Research Organization’s Medical Monitor and Safety Physician: 
Name: 
 
Date:  
 
Position: 
 
Signature: 
 
 
Coordinating Investigator: 
Name: 
Professor Michael Schilsky, MD 
Date:  
 
Position: 
 
Signature: 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 4 of 223 
INVESTIGATOR SIGNATURE 
The signature below constitutes the approval of this protocol and its attachments and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations, EU regulations and ICH 
guidelines. 
Name: 
 
Date:  
 
Site Name: 
 
Site Address: 
Signature: 
 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 5 of 223 
TABLE OF CONTENTS 
COMPLIANCE STATEMENT 
2 
PROTOCOL SIGNATURES 
3 
INVESTIGATOR SIGNATURE 
4 
TABLE OF CONTENTS 
5 
LIST OF TABLES 
12 
LIST OF FIGURES 
13 
LIST OF ABBREVIATIONS 
14 
PROTOCOL SUMMARY 
19 
1 
ROLES AND RESPONSIBILITIES 
43 
2 
INTRODUCTION 
45 
2.1 
Wilson’s Disease and Copper Metabolism 
45 
2.2 
Unmet Needs 
46 
2.3 
Non-Clinical Studies 
47 
 
Pharmacology studies 
47 
 
Safety and toxicology studies 
49 
2.4 
Study Rationale 
51 
2.5 
Summary of Potential Risks and Benefits 
51 
 
Risk of drug-induced liver toxicity: 
51 
3 
OBJECTIVES AND ENDPOINTS 
55 
3.1 
Study Objectives 
55 
 
Primary Objective 
55 
 
Secondary Objectives 
55 
3.2 
Study Endpoints 
55 
 
Primary Endpoints 
55 
 
Secondary Endpoints 
55 
 
Exploratory Endpoints 
56 
4 
STUDY DESIGN 
57 
4.1 
Overview 
57 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 6 of 223 
4.2 
VTX-801 Dose Escalation 
58 
4.3 
Expansion at the Selected VTX-801 Dose 
61 
4.4 
Patient Treatment and Follow-up Scheme 
62 
4.5 
Responder/Insufficient Responder Definitions 
63 
4.6 
Background or Standard of Care WD Therapy Withdrawal, Adjustment or Reinstatement 
65 
4.7 
Study Committees 
67 
 
Data Monitoring Committee 
67 
 
Hepatic Adjudication Committee 
68 
 
Eligibility Review Committee 
68 
4.8 
Long Term Follow-up 
68 
4.9 
Study Start and End of Study Definitions 
68 
5 
STUDY POPULATION 
69 
5.1 
Number of Patients 
69 
5.2 
Inclusion Criteria 
69 
5.3 
Exclusion Criteria 
70 
6 
ENROLLMENT AND MANAGEMENT OF DROPOUT PATIENTS 
74 
6.1 
Enrollment Procedures 
74 
6.2 
Treatment Assignment/Randomization Procedures 
75 
6.3 
Stopping Rules 
75 
6.4 
Patient Withdrawal Criteria 
76 
6.5 
Patient Withdrawal Procedures 
76 
6.6 
Premature Termination or Suspension of the Study 
77 
7 
VTX-801 TREATMENT, AUXILIARY TREATMENTS, DIET AND OTHER STUDY 
SPECIFICATIONS 
79 
7.1 
Wilson’s Disease Background Therapy 
79 
 
Zinc Salt Treatments 
79 
 
Copper Chelator Treatments 
79 
7.2 
Investigational Product: VTX-801 
80 
 
VTX-801 Description and Supply 
80 
 
Selection of VTX-801 Doses Used in the Study 
80 
 
VTX-801 Packaging and Labelling 
81 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 7 of 223 
 
VTX-801 Storage and Stability 
81 
 
VTX-801 Dosage, Preparation and Administration 
82 
 
VTX-801 Accountability Procedures 
84 
 
VTX-801 Compliance 
85 
7.3 
Diluent for VTX-801 
85 
7.4 
Radiocopper - [64Cu]CuCl2 
85 
 
Radiocopper Description and Supply 
86 
 
Selection of the Radiocopper Dose for this Study 
86 
 
Radiocopper Packaging and Labelling 
87 
 
Radiocopper Dosage, Preparation and Administration 
88 
 
Radiocopper Storage, Disposal and Accountability 
88 
7.5 
Immunosuppressive Regimens and 
 
88 
 
Prophylaxis of IARs, Immune T-cell Response Against the AAV Capsid and
 
 
89 
 
Mitigation of Overt Transaminase Increase 
93 
7.6 
Other Concomitant Medications/Treatments 
95 
 
Contraception 
95 
 
Drug Interactions and Prohibited Medications 
96 
 
 
98 
7.7 
Dietary or Other Protocol Restriction or Specification 
98 
8 
STUDY PROCEDURES AND EVALUATIONS 
99 
8.1 
Clinical Evaluations 
99 
 
Demographics and Medical History 
99 
 
Prior and Concomitant Medications 
99 
 
Physical Examination 
100 
 
Vital Signs 
100 
 
Electrocardiogram 
100 
 
Ophthalmology 
101 
 
Questionnaires 
101 
 
Abdominal MRI, Liver MR Elastography 
102 
 
Brain MRI 
102 
 Central and Local Laboratories for Standard Clinical Evaluations 
103 
 Central Laboratory Standard Evaluations 
103 
 Local Laboratory Standard and Special Evaluations 
106 
 Ceruloplasmin and Copper-Related Assays 
108 
 Clinical Calculations Based on Laboratory Tests 
108 
8.2 
Central Laboratories for Specialized Evaluations 
109 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 8 of 223 
 
Anti-AAV3B Neutralizing Antibodies 
109 
 
Genotyping 
110 
 
Viral Vector Shedding 
110 
 
Immunogenicity 
111 
 
Liver Biopsy 
111 
 
Local Nuclear Laboratories for Radiocopper-Related Evaluations 
112 
8.3 
Total Blood Volume 
114 
9 
ASSESSMENT OF SAFETY 
115 
9.1 
Specification of Safety Parameters 
115 
9.2 
Adverse Events 
115 
 
Definition of Adverse Events 
115 
 
Severity of Adverse Events 
115 
 
Causality Assessment 
116 
 
Abnormal Laboratory Test Values and Other Objective Measurements 
117 
 
Eliciting Adverse Events 
117 
 
Recording Adverse Events 
118 
 
Follow-up of Adverse Events 
119 
9.3 
Serious Adverse Events 
120 
 
Definition of Serious Adverse Event 
120 
 
Reporting of Serious Adverse Events and Adverse Events of Special Interest 
121 
9.4 
Regulatory Reporting of Safety Events 
123 
9.5 
Reporting of Pregnancy 
124 
9.6 
Adverse Event of Special Interest 
125 
9.7 
Copper Deficiency Detection and Management 
126 
10 STUDY SCHEDULES 
128 
10.1 Visits 1A and 1B: Screening Period 
129 
 Visit 1A - Screening 1 
129 
 Visit 1B - Screening 2 
131 
10.2 Visits 2-5: Baseline and Pre-VTX-801 Period 
133 
10.3 Visit 6: Day 1, Week 1 
138 
10.4 Visit 7: Day 2, Week 1: Post-VTX-801 Administration 
140 
10.5 Visits 8-46: Follow-up Until End of Year 1 Post-VTX-801 Administration 
141 
 Visit 8 (Day 8 ± 2 days) 
141 
 Visit 9 (Day 15 ± 2 days) 
142 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 9 of 223 
 Visit 10 (Week 4 ± 2 days) 
142 
 Visits 11-17 (Weeks 4, 5, 6 and 7 ± 2 days) 
144 
 Visit 18 (Week 8 ± 2 days) 
144 
 Visits 19-25 (Weeks 8, 9, 10 and 11 ± 2 days) 
145 
 Visits 26-29 (Week 12) 
146 
 Visits 30 and 31 (Weeks 12 and 13 ± 3 days) 
151 
 Visit 32 (Week 14 + 2 days) 
151 
 Visits 33-35 (Weeks 15, 16 and 20 ± 3 days) 
152 
 Visit 36 (Week 24 ± 3 days) 
152 
 Visits 37-38 (Weeks 28 and 32 ± 3 days) 
154 
 Visits 39-42 (Week 36) 
154 
 Visit 43 (Week 38) 
158 
 Visits 44-45 (Weeks 40 and 44 ± 3 days) 
159 
 Visit 46 (Week 52 ± 7 days) 
159 
10.6 Visits 47-50: Follow-up (Year 2) 
161 
 Visit 47 (Year 2, Month 3 ± 14 Days) 
161 
 Visit 48 (Year 2, Month 6 ± 14 Days) 
163 
 Visit 49 (Year 2, Month 9 ± 14 Days) 
163 
 Visit 50 (Year 2, Month 12 ± 14 Days) 
164 
10.7 Visits 51-52: Follow-up (Year 3) 
165 
 Visit 51 (Year 3, Month 6 ± 14 Days) 
166 
 Visit 52 (Year 3, Month 12 ± 14 Days) 
166 
10.8 Visits 53-54: Follow-up (Year 4) 
168 
 Visit 53 (Year 4, Month 6 ± 14 Days) 
168 
 Visit 54 (Year 4, Month 12 ± 14 Days) 
169 
10.9 Visits 55-56: Follow-up (Year 5) 
170 
 Visit 55 (Year 5, Month 6 ± 14 Days) 
171 
 Visit 56 (Year 5, Month 12, ± 14 Days) – End of Study Visit 
172 
10.10 Early Termination Visit 
173 
10.11 Unscheduled Visit 
177 
11 STATISTICAL CONSIDERATIONS 
178 
11.1 Sample Size Considerations 
178 
11.2 Planned Interim Analyses 
178 
11.3 Analysis Sets 
178 
11.4 Statistical Methodology 
179 
 Demographics and Medical History 
179 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 10 of 223 
 Extent of Exposure 
179 
 Concomitant Medications 
179 
 Safety Analyses 
179 
 Pharmacodynamics and Efficacy Analyses 
181 
 Other Analyses 
182 
11.5 Changes to the Planned Statistical Methods 
183 
12 STUDY OPERATIONS 
184 
12.1 Study Sites 
184 
 Investigational Sites 
184 
 Referral Sites 
184 
 Home Nurses 
184 
12.2 Study Monitoring 
185 
12.3 Source Documents 
185 
 Access to Source Data and Documents 
186 
12.4 Data Handling and Record Keeping 
186 
 Data Capture Methods 
186 
 Study Site Responsibilities 
187 
 Data Management Responsibilities 
187 
 Study Records Retention and Archiving 
188 
13 QUALITY CONTROL AND QUALITY ASSURANCE 
189 
13.1 Quality Management Systems 
189 
13.2 Audit 
189 
13.3 Protocol Amendment 
190 
13.4 Protocol Deviation 
190 
14 ETHICS/PROTECTION OF HUMAN PATIENTS 
191 
14.1 Ethical Standard 
191 
14.2 Institutional Review Board / Independent Ethics Committee 
191 
14.3 Informed Consent Process 
192 
 Exclusion of Women, Minorities, and Children 
192 
14.4 Patient Confidentiality 
192 
14.5 Treatment Plan in The Event of Study Discontinuation 
193 
14.6 Future Use of Stored Specimens 
193 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 11 of 223 
14.7 Insurance 
194 
15 PUBLICATION POLICY 
195 
16 LITERATURE REFERENCES 
196 
17 APPENDICES 
205 
17.1 Blood Sample Volume Tables 
206 
 Screening 
206 
 Baseline (V2) to Week 12 (V29) 
207 
 Week 13 (V31) to Week 52 (V46) 
209 
 Year 2 to Year 5 Follow-up 
210 
17.2 Modelling and Simulation 
211 
17.3 Low-copper Diet 
223 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 12 of 223 
LIST OF TABLES 
Table 6 
Dose Tapering for Oral Steroid .................................................................... 91 
Table 7 
 
Table 8 
Standard Parameters to be Analyzed by the Central Laboratory ............... 104 
Table 9 
Sampling Frequency of Liver Biochemistry Panel Following VTX-801 
Administration ............................................................................................ 106 
Table 10 Standard and Special Parameters to be Analyzed by the Local 
Laboratory .................................................................................................. 107 
Table 11 Blood Ceruloplasmin and Copper-Related Assays to be Performed by 
Specialized Central Laboratories ............................................................... 108 
Table 12 Clinical Calculations Based on Laboratory Tests ....................................... 109 
Table 13 Humoral and Cellular Immune Response Tests to be Performed by 
Specialized Central Laboratories ............................................................... 111 
Table 14 Liver Biopsy Related Tests to be Performed by Specialized Central 
Laboratories ............................................................................................... 112 
 
Table 16 Capture of Adverse Events in the eCRF .................................................... 119 
Table 17 Blood Sample Volumes at Screening 1 (V1A) and Screening 2 (V1B) ...... 206 
Table 18 Blood Sample Volumes from Baseline (V2) to Week 12 (V29) .................. 207 
Table 19 Blood Sample Volumes from Week 13 (V31) to Week 52 (V46) ................ 209 
Table 20 Blood Sample Volumes from Year 2 to Year 5 Follow-up .......................... 210 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 13 of 223 
LIST OF FIGURES 
Figure 1 
Study Design ............................................................................................... 58 
Figure 2 
Enrollment Decision Tree ............................................................................. 60 
Figure 3 
Patient Treatment and Follow-up Scheme ................................................... 62 
Figure 4 
Responder Decision Tree - SoC Withdrawal Only in Responders ............... 64 
Figure 5 
Responder/Insufficient Responder Process Associated Timelines .............. 65 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 14 of 223 
LIST OF ABBREVIATIONS  
AAV3B 
Adeno-Associated Virus serotype 3B 
ACE 
Angiotensin-Converting Enzyme 
AE 
Adverse Event/Adverse Experience 
ALF 
Acute Liver Failure 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear Antibodies 
ANC 
Absolute Neutrophil Count 
ANCC 
Accurate non-ceruloplasmin-bound Cu 
APRI 
AST to platelet ratio index 
aPTT 
Activated Partial Thromboplastin time 
AST 
Aspartate Aminotransferase 
ATP7B 
Copper-transporting P-type ATPase  
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BQL 
Below Quantification Limit 
BSL 
Biosafety Level 
BUN 
Blood Urea Nitrogen 
CAP 
Controlled Attenuation Parameter 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum Plasma Concentration 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive Protein 
CSR 
Clinical Study Report 
CTCAE 
Common Toxicity Criteria for Adverse Events 
64Cu/[64Cu]CuCl2 
Radiocopper 
Cu 
Copper 
CuEXC 
Exchangeable Copper 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 15 of 223 
Cp-Copper 
Ceruloplasmin-bound copper 
D 
Day 
DB 
Direct Bilirubin 
DILI 
Drug-Induced Liver Injury 
DL 
Dose Level 
DLT 
Dose limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-Linked ImmunoSorbent Assay 
ELISpot 
Enzyme-Linked ImmunoSpot 
EMA 
European Medicines Agency 
ERC 
Eligibility Review Committee 
ESLD 
End-Stage Liver Disease 
EU 
European Union 
FIB4 
Fibrosis-4 Index for Liver Fibrosis 
FIH 
First-in-Human 
FDA 
Food and Drug Administration 
GaTeWay 
Gene Therapy in Wilson disease 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl Transpeptidase 
GMP 
Good Manufacturing Practice 
H 
Hour 
HAC 
Hepatic Adjudication Committee 
HAV 
Hepatitis A Virus 
HBV 
Hepatitis B Virus 
HCP 
Health Care Provider 
HCV 
Hepatitis C virus 
HDL 
High Density Lipoprotein 
HEV 
Hepatitis E Virus 
HIV 
Human Immunodeficiency Virus 
HLT 
High Level Term 
HLGT 
High Level Group Term 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 16 of 223 
HSV 
Herpes Simplex Virus 
HTLV 
Human T-cell Lymphotropic Virus 
IAR 
Infusion-Associated Reactions 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICRP 
International Commission on Radiological Protection 
ID 
Injected Dose 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL-2,6 or 10 
Interleukin-2, 6 or 10, respectively 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ERC 
Eligibility Review Committee 
IS 
Immunosuppressive Regimen 
ISH 
In Situ Hybridization 
ISM 
Independent Safety Monitor 
IU 
International Unit 
IUD 
Intrauterine Device 
IV 
Intravenous 
KVO 
Keep-Vein-Open 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein 
LFT 
Liver Function Test 
LKM1 
Liver-Kidney Microsome Type 1 
LLT 
Lower-Level Term 
LoQ 
Limit of Quantification 
LS 
Liver Stiffness 
MBq 
Megabecquerel 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-Stage Liver Disease 
M.I.N.I 
Mini International Neuro-psychiatric Interview 
MoCA 
Montreal Cognitive Assessment 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 17 of 223 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
mSv 
Millisievert 
mTOR 
Mammalian target of rapamycin 
NAb 
Neutralizing Antibody 
NCC 
Non‐ceruloplasmin‐bound copper 
NHP 
Non-Human Primates 
NIH 
National Institutes of Health 
NIMP 
Non-Investigational Medicinal Product 
P 
Pulse 
PET 
Positron Emission Tomography 
PCP 
Phencyclidine 
PCR 
Polymerase Chain Reaction 
P-gp 
P-glycoprotein 
PHI 
Protected Health Information 
PI 
Principal Investigator 
 
 
PoC 
Proof of Concept 
PT 
Preferred Term 
QA 
Quality Assurance 
QC 
Quality Control 
RAC 
Relative ANCC 
rAAV 
Recombinant Adeno-Associated Viral Vector 
RBC 
Red Blood Cell 
REC 
Relative Exchangeable Cu 
RNA 
RiboNucleic Acid 
RR 
Respiration Rate 
SAE 
Serious Adverse Event 
SDMT 
Symbol Digit Modality Test 
SIV 
Site Initiation Visit 
SMA 
Smooth Muscle Antibodies 
SoC 
Standard of Care 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction 
TB 
Tuberculosis  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 18 of 223 
TEAE 
Treatment-Emergent AE 
Tmax 
Time to Maximum Plasma Concentration 
ULN 
Upper Limit of Normal 
US 
United States 
UWDRS 
Unified Wilson's Disease Rating Scale 
W 
Week 
WBC 
White Blood Cell 
WD 
Wilson’s Disease 
WHO 
World Health Organization 
Zn 
Zinc 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 19 of 223 
PROTOCOL SUMMARY  
 
 
 
Title 
A Phase I/II, Multicenter, Non-randomized, Open Label, 
Adaptive Design, 5-year Follow-up, Single Dose-escalation 
Study of VTX-801 in Adult Patients with Wilson’s Disease 
Phase 
Phase I/II 
Number of Sites 
Approximately 10 sites in Europe and North America 
Objectives 
Primary: 
• 
Assessing, for up to 5 years, the safety and tolerability 
of single ascending doses of VTX-801 administered 
intravenously (IV) to adult patients with Wilson’s 
Disease prior to and following background WD 
therapy withdrawal. 
Secondary: 
• 
Exploring VTX-801 pharmacodynamics and efficacy 
• 
Assessing humoral and cellular immune responses to 
VTX-801 
• 
Providing data to support VTX-801 dose level 
selection 
Study Duration 
Approximately 7 years 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 20 of 223 
Study Design 
General Design 
Up to approximately 16 Wilson’s Disease male and female 
adult patients will be administered VTX-801 in 3 dose-
escalation cohorts each consisting of approximately 
4 patients and one expansion cohort consisting of 
approximately 4 patients treated at the selected VTX-801 
dose. 
 
Only if and when an optimal VTX-801 dose level has been 
selected 
from 
the 
escalation 
phase 
based 
on 
pharmacodynamic studies with radiocopper and other 
biomarkers of copper metabolism, four patients will be 
enrolled in the additional cohort and will receive one infusion 
of VTX-801 at the Selected Dose level.  
 
The adaptive nature of the study intends to minimize the 
number of patients exposed to a sub-optimal VTX-801 dosing 
regimen, since for them re-treatment with a therapeutic dose 
might not be possible due to seroconversion to the AAV3 
capsid. 
 
Dose Escalation  
Adult male and female WD patients receiving standard of 
care therapy with either a zinc salt, a copper chelator (D-
penicillamine or trientine) or the association thereof and who 
meet eligibility criteria will be sequentially enrolled and 
treated with escalating doses of VTX -801 in up to 3 
consecutive cohorts of approximately 4 patients each; each 
patient will receive a single VTX-801 infusion, starting with a 
potentially therapeutic dose. The best efforts will be made to 
enroll at least 1 patient of each gender in each cohort of 4. 
 
Note: A chelator-wash-out period will be required around 
each radiocopper injection (starting 3 days before 
radiocopper injection and continuing until the end of the 
radiocopper investigations) that will occur during the week 
preceding the VTX-801 administration and at Weeks 12 and 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 21 of 223 
36 from VTX-801 administration. The objective of the wash-
out period is to prevent any possible interference of chelators 
with 24-hour urinary copper and radiocopper assessments 
(no wash-out is required for patients on any zinc-only 
treatment). 
 
Dose escalation will proceed according to the following 
enrollment scheme [response to VTX-801 will be assessed 
per pre-defined criteria based upon radiocopper associated 
assessments at W12 and W36]: 
• ≥ 6-week intervals will be maintained between the VTX-
801 infusion of the first 2 patients of each cohort.  
• if VTX-801 is well tolerated in both patients, as per the pre-
defined stopping rules, then ≥ 12-week data (W12) from 
the first 2 patients of each cohort will be reviewed by the 
Sponsor and the Data Monitoring Committee (DMC): 
o if first 2 patients are VTX-801 Responders at W12, the 
remaining 2 patients of the concerned cohort may be 
enrolled; the decision of dose escalation will be based 
on the review of all available safety data of 3 to 4 
patients at 12 weeks by the DMC. If well tolerated 
according to DMC, dose escalation may proceed after 
Sponsor agreement. 
o if either or both first patients are Insufficient VTX-801 
Responders at W12, dose escalation may proceed 
without dosing the remaining 2 patients of the 
concerned cohort, in order to limit the exposure of 
patients who do not benefit sufficiently from the 
treatment and may not be retreated with an efficacious 
dose because of seroconversion to the vector 
o In case at least 1 out of the 2 first patients is an 
Insufficient VTX-801 Responder at W12 and both are 
VTX-801 Responders at W36 for a given dose level, 2 
additional patients may be enrolled subsequently, 
based upon DMC recommendation and upon Sponsor 
decision. 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 22 of 223 
Dose Expansion at the Selected Dose  
Only when an optimal VTX-801 dose level has been selected 
from the escalation phase, based on the results of 
pharmacodynamic with radiocopper and other biomarkers of 
copper metabolism, additional patients will be enrolled in 
parallel in an expansion cohort to reach a total of 8 patients 
receiving VTX-801 at the Selected Dose level.  
 
Treatments, Radiocopper and Follow-Up Scheme for 
each patient 
• 
After inclusion, each patient of each cohort will (i) 
initiate the immunosuppressive regimen, (ii) complete 
the radiocopper-related assessments, (iii) receive a 
single VTX-801 infusion without interrupting their 
background WD therapy (except for planned wash-
out periods in patients on chelators or dual chelator 
and zinc therapy).  
• 
At Week 12, each patient will undergo a second set 
of radiocopper-related assessments, and their 
Responder status will be determined. 
• 
At Week 36, patients will receive a third radiocopper 
injection and the Responder status will be assessed 
again, in order to evaluate the sustainability of the 
effects in Responders and to detect possible late 
Responders.  
• 
Patients will be followed up for a total of 5 years from 
the time of VTX-801 administration.  
 
Background 
or 
Standard 
of 
Care 
WD 
Therapy 
Withdrawal, Adjustment or Reinstatement 
Considering Responder status and based upon DMC review 
and recommendations, the following actions may be taken 
after Sponsor approval: 
 Week 14: Background WD therapy may be withdrawn for 
Week 12 Responders but will be continued for Week 12 
Insufficient Responders. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 23 of 223 
 Week 38: Background WD therapy may be withdrawn in 
Week 36 Responders but will be re-initiated (if previously 
interrupted) in Week 36 Insufficient Responders. In case of 
biochemical or chemical WD deterioration, the DMC may 
recommend WD SoC therapy re-initiation in such patients. 
Eligibility Criteria 
Inclusion: 
1. Male or female aged 18 - 65 years (inclusive) at the time 
of signing the informed consent.  
2. Patient diagnosed with WD, as established (by historical 
and/or current data), documented by Leipzig score ≥ 4, as 
per the 2012 EASL Clinical Practice Guidelines (EASL, 
2012) and either: 
i) historical or current 24h urinary Cu > 40 µg/day (or 
0.6 µmol/day) off chelator therapy, if any OR  
ii) two pathogenic or likely pathogenic ATP7B variants.  
3. Patient has the ability to understand, date and sign 
informed consent prior to initiation of any study 
procedures. 
4. Male patients: willing to use two methods of contraception 
from the day of the first radiocopper injection through 6 
months following VTX-801 infusion and also for the week 
following the W36 radiocopper injection (sperm donation 
during this time is also prohibited). 
5. Female patients: if of childbearing potential, willing to use 
two methods of contraception from signing informed 
consent through at least one week after W36 radiocopper 
injection. If using oral contraception, it must have 
remained unchanged for ≥ 3 months prior to inclusion.  
6. Treated 
for 
WD 
according 
to 
international 
recommendations with no current evidence for inadequate 
treatment (EASL, 2012; Schilsky et al, 2022)  
o 
for at least 1 year with either zinc salt, a copper 
chelator [trientine or D-penicillamine], or a combination of 
thereof; previous treatment with investigational bis-
choline-tetrathiomolybdate is acceptable as well, provided 
that it has been stopped ≥6 months prior to study entry; 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 24 of 223 
o 
 without any changes in dosing regimen for at least 
the last 6 months prior to study entry;  
o 
compliant with current WD treatment, as judged by 
the Investigator. 
7. Stable WD for ≥ 1 year, defined as:  
a. 
No significant change in neurologic examination and 
in status of mood disorder, if present, as judged by a 
physician-expert(s) 
in 
assessing 
neurological 
and 
psychiatric manifestations of WD. 
b. 
Stable laboratory parameters used to assess copper 
metabolism including 24-hour urinary copper, free serum 
copper such as NCC or CuEXC (when available), as well 
as liver enzymes, hemoglobin, and white blood cell count.  
The last assessments should be stable (no significant 
change), on at least 2 occasions assessed 6 to 8 weeks 
apart prior to enrollment (the interval may be extended as 
needed for logistical reasons beyond 8 weeks, after 
sponsor approval). The US and EU guidelines, as well as 
more recent publications should be used as a reference 
for WD management (EASL, 2012; Schilsky, 2017, 
Schilsky et al, 2022).  
8. Patient expected to live for the study duration in the 
Investigator’s opinion. 
 
Exclusion 
1.  ALT level ≥ 2 x ULN that is not readily explained by 
extrinsic factors (e.g., strenuous exercise, medication 
use). 
2. Total bilirubin > 1.5x ULN in the absence of proven 
Gilbert’s syndrome; in case of Gilbert’s syndrome, direct 
bilirubin > ULN.  
3. INR > 1.2. 
4. Platelet count < 120,000/µL. 
5. Absolute neutrophil count (ANC) < 1,000/µL. 
6. Patient with fasting triglycerides ≥ 200 mg/dL [> 2.3 
mmol/L], on optimal therapy, if any. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 25 of 223 
7. On liver biopsy at inclusion: severe liver fibrosis (Metavir 
stage F3) or liver cirrhosis (Metavir stage F4) or steatosis 
> 33 % (steatosis score ≥ 2, per NASH-CRN scoring 
system). The liver biopsy may be replaced Fibroscan®, in 
patients of the dose escalation cohorts only; the cut offs 
are defined as (Sini et al, 2012; Park et al, 2017): 
a. In sites equipped with Fibroscan® 
i. LS ≥ 8.4 kPa 
ii. CAP score (Controlled attenuation parameter) 
≥ 305 dB/m 
b. If the patient meets any of the above criteria and still 
declines the liver biopsy, he/she will be excluded; a 
liver biopsy (if performed finally) will however prevail 
for eligibility over Fibroscan® as the gold standard. 
8. Any signs of liver cirrhosis decompensation, including 
gastrointestinal bleed within 6 months (24 weeks) prior to 
screening/enrollment visit. 
9. Patient has moderate or severe renal impairment defined 
as eGFR CKD-EPI < 60 mL/min/1.73 m2, or patient has 
nephritis or nephrotic syndrome.  
10. Active infection requiring systemic antibiotic treatment or 
immunocompromised patients. 
11. Any history or current evidence of HIV-1, HIV-2, HTLV-1 
or HTLV-2 infection. 
12. Any history or current evidence of hepatitis B infection, 
i.e. HBs antigen or antibodies anti-HBc positive. 
13. Any history of hepatitis C infection, unless previous viral 
RNA assays in two samples, collected at least 6 months 
apart, are negative  
14. Positive QuantiFERON®-TB Gold tuberculosis test result, 
history of active or latent tuberculosis or a history of 
positive PPD or Tine test; however, a history of positive 
PPD or Tine test in a patient who has received a BCG 
vaccine will not be exclusionary if QuantiFERON®-TB 
Gold test is negative. 
15. Positive for in vitro anti-AAV3B neutralizing antibody 
activity.  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 26 of 223 
16. Any concomitant disorder/condition - including hepatic 
disorder - or treatment possibly interfering with the 
conduct or evaluation of the study, according to the 
Investigator. 
17. Any history of angioedema. 
18.  Any history of diabetes. 
19. Known allergy or hypersensitivity to components of VTX-
801. 
20. Contraindication to corticosteroid or Sirolimus use, as 
judged by the Investigator. 
21. Contraindication 
 
.  
22. Psychosis or history (less than 10 years ago) of 
hospitalization for depression. 
23. Severe neurological impairment defined as either 
[UWDRS part II subscales 2, 4 or 11 ≥ 3] or [UWDRS 
part II subscales 3, 6, 7, 8, 9 or 10 >3], or history of 
seizure activity within 6 months prior to signing informed 
consent.  
24. Patients with dementia or moderate to severe cognitive 
impairment defined as MoCA score < 18 (as corrected for 
educational level).  
25. Pregnancy or breastfeeding. 
26. BMI ≥ 35 kg/m2. 
27. Moderate or heavier alcohol drinker, defined as drinking 
> 3 drinks/week on average over the past year. 
28. Recent drug (amphetamines, opiates, cocaine or 
phencyclidine (PCP)) use: history or positive urinary drug 
screen results for either amphetamines, opiates, cocaine, 
or phencyclidine (PCP) at any of the Screening visits 
(Screening 1 or Screening 2); however, positive detection 
of 
licit, 
medically 
prescribed 
medication 
is 
not 
exclusionary. 
29. Received a gene therapy treatment or participated in a 
gene therapy clinical trial. 
30. Received any investigational drug and/or participated in 
any interventional clinical trial within the past 6 months. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 27 of 223 
31. Individuals with documented history of malignancy, 
excepted basal or squamous cell carcinoma which has 
been treated and fully resolved for a minimum of 5 years.  
32. Prior vaccination with live vaccine within 30 days before 
Sirolimus administration. 
Description of 
Investigational Product 
The investigational medicinal product (VTX-801) is a 
replication-deficient recombinant adeno-associated viral 
vector (rAAV) consisting of an AAV3B capsid containing a 
single-stranded DNA genome carrying a shortened version 
of the ATP7B gene (ATP7B-minigene). 
VTX-801 is provided in its final formulation and in a container 
closure system; a subsequent reconstitution will be 
performed on site. 
VTX-801 should be handled as a biohazardous product 
according to local regulations for biosafety level class 1 
agents (BSL1). 
The IMP will be administered as a single dose intravenous 
(IV) administration per patient, at up to 3 different dose levels.  
The initial VTX-801 dose, 5E12 VG/kg, has been selected 
primarily based upon non-clinical pharmacology and 
toxicology studies, as a balance between expected 
pharmacodynamics and safety. Since re-treatment of 
patients exposed to a sub-optimal VTX-801 dose may not be 
possible due to seroconversion to the AAV capsid, the 
starting dose has been selected to be potentially therapeutic. 
VTX-801 dose will be incremented by a factor of 3 between 
escalation cohorts 1 and 2 and by a factor of 2 between 
escalation cohorts 2 and 3. The following will be used: 
o Cohort 1: 5E12 VG/kg  
o Cohort 2: 1.5E13 VG/kg 
o Cohort 3: 3E13 VG/kg 
The Selected Dose for the expansion cohort will be one of 
the previously tested doses. VTX-801 will be provided to the 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 28 of 223 
 
 
 
responsible pharmacist at the study site, who will handle and 
dispense study product in accordance with the VTX-801 
Pharmacy Manual that includes the reconstitution protocol 
which will be developed according to ICH GCP guidelines 
and applicable local laws. 
Clinical Study Reports 
and Periodic Analyses 
A data lock will be done when all patients reach one year of 
follow-up post-VTX-801 administration and the results will be 
reported in a first CSR. The long-term follow-up will continue 
until up to 5-years post-treatment, in line with the current 
EMA and FDA guidelines on follow-up of patients 
administered with non-integrative, non-replicative gene 
therapy medicinal products. A second and final CSR will 
cover all 5 years of follow-up. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 45 of 223 
2 INTRODUCTION 
2.1 Wilson’s Disease and Copper Metabolism 
Wilson´s Disease (WD), or progressive hepatolenticular degeneration, is a rare, 
debilitating, life-threatening disorder of copper homeostasis that is inherited in an 
autosomal recessive manner. It is due to variants in ATP7B, a copper transporting P-type 
ATPase. In the liver, which is the site of metabolism for dietary copper, ATP7B is 
responsible for the dual role of (i) regulating copper hepatocyte concentration by 
eliminating excess copper into the feces via the biliary route and (ii) transferring Cu to Cu-
dependent enzymes, including circulating ceruloplasmin. In WD, ATP7B variants lead to 
decreased biliary copper excretion and tissue copper accumulation on the one hand, and 
to reduced circulating ceruloplasmin levels on the other hand. The primary site of copper 
accumulation is the liver, but central nervous system (CNS) as well as other organs 
accumulate copper, that may eventually result in organ dysfunction or failure. At time of 
diagnosis, patients typically present with low serum ceruloplasmin levels and increased 
urinary copper, associated or not with elevated transaminases, hepatic and/or 
neuropsychiatric symptoms and/or a Kayser-Fleischer ring. Onset of symptoms typically 
occurs in the teenage years or in young adulthood. Left untreated, the condition 
progresses to severely debilitating complications and death. The prevalence of WD is 
approximately one in 30,000 individuals worldwide, with wide geographical variations. For 
a full review see Członkowska et al, 2018b. 
The goals of WD treatment depend upon the phase of disease and must consider both 
drug safety and efficacy in the individual patient (EASL, 2012; Schilsky et al, 2022); the 
approach to treatment initiation (D-penicillamine, trientine, zinc salt) depends on whether 
the patient is symptomatic or not and whether organ damage is present. A low-copper 
diet is recommended as an adjunct to medical therapy, especially during the de-coppering 
phase. If WD is detected early and treated properly over the course of a life-time, then 
the patient may have a favorable prognosis including control of symptoms and normal life 
expectancy with an overall better outcome for patients with the hepatic course, as 
compared to patients having predominantly neuropsychiatric symptoms (Merle et al, 
2007). 
While liver transplantation is the only curative option, it is reserved for severe liver disease 
and liver failure. Of note, a few case reports and a retrospective study describe liver 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 46 of 223 
transplantations indicated for neurological worsening despite available medication, and 
neurological improvement or stabilization has been observed in several cases (Walker et 
al, 2018; Poujois et al, 2020). VTX-801 is a replication-deficient recombinant adeno-
associated viral vector (rAAV) consisting of an AAV3B capsid containing a single-
stranded DNA genome carrying a shortened version of the ATP7B gene (ATP7B-
minigene) under the control of a liver-specific promoter and flanked by AAV2 ITRs. Based 
upon preclinical studies, liver-directed AAV-based gene therapy offers a potential 
alternative to current therapeutic options: by transferring a corrective ATP7B gene into in 
the liver, gene therapy may allow for a prolonged, physiological restoration of copper 
homeostasis, with ensuing clinical benefit to WD patients.  
A comprehensive review of VTX-801 preclinical studies is contained in the Investigator 
brochure (IB) supplied by Vivet Therapeutics. Investigators are to review this document 
prior to initiating this study. 
2.2 Unmet Needs 
All diagnosed WD patients must be treated for life to prevent the occurrence of severely 
debilitating and life-threatening complications. However, despite recognized benefits, 
current management options have limitations (Schilsky et al (AASLD) 2022; EASL, 2012): 
• 
Current WD medications may be associated with side effects; in particular, up to 31% 
patients experienced severe side effects with widely used D-penicillamine and 10-
30% patients suffered paradoxical neurological worsening upon initiating chelator 
treatments (Merle et al, 2007; Ala et al, 2007).  
• 
All current WD treatment regimens are constraining since they must be taken up to 
3-4 times/day for life, at specific times away from meals and as mentioned above may 
be associated with significant side effects. As a result, adherence to treatment is sub-
optimal: up to 50% non-compliance has been reported. Non-compliance or drug 
interruption may result in poor outcomes, including dramatic complications such as 
acute liver failure (ALF) or severe irreversible neuro-psychiatric deterioration 
(Scheinberg et al, 1987; Maselbas et al, 2010; Maselbas et al, 2019).  
• 
Today, liver transplantation remains the only curative option for WD and it is indicated 
only for acute liver failure (ALF) or end stage liver disease (ESLD); in addition, it is 
limited by organ supply, significant morbidity, immunosuppression for life and cost. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 47 of 223 
• 
Long-term outcomes of WD cohorts have been studied by several authors; in a 
representative Austrian cohort of 229 WD patients followed for a mean of 14.8 years 
(3,116 patient-years) and treated with chelation therapy, 35% patients clinically 
stabilized, 26% improved, 15% deteriorated, 8% required a liver transplant and 7.4% 
died within the observation period (71% of deaths directly related to WD); overall, a 
lower proportion of WD patients survived for 20 years (92%) as compared to healthy 
Austrians (97%) and only 84% of patients with cirrhosis survived 20 years after 
diagnosis (Beinhardt et al, 2014). 
• 
Recent studies showed that despite Standard of Care (SoC) treatment availability, 
overall survival of WD patients remains significantly reduced (Chand et al, 2021, Choe 
et al, 2020, Członkowska et al, 2022, Daniel-Robin et al, 2022). 
Therefore, although the use of copper chelators - and later on zinc – have greatly 
improved WD prognosis, there is still a need for improved treatment options in order to 
further reduce the morbidity and the mortality of this severe condition.  
2.3 Non-Clinical Studies  
For details of the non-clinical studies and results, please refer to the current version of 
the VTX-801 IB. A summary of the main findings is provided below. 
 Pharmacology studies 
The non-clinical VTX-801 Proof of Concept (PoC) studies were performed in the Atp7b-/- 
(WD) mouse model, which spontaneously recapitulates the hepatic (but not neurological) 
component of WD. Because the vector used for VTX-801 (AAV3B) efficiently transduces 
human hepatocytes but not mouse livers, surrogate vectors AAV8 and AAVAnc80 known 
to have high liver tropism in mice were used instead and the resulting study products 
have been named VTX-801(8) or VTX-801(Anc80), respectively.  
The PoC pharmacology studies in 6-week-old WD mice demonstrated that the 
administration of VTX-801(8) or VTX-801 (Anc80) at doses ranging from 5E11 to 1.5E13 
VG/kg was leading to a: 
• 
Significant dose-dependent reduction in hepatic copper content, urinary copper 
excretion and increase of 64Cu fecal elimination; 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 48 of 223 
• 
Significant dose-dependent increase in ceruloplasmin levels in WD mice treated with 
5E12 VG/kg and high (1.5E13 VG/kg) doses; 
• 
Significant reduction and normalization of the liver damage biomarker alanine 
aminotransferase (ALT), bilirubin, and leukocytes at all tested doses (1.5E12, 5E12 
and 1.5E13 VG/kg);  
• 
Protection of the liver irrespective of the dose injected, with histological analysis of 
liver sections showing that livers of treated mice were indistinguishable from liver of 
WT mice and clearly different from untreated WD mouse livers; 
• 
Dose-dependent proportion (%) of vector expressing cells measured by in situ 
hybridization (ISH) quantification of VTX-801 expression (mRNA);  
• 
Correlation between the liver function correction and the percentage of hepatocytes 
expressing miniATP7B, showing that an average of 11% liver cells positive for VTX-
801 transcript (at a vector dose of 1.5E12 VG/kg) led to a significant improvement of 
the disease, while approximately 32% of hepatocytes positive for miniATP7B mRNA 
(with a vector dose of 5E12 VG/kg) led to a phenotypic correction. 
Efficacy was sustained at least 1 year after VTX-801(Anc80) administration and no deaths 
were observed in the WD treated group, while 4 out of 13 mice died in the untreated group 
due liver damage associated with the progression of the disease. Urinary copper 
excretion rate and liver biochemistry i.e. transaminase levels, bile acids and bilirubin 
remained comparable to those observed in WT animals and significantly different from 
untreated WD controls. Histopathology analysis of liver tissue showed no significant 
differences from healthy control. Administration of VTX-801(Anc80) to young 6-week old 
WD mice prevented liver inflammation, hepatocyte ballooning and necrosis, in contrast 
with the severe chronic inflammation and extensive fibrosis observed in livers of untreated 
WD animals. 
Older WD mice were then treated with VTX-801(Anc80) doses of 5E12 or 1.5E13 VG/kg 
at 12- 16- and 20-weeks of age, when progressive liver inflammation develops. Although 
most pharmacodynamic effects of VTX-801(Anc80) observed in younger mice were 
retained and significant copper reduction in liver was observed, liver transduction 
efficiency measured 24-week post treatment showed lower levels when treated at 
advanced disease stage of the disease. Moreover, a vector dose-dependent transient 
transaminase increase was observed in some animals following VTX-801(Anc80) 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 49 of 223 
administration and this effect was more pronounced in males and older animals with 
advanced disease stage that included liver inflammation. At necropsy (24 weeks after 
vector administration), the same animals had developed extensive liver fibrosis. In further 
experiments, when 5E12 VG/kg VTX-801(Anc80) was administered to 20-week old WD 
mice pretreated with zinc salts or a copper chelator (D-penicillamine), no toxicity was 
observed, and the pretreatments had a protective effect over transaminase elevation and 
development of liver fibrosis. Such beneficial effect of D-penicillamine is likely attributable 
to the stabilization of the liver disease in these mice prior to vector infusion. Regarding 
zinc salts treatment alone, at the dose and mode of administration used in this study, it 
had little effect on disease progression and copper accumulation. 
 Safety and toxicology studies 
The non-clinical safety assessment of VTX-801 to be used in the clinical trial was 
performed in a 6-month follow up GLP toxicology and biodistribution study in non-human 
primates (NHP), following a single administration of VTX-801. At 3 months interim 
timepoint, single doses of VTX-801 up to 
 VG/kg were well tolerated with no 
treatment-related effect on clinical signs, food consumption, body weights, ophthalmic, 
cardiovascular, respiratory, hematological, coagulation and urinalysis parameters 
evaluated. There was no treatment-related effect on cytokine or complement levels 
evaluated in this study. Mild, transient test article-related increases in ALT and AST were 
observed at the high dose of 
 VG/kg on Days 3 and/or 8 post administration. These 
changes are non-adverse due to their low magnitude, low incidence, transient nature and 
lack of associated microscopic findings.  
Immunogenicity: Dosing with VTX-801 did not result in antigen-specific T-cell IFN-γ 
responses following incubation with peptide pools covering the entire AAV3B capsid or 
miniATP7B protein sequences.  
The assessment of AAV neutralizing antibodies from Day 8 up to Day 183 after treatment 
indicated that the antibodies titers in serum increased in both males and females following 
VTX-801 administration. NAbs increased more markedly in animals receiving the highest 
dose, with some showing titers over upper limit of quantification (titer >1:10935). 
Biodistribution: At 1, 3 and 6 months post-administration, biodistribution assessment in 
NHP showed that liver was the organ predominantly targeted by VTX-801 (from 4.9E5 to 
1.8E7 copies/µg of total DNA) in all animals analyzed and at both doses tested (
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 50 of 223 
and 
VG/kg). Other tissues where VTX-801 genome was detected at 1 month post-
administration were, in order of importance, spleen, gall bladder, lymph nodes, kidneys 
and adrenals. 
No vector was detected in CNS and related structures for both doses at 3-month post-
administration.  
 
 
 
 
No gender differences were observed in the biodistribution profile of VTX-801 and no 
histological findings in all analyzed organs were reported. 
Altogether, these results confirmed the strong tropism of AAV3B for the liver in NHP and 
are in agreement with the biodistribution profile reported for liver tropic AAVs (including 
AAV3B), also showing no associated toxicity in NHP (Wang et al, 2015).  
Shedding: Results from shedding after a single IV administration of VTX-801 in NHP 
showed that in: 
• 
Plasma: five (5) animals out of nine (9) injected with the lowest dose of vector were 
positive at D8, two (2) animals were still positive at D15 and only one (1) animal had 
quantifiable amount of vector genome at D29. All animals that received the highest 
dose of VTX-801 (
 VG/kg) were positive for the presence of the vector genome 
in plasma until D8, and three (3) out of nine (9) animals remained positive until D15, 
while one (1) out of nine (9) animals remained positive until D29. All animals were 
negative from D57.  
• 
Saliva: vector genome was detected in four (4) animals out nine (9) from the low-
dosed group and in six (6) animals out of nine (9) from the high-dosed group until D29. 
Only one (1) animal remained positive until D57 and became negative at the next two 
(2) testing points (D92 and D120).  
• 
Nasal fluid: vector genome was detected until D57 only in one (1) animal injected 
with the lowest dose of vector and at D92 all animals were negative. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 51 of 223 
• 
Urine: vector genome was detected for both doses of VTX-801 until D8 and all 
animals were negative for the presence of vector genome in urine at D15. 
• 
Feces: vector genome was detected in animals treated with the lowest dose of 
VTX-801 until D15 and only four (4) animals injected with the high dose of VTX-801 
were positive at D15. At D29 all animals were negative.  
In conclusion, no dissemination of VTX-801 in blood, saliva, nasal fluid, urine and feces 
was observed from 3 months after administration and onward. It should be noted that the 
maximal dose tested in NHP is higher than the maximal dose to be tested in trial subjects. 
2.4 Study Rationale 
VTX-801_CLN_001 is a First-in-Human (FIH) clinical study designed to assess the 
relationship of vector dose (single IV administration) with the restoration of physiological 
copper metabolism in adult WD patients, and whether this restoration is maintained 
durably and safely after withdrawal of WD SoC therapy.  
In order to prevent WD worsening, WD SoC therapy may be withdrawn only in VTX-801 
Responders and after Data Monitoring Committee (DMC) consultation and Sponsor 
approval. All patients will be followed for a total of 5 years, in agreement with current FDA 
and EMA guidelines for the use of non-integrating gene therapy vectors (FDA guideline, 
2020; EMA guideline, 2009). 
2.5 Summary of Potential Risks and Benefits 
For details of the non-clinical studies and results, please refer to the current version of 
the VTX-801 IB. 
 Risk of drug-induced liver toxicity:  
• 
Systemic AAV gene therapy has been often associated with transient rises in 
transaminases, most often within the first 12 weeks after vector administration, which 
has been associated with subsequent loss of clinical efficacy (for a review see 
Nathwani et al, 2017). Transient oral steroid treatment initiated upon transaminase 
increase onset, or even better, prophylactically, has shown efficacy to reduce or 
prevent such effect in several cases, but it has been insufficient in others (Nathwani 
et al, 2017; Pipe et al, 2017). An improved immune modulation regimen may therefore 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 52 of 223 
be useful to optimally mitigate such effects. Therefore, in study VTX-801_CLN_001, 
a combination of sirolimus and oral steroids (prednisone or prednisolone) will be 
administered transiently as a prophylaxis against potential AAV associated ALT 
increase, together 
.  
• 
 
 
 
 
 
 
 
• 
In WD patients, hepatic presentation at time of WD diagnosis may naturally vary from 
persistently elevated serum aminotransferases to chronic hepatitis, cirrhosis 
(decompensated or compensated) or acute liver failure (with or without haemolytic 
anemia) (Członkowska et al, 2018b). Upon treatment for Wilson’s Disease, hepatic 
biochemistry metrics typically show a progressive improvement, but may not 
normalize completely in all patients. In order to minimize the risk of drug-induced liver 
toxicity that might be favored by a progressive and/or severe underlying WD liver 
pathology, VTX-801 will be administered in this FIH study only to patients on stable 
SoC medical treatment according to current WD management guidelines (Schilsky et 
al, 2022; EASL, 2012), with stable and preserved disease-related liver biochemistry 
(ALT<2xULN) and hematology parameters as well as non-severe liver histology.  
• 
Of note, a few cases of fatal hepatotoxicity have been reported after high dose (1.4-
3.4 E14 vg/kg) AAV-mediated gene therapy with different vectors in patients with 
severe neuromuscular disorder (Morales et al, 2020; Shieh et al, 2020 and Shieh, 
2021 - European Society of Gene and Cell Therapy Congress; Chand et al, 2021; 
Philippidis, 2022).  
Risk of Infusion-Associated Reactions (IARs): To prevent potential IARs to VTX-801 
that may occur during or within 24 hours post-VTX-801 infusion, methylprednisolone will 
be administered IV prior to VTX-801 infusion.  
Risk of complement activation: In a few patient who received intravenously AAV gene 
therapy products for various indications at dose levels ranging from 5E13 to 3E14 vg/kg, 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 53 of 223 
i.e. higher than those being evaluated in the current study, complement activation has 
been observed and presented as different combinations of thrombocytopenia, acute 
kidney injury, hematuria, proteinuria and/or anemia, and the outcome was fatal in one 
case (Duan, 2018; Sini et al, 2012; Smith et al, 2022; Guillou et al, 2022). When patients 
were treated with a complement inhibitor (eculizumab), these effects usually resolved 
within 2-3 weeks (Binks, 2021). 
Risk of copper deficiency: The theoretical risk of copper deficiency as a result of 
potential overdosing with VTX-801 has been carefully considered: copper deficiency did 
not occur in any of the preclinical studies conducted to date with VTX-801 in WD or 
healthy animals. Nevertheless, in the VTX-801_CLN_001 study, total serum copper, 
hematology parameters and neurological status will be regularly monitored. Overall, there 
is a theoretical risk that hypocupremia would result from VTX-801 treatment; response to 
dietary copper supplementation (Kumar, 2006) is unknown, and it is possible that such 
condition would be permanent.  
Risk of worsening of neurological and psychiatric disorders: CNS symptoms 
observed in WD patients may be the consequence of acute copper toxicity linked to “free” 
circulating copper and/or accumulated copper causing chronic damage and neuronal 
loss. Although no neurological toxicity has been observed in preclinical studies, there is 
a theoretical risk that VTX-801 would result in a worsening of pre-existing neurological 
conditions or in the onset of new neurological conditions, and it is possible that such 
condition would be permanent. 
Risk of insertional mutagenesis: The risk of AAV-vector-induced insertional 
mutagenesis and tumorigenesis has been documented in preclinical and clinical studies 
and is viewed as minimal (Tenenbaum et al, 2003; Gil-Farina et al, 2016). 
Risks of inadvertent germ‐line transmission:
 
 
risks of germ-line transmission with AAV 
vectors is considered low (Tenenbaum et al, 2003; Gil-Farina et al, 2016). 
Risk related to radiocopper administration: [64Cu]CuCl2 (thereafter also referred to as 
“radiocopper”) will be administered intravenously as a tracer for pharmacodynamics 
evaluations. Each patient is planned to receive, on 3 separate occasions, one intravenous 
administration of a 
 MBq (±10%) dose; the total effective dose received by each patient 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 54 of 223 
in this study is estimated to be < 10 mSv, which is well below deterministic thresholds and 
corresponds to a minor to intermediate cumulative risk level based on ICRP Publication 
(see radiocopper IB and Section 7.4 for rationale). The radioactivity levels to be injected 
have precedence (Section 7.4) and are considered acceptable, based upon applicable 
regulations. 
Risks related to study procedures and concomitant treatments: Repeated liver 
biopsies carry some well-described risks, but all study sites have been selected to be 
hepatology centers with extensive experience in performing liver biopsy, thus minimizing 
the risks of this procedure. The side effects of prophylactic immunosuppression or 
 have been well described and are considered 
acceptable within the context of this study.  
Risk of treatment failure: The starting dose has been selected to be potentially 
therapeutic. Withdrawal of background WD treatment is planned only after demonstrating 
pre-defined VTX-801 pharmacodynamic effects, and close monitoring after withdrawal is 
planned thereafter to ensure patient safety and prompt background WD treatment 
reinstatement, as appropriate. 
Benefits and risk-benefit assessment: Recent or emerging favorable data in various 
genetic disorders highlight the potential clinical benefits of AAV-based gene therapy 
(Mendell et al, 2021; Ohmori, 2020 and D'Antiga et al, 2021, European Society of Gene 
and Cell Therapy Congress). Participants to study VTX-801_CLN_001 have the potential 
to benefit from long-term disease stabilization (possibly an improvement) together with 
complete cessation of SoC WD therapy and low copper diet, if any. The risks of the study, 
especially those associated with pre-existing liver disease and systemic AAV3B vector 
administration, have been carefully considered, gaining insight from recent gene therapy 
trials, and have led to the definition of strict enrollment criteria and provision of extensive 
monitoring as well as prophylactic or reactive treatments. Based upon these 
considerations, the potential risks of participation in the VTX-801_CLN_001 study have 
been minimized, while patients may potentially benefit from VTX-801 treatment. 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 56 of 223 
• Time to SoC withdrawal 
• Need for SoC adjustments 
• Need for reinstatement of SoC after withdrawal and whether response occurs 
at the pre-study SoC dose 
• Time to copper deficiency and whether correction occurs 
• Humoral and cellular immune responses to VTX-801:  
o In vitro neutralizing antibodies (NAb) anti-AAV3B capsid assay 
o ELISA: antibodies against AAV3B capsid and miniATP7B transgene 
o IFN-gamma ELISpot to AAV3B capsid and miniATP7B transgene 
 
 Exploratory Endpoints 
• Hepatic Cu and histology from liver biopsy 
• Ceruloplasmin level determination by nephelometry 
• Unified Wilson's Disease Rating Scale (UWDRS) 
• Liver Magnetic Resonance (MR) elastography 
• Hepatic synthetic function (INR, platelet count, albumin) 
• Model for End-Stage Liver Disease (MELD), AST to platelet ratio index (APRI), 
Fibrosis-4 Index for Liver Fibrosis (FIB4) 
• Mini International Neuro-psychiatric Interview (M.I.N.I.) 
• Symbol Digit Modality Test (SDMT) and Stroop test  
• Other biomarkers that may inform long term disease outcomes or responses to 
treatment with VTX-801 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 57 of 223 
4 STUDY DESIGN 
4.1 Overview  
VTX-801_CLN_001 is a phase I/II, multicenter, non-randomized, open label, adaptive 
design, 5-year follow-up, single dose-escalation study of VTX-801 in adult patients on 
background WD therapy (Figure 1).  
The dose-escalation phase will involve up to 3 cohorts, each consisting of approximately 
4 adult WD patients on chronic and stable treatment with SoC; once a safe and potentially 
efficacious VTX-801 dose level has been selected for further evaluation, an expansion 
cohort of approximately 4 adult WD patients on chronic and stable treatment with SoC 
will be enrolled at this Selected Dose level.  
The adaptive nature of the study intends to minimize the number of patients exposed to 
a sub-optimal VTX-801 dosing regimen, since for them re-treatment with a therapeutic 
dose may not be possible due to seroconversion to the AAV capsid. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 58 of 223 
 
Abbreviations: DMC= Data Monitoring Committee; N= Number of patients. 
Figure 1 
Study Design 
The above scenario assumes an efficacious dose is reached at Cohort 3. 
Full line = enrolled patients 
Dashed lines = patients that may be omitted due to insufficient pharmacodynamic response in 
a cohort (see Section 4.2, below) 
 
4.2 VTX-801 Dose Escalation  
Adult male and female WD patients receiving SoC therapy with either zinc salt, a copper 
chelator (D-penicillamine or trientine) or the association thereof and who meet all eligibility 
criteria will be sequentially enrolled and treated with escalating doses of VTX-801 in up 
to 3 consecutive cohorts of approximately 4 patients each; each patient will receive a 
single VTX-801 infusion, starting with a potentially therapeutic dose (Section 7.2). The 
best efforts will be made to enroll at least 1 patient of each gender in each cohort of 4. 
Note for patients receiving chelators or dual chelator and zinc therapy, a chelator wash-
out period will be required around each radiocopper injection (starting 3 days before 
radiocopper injection and continuing until the end of the radiocopper investigations – refer 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 59 of 223 
to Sections 8.2.6.1 and 8.2.6.2) planned during the week preceding the VTX-801 
administration and at Weeks 12 and 36 from VTX-801 administration. The objective of 
the wash-out period is to prevent any possible interference of chelators with 24-hour 
urinary copper and radiocopper assessments (no wash-out is required for patients on any 
zinc-only treatment). Importantly, such a short wash-out period is not considered to put 
patients at risk, since accumulation of copper is a slow process. 
Dose escalation will proceed according to the following enrollment scheme (refer to the 
Enrollment Decision Tree in Figure 2 and the Stopping Rules in Section 6.3): 
• ≥ 6-week intervals will be maintained between the VTX-801 infusion of the first 2 
patients of each cohort  
• if VTX-801 is well tolerated in both patients, as per the pre-defined Stopping Rules 
outlined in Section 6.3, then ≥ 12-week data (W12) from the first 2 patients of each 
cohort will be reviewed by the Sponsor and the DMC: 
o 
if first 2 patients are VTX-801 Responders at W12 (see Section 4.5), the 
remaining 2 patients of the concerned cohort may be enrolled; the decision 
of dose escalation will be based on the review of all available safety data of 
3 to 4 patients at 12 weeks by the DMC. If well tolerated according to DMC, 
dose escalation may proceed after Sponsor agreement. 
o 
if either or both first patients are Insufficient VTX-801 Responders at W12, 
dose escalation may proceed without dosing the remaining 2 patients of the 
concerned cohort, in order to limit the exposure of patients who do not 
benefit sufficiently from the treatment (and may not be retreated with an 
efficacious dose because of seroconversion to the vector).  
 
In case at least 1 out of the 2 first patients is an Insufficient VTX-801 
Responder at W12 and at least 1 out of the 2 is a VTX-801 Responder 
at W36 for a given dose level, 2 additional patients may be enrolled 
subsequently, based upon DMC recommendation and upon Sponsor 
decision. 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 60 of 223 
 
Abbreviations: DL=Dose Level 
Figure 2 
Enrollment Decision Tree 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 61 of 223 
 
In case of safety signal in a sentinel cohort (first 3 patients at ≥ 12 weeks), the following 
rules will apply: 
• 
If 1 patient with AE Grade 3 that resolved quickly and that can be addressed by 
supportive care, dose escalation may proceed after DMC positive recommendation; 
• 
If 1 patient with AE Grade 3 persistent or 1 patient with AE > Grade 3, bring cohort to 
total N=6; however, if less than 2 patients are Responders in the sentinel cohort, dose 
escalation may proceed without additional patients in the concerned cohort after 
review and positive recommendation of the DMC. 
Adverse events that are incontrovertibly not related to IMP will not count in dose 
escalation rules. 
In case a Stopping Criterion is reached, the procedure described in Section 6.3 will be 
implemented. If dose escalation is terminated, the DMC will then provide a 
recommendation from a benefit/risk perspective on whether de-escalation may be 
acceptable and the Sponsor will decide if it is useful or futile to continue the study. If de-
escalation occurs, the dose will be divided by 2 compared to the dose limiting level. 
At the end of the dose escalation, a VTX-801 dose level that has been determined to be 
both safe and potentially efficacious following DMC review will be selected by the Sponsor 
for further testing (the Selected Dose) as outlined in Section 4.3.  
4.3 Expansion at the Selected VTX-801 Dose 
Only if and when an optimal VTX-801 dose level has been selected from the escalation 
phase based on pharmacodynamic studies with radiocopper and other biomarkers of 
copper metabolism, additional patients will be enrolled in parallel in an expansion cohort 
to reach a total of 8 patients receiving VTX-801 at the Selected Dose level.  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 62 of 223 
 
4.4 Patient Treatment and Follow-up Scheme 
 
Abbreviations:64Cu= Radiocopper; W= Week; WD= Wilson’s Disease. 
Figure 3 
Patient Treatment and Follow-up Scheme 
Each patient of each cohort will follow the scheme depicted in Figure 3; enrolled patients 
will start the immunosuppressive regimen before undergoing the first radiocopper related 
assessments. They will then receive a single VTX-801 infusion without interrupting their 
background WD therapy (except for planned chelator wash-out periods in chelator-treated 
patients, Section 10.2).  
Patients will have an increased frequency of assessments for 12 weeks post-VTX-801 
administration; the rationale behind this being: 
(i) 
in two published experiences of liver-directed gene therapy in hemophilia, the 
pharmacodynamics endpoint (blood coagulation factor levels) tended to reach 
a maximum and to stabilize by around Week 12 post administration 
(Rangarajan et al, 2017; George et al, 2017);  
(ii) 
most ALT increases occurred within the first 12 weeks post AAV administration 
(Nathwani et al, 2017). Therefore, at Week 12, each patient will undergo a 
second radiocopper injection and the VTX-801 Responder status will be 
determined.  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 63 of 223 
In addition, at Week 36, patients will receive a third radiocopper injection and the 
Responder status will be assessed again, in order to evaluate the sustainability of the 
effects in Responders and to detect possible late Responders. 
Patients will then be followed up for a total of 5 years from the time of VTX-801 
administration.  
Considering Responder status and based upon DMC review and recommendations the 
following actions may be taken after Sponsor approval: 
- 
Week 14: Background WD therapy may be withdrawn for Week 12 Responders 
but will be continued for Week 12 Insufficient Responders. 
- 
Week 38: Background WD therapy may be withdrawn in Week 36 Responders but 
will be re-initiated (if previously interrupted) in Week 36 Insufficient Responders. 
The same schedule of investigations will be followed for Responders and Insufficient 
Responders until the end of Year-1 follow up (Visit 46).  
4.5 Responder/Insufficient Responder Definitions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 64 of 223 
 
 
 
 
 
 
Figure 4 
Responder Decision Tree - SoC Withdrawal Only in Responders  
 
 
 
 
 
 
 
Responder status will be evaluated for each patient after review of data collected until 
Week 12 and Week 36.  
The Responder/Insufficient Responder process associated timelines are described in 
Figure 5. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 65 of 223 
 
Abbreviations: D= Day; DMC= Data Monitoring Committee; W= Week. 
Figure 5 
Responder/Insufficient Responder Process Associated Timelines 
4.6 Background or Standard of Care WD Therapy Withdrawal, Adjustment or 
Reinstatement 
WD treatment withdrawal or reinstatement based upon Responder status: the DMC 
will review patient data collected up to and including Week 12 and Week 36, as 
appropriate, in order to provide a recommendation from a safety standpoint regarding 
background WD therapy withdrawal, adjustment or reinstatement, as appropriate.  
For background WD therapy withdrawal, the DMC will:  
1. Evaluate if the WD of the patient is stable, based upon clinical and biochemical 
data, including: 
 
 
 
 
 
 
2. 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 66 of 223 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
. 
Management of copper deficiency: in case a patient would develop copper deficiency 
at any time during the trial, background or WD SoC therapy (if any), dose and regimen 
may be adjusted and/or the patient may receive dietary copper supplementation, after 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 67 of 223 
DMC consultation and upon Sponsor confirmation. Please refer to Section 9.7 for further 
details. 
Management of immediate patient safety: the Investigator should make every effort to 
follow the planned protocol treatments and schedule and to await DMC recommendations 
when needed; however, at any time during the trial, the Investigator may not be able to 
await Sponsor or DMC response before taking appropriate urgent therapeutic measures 
needed to ensure immediate patient safety (see Section 13.4). 
4.7 Study Committees 
 Data Monitoring Committee 
A DMC will be involved throughout the trial duration. The DMC will be independent from 
any investigational sites and will not include any members from Vivet Therapeutics. It will 
be comprised of 4 medical clinician members experienced with WD, including a 
Chairman.  
The DMC members, roles and responsibilities, as well as the timing and support required 
will be fully detailed in a DMC Charter (reviewed and approved by the DMC members). 
In summary, the DMC will review patients’ data in order to provide recommendations, 
mostly relative to patient safety. The reviews will be done: 
• At pre-defined time points: patient-level review for Responder status determination 
(see Section 4.5), cohort-level review and determination of acceptable risk/benefit 
prior to first VTX-801 dosing in next dose escalation, background WD therapy 
withdrawal, adjustment or SoC reinstatement.  
• On an ad-hoc basis, especially in case of significant clinical or biological deterioration 
post background WD therapy withdrawal, oral steroid (prednisone or prednisolone) 
and/or sirolimus withdrawal, or after an SAE.  
Pre-defined DMC reviews will be based on patient profiles, and/or on aggregated 
statistical outputs (tables, listings, figures), as required. Data/information required for 
ad-hoc DMC reviews will be determined on a case-by-case basis. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 68 of 223 
 Hepatic Adjudication Committee 
The Hepatic Adjudication Committee (HAC) will be comprised of 2 or 3 hepatologists 
(including at least 2 U.S.-based hepatologists), who can also be DMC members and have 
expertise in review and adjudication of suspected Drug Induced Liver Injury (DILI). 
The HAC is responsible for reviewing and adjudicating all suspected DILI reports 
completed and submitted by the clinical sites and they are responsible for providing an 
overall event assessment to the clinical site, the DMC and the Sponsor. 
 Eligibility Review Committee 
The Eligibility Review Committee (ERC) will include at least 4 US-licensed physicians 
(Principal Investigators, Co-Investigators or physicians) who have experience and 
expertise in the management of patients in Wilson’s Disease and experience in the 
recruitment and monitoring of clinical trials.  
• The ERC will advise on the determination of patient eligibility prior to inclusion in the 
VTX-801_CLN_001 study and dosing of VTX-801. 
4.8 Long Term Follow-up 
A long-term follow up will be performed for all patients treated with VTX-801. Patients 
withdrawn before VTX-801 administration will not be followed for 5 years. 
A first data lock will be done when all patients reach one year of follow-up post-VTX-801 
administration and the results will be reported in a first CSR. The long-term follow-up will 
continue until up to 5-years post-treatment, in line with the current EMA and FDA 
guidelines on follow-up of patients administered with non-integrative, non-replicative gene 
therapy medicinal products (EMA guideline, 2009; FDA guideline, 2020). A second and 
final CSR will cover all 5 years of follow-up. 
4.9 Study Start and End of Study Definitions 
The expected duration of participation for each patient is approximately 5 years. The 
study will start from first patient first visit and end after completion of Last Patient Last 
Visit. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 69 of 223 
5 STUDY POPULATION 
5.1 Number of Patients 
As part of this study, up to approximately 16 WD male and female adult patients will be 
administered VTX-801 in 3 dose-escalation cohorts consisting of approximately 4 patients 
and one expansion cohort consisting of approximately 4 patients treated at the Selected 
VTX-801 dose.  
• Patients for whom radiocopper data is missing at Week 12 may be replaced, as 
appropriate, however, the total number of patients will not exceed 16 patients. 
• The Sponsor may consider amending the protocol to include additional patients at the 
Selected Dose if judged necessary and/or to include a cohort of patients with more 
advanced liver disease (Metavir hepatic fibrosis stage ≥ F3 or higher) after (1) safety 
data in non-cirrhotic patients is available and reviewed by the DMC; and (2) FDA and 
the other concerned Regulatory Authorities have approved the amended protocol. 
5.2 Inclusion Criteria 
Patients may be enrolled into the study if they fulfil all of the following criteria:  
1. Male or female aged 18 – 65 years (inclusive) at the time of signing the informed 
consent.  
2. Patient diagnosed with WD, as established (by historical and/or current data), 
documented by Leipzig score ≥ 4, as per the 2012 EASL Clinical Practice 
Guidelines (EASL, 2012) and either:  
i) 
historical or current 24h urinary Cu > 40 µg/day (or 0.6 µmol/day) off 
chelator therapy, if any OR  
ii) 
two pathogenic or likely pathogenic ATP7B variants 
3. Patient has the ability to understand, date and sign informed consent prior to 
initiation of any study procedures. 
4. Male patients: willing to use two methods of contraception from the day of the first 
radiocopper injection through 6 months following VTX-801 infusion and also for the 
week following the W36 radiocopper injection (sperm donation during this time is 
also prohibited). 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 70 of 223 
5. Female patients: if of childbearing potential, willing to use two methods of 
contraception from signing informed consent through at least one week after W36 
radiocopper injection. If using oral contraception, it must have remained unchanged 
for ≥ 3 months prior to inclusion. 
6. Treated for WD according to international recommendations with no current 
evidence for inadequate treatment (EASL, 2012; Schilsky et al, 2022); 
o 
for at least 1 year with either zinc, a copper chelator [trientine or D-
penicillamine], or a combination of thereof; previous treatment with 
investigational bis-choline-tetrathiomolybdate is acceptable as well, 
provided that it has been stopped ≥6 months prior to study entry.;  
o 
without any changes in dosing regimen for at least the last 6 months prior 
to study entry; 
o 
compliant with current WD treatment, as judged by the Investigator. 
7. Stable WD for ≥ 1 year, defined as: 
a. No significant change in neurologic examination and in status of mood 
disorder, if present, as judged by a physician-expert(s) in assessing 
neurological and psychiatric manifestations of WD. 
b. Stable laboratory parameters used to assess copper metabolism including 
24-hour urinary copper, free serum copper such as NCC or CuEXC (when 
available), as well as liver enzymes, hemoglobin, and white blood cell 
count.  
The last assessments should be stable (no significant change), on at least 2 
occasions assessed 6 to 8 weeks apart prior to enrollment (the interval may be 
extended as needed for logistical reasons beyond 8 weeks, after sponsor 
approval). The US and EU guidelines, as well as more recent publications should 
be used as a reference for WD management (EASL, 2012; Schilsky, 2017, 
Schilsky et al, 2022). 
8. Patient expected to live for the study duration in the Investigator’s opinion. 
5.3 Exclusion Criteria 
Patients will be excluded from enrollment into the study if they have any of the following:  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 71 of 223 
1. ALT level ≥ 2 x ULN that is not readily explained by extrinsic factors (e.g., strenuous 
exercise, medication use). 
2. Total bilirubin > 1.5 x ULN in the absence of proven Gilbert’s syndrome; in case of 
Gilbert’s syndrome, direct bilirubin > ULN.  
3. INR > 1.2. 
4. Platelet count < 120,000/µL. 
5. Absolute neutrophil count (ANC) < 1,000/µL. 
6. Patient with fasting triglycerides ≥ 200 mg/dL [> 2.3 mmol/L], on optimal therapy, if 
any. 
7. On liver biopsy at inclusion: severe liver fibrosis (Metavir stage F3) or liver cirrhosis 
(Metavir stage F4) or steatosis > 33 % (steatosis score ≥ 2, per NASH-CRN scoring 
system). The liver biopsy may be replaced by Fibroscan® in the dose escalation 
cohorts only; the cut offs are defined as (Sini et al, 2012; Park et al, 2017) 
a. In sites equipped with Fibroscan® 
i. 
LS ≥ 8.4 kPa 
ii. 
CAP score (Controlled attenuation parameter) ≥ 305 dB/m 
b. If the patient meets any of the above criteria and still declines the liver biopsy, 
he/she will be excluded; a liver biopsy (if performed finally) will however prevail 
for eligibility over Fibroscan® as the gold standard. 
8. Any signs of liver cirrhosis decompensation, including gastrointestinal bleed within 
6 months (24 weeks) prior to Screening/enrollment visit. 
9. Patient has moderate or severe renal impairment defined as eGFR CKD-EPI < 
60 mL/min/1.73 m2, or patient has nephritis or nephrotic syndrome.  
10. Active infection requiring systemic antibiotic treatment or immunocompromised 
patients. 
11. Any history or current evidence of HIV-1, HIV-2, HTLV-1 or HTLV-2 infection. 
12. Any history or current evidence of hepatitis B infection, i.e. HBs antigen or 
antibodies anti-HBc positive. 
13. Any history of hepatitis C infection, unless previous viral RNA assays in two 
samples, collected at least 6 months apart, are negative.  
14. Positive QuantiFERON®-TB Gold tuberculosis test result, history of active or latent 
tuberculosis or a history of positive PPD or Tine test; however, a history of positive 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 72 of 223 
PPD or Tine test in a patient who has received a BCG vaccine will not be 
exclusionary if QuantiFERON®-TB Gold test is negative.  
15. Positive for in vitro anti-AAV3B neutralizing antibody activity.  
16. Any concomitant disorder/condition - including hepatic disorders - or treatment (see 
Section 7.6.2) possibly interfering with the conduct or evaluation of the study, 
according to the Investigator. 
17. Any history of angioedema. 
18. Any history of diabetes. 
19. Known allergy or hypersensitivity to components of VTX-801. 
20. Contraindication to corticosteroid or Sirolimus use, as judged by the Investigator. 
21. Contraindication 
 
  
22. Psychosis or history (less than 10 years ago) of hospitalization for depression. 
23. Severe neurological impairment defined as either [UWDRS part II subscales 2, 4 
or 11 ≥ 3 (greater than or equal to 3)] or [UWDRS part II subscales 3, 6, 7, 8, 9 or 
10 >3 (greater than 3)] or history of seizure activity within 6 months prior to signing 
informed consent. 
24. Patients with dementia or moderate to severe cognitive impairment defined as 
MoCA score < 18 (as corrected for educational level).  
25. Pregnancy or breastfeeding. 
26. Body Mass Index ≥ 35 kg/m2. 
27. Moderate or heavier alcohol drinker, defined as drinking > 3 drinks/week on 
average over the past year. 
28. Recent drug (amphetamines, opiates, cocaine or phencyclidine (PCP)) use: history 
or positive urinary drug screen results for either amphetamines, opiates, cocaine or 
phencyclidine (PCP) at any of the Screening visits (Screening 1 or Screening 2); 
however, positive detection of licit, medically prescribed medications is not 
exclusionary.  
29. Received a gene therapy treatment or participated in a gene therapy clinical trial. 
30. Received any investigational drug and/or participated in any interventional clinical 
trial within the past 6 months. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 73 of 223 
31. Individuals with documented history of malignancy except basal or squamous cell 
carcinoma which has been treated and fully resolved for a minimum of 5 years.  
32. Prior vaccination with live vaccine within 30 days before Sirolimus administration. 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 74 of 223 
6 ENROLLMENT AND MANAGEMENT OF DROPOUT PATIENTS 
6.1 Enrollment Procedures 
The study begins for a patient with the signing and dating of the informed consent form in 
accordance with Section 14.3.  
A master patient list will be maintained by the site. This list will include screen failures, 
i.e., patients who are screened but fail to meet all eligibility criteria and patients who are 
enrolled but do not receive VTX-801. Waivers for eligibility will not be granted. 
The presence of inclusion criteria listed in Section 5.2 and absence of exclusion criteria 
listed in Section 5.3 will be documented in the source data and the eCRF (electronic Case 
Report Form). 
The Screening period (Section 10.1) will include 2 mandatory parts (Screening 1 and 
Screening 2) in order to determine patient suitability. Patient eligibility will be assessed in 
full at V1B. Based upon V1A results, only those patients that are anti-AAV3B NAb-
negative (see Section 8.2.1) may be allowed to proceed to V1B visit to assess patient 
eligibility. 
 
According to the dose escalation design and the competitive inclusion, approval by the 
Sponsor is required for each patient: 
• Prior to Screening 1 visit; 
• Prior to Screening 2 visit; 
• Prior to inclusion (after ERC review and approval); 
• Prior to re-screening any patient who never received VTX-801. 
The enrollment procedure will be detailed in the Medical Monitoring Plan and in the 
Eligibility Review Committee Charter. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 75 of 223 
6.2 Treatment Assignment/Randomization Procedures 
Since this is a non-randomized study, randomization procedures are not applicable. 
Patients will be assigned to treatment with a unique patient number in ascending, 
sequential order. The Investigator will enter the patient number in the eCRF.  
6.3 Stopping Rules  
Any of the following occurrences will result in pause of further dosing (including 
escalation to a higher dose level) while the events are under investigation: 
• 
Any death during the study period; 
• 
Any patient develops Grade 3-4 (CTCAE) toxicity; 
• 
Any patient develops copper deficiency (Section 9.7);  
• 
Any occurrence of a newly diagnosed malignancy at any point after vector infusion; 
• 
Neurological, psychiatric or behavior-related adverse event (either new or worsening 
from baseline) suggestive of IMP-induced deterioration (possibly, probably or 
definitely related), per Investigator judgment; 
• 
Dose limiting toxicity (DLT), as per DLT definition below;  
• 
Two cases of DILI, as defined below, irrespective of causality. 
Definition of DILI criteria: 
a. For patients with baseline AST and ALT values ≤ULN: ALT or AST ≥ 3x ULN 
and Total Bilirubin ≥ 2x ULN; 
For Patients with baseline AST or ALT values >ULN: AST or ALT >2x baseline 
and ≥3x ULN] and Total Bilirubin ≥ 2x ULN. 
b. ALP ≥ 2x ULN and Total Bilirubin ≥ 2x ULN; 
c. For patients with Gilbert’s syndrome: ALP ≥ 2x ULN and Direct Bilirubin ≥ 2x 
ULN; 
d. ALT or AST ≥ 3x ULN and INR ≥ 1.5; 
e. ALP ≥ 2x ULN and Direct Bilirubin or Total Bilirubin ≥ 2x ULN and INR ≥ 1.5; 
f. ALT or AST ≥ 5x ULN; or 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 76 of 223 
g. Hepatic decompensation. 
In the event a patient meets any of these DILI triggers, a search for causality should be 
conducted (as per current guidelines: Clinical Practice Guidelines: Drug-induced liver 
injury, EASL, 2019 and Guidance for Industry Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation, FDA guideline, 2009), the corresponding suspected DILI forms should 
be completed and the event reported (see Section 9.6). Testing of liver biochemistry 
should be repeated within 48 to 72 hours to confirm the abnormalities and the patient 
should be placed in close monitoring and followed until they normalize or stabilize.  
If two patients experience serious liver injury (as defined by above thresholds) or a hepatic 
decompensation event, the trial should be paused, and the DMC should conduct a review 
and provide supplemental causality assessment. If the DILIs are deemed to be related to 
VTX-801, then the study will remain on hold and further study continuation should be 
discussed with FDA.  
Definition of DLT: Two patients receiving the IMP develop similar > Grade 3 (CTCAE) 
laboratory, ECG or vital signs abnormalities, or severe AEs in the same organ class, 
indicating dose limiting intolerance. Adverse events that are incontrovertibly not related 
to IMP will not count in determining DLT. 
Overall, enrollment and dosing in the trial may resume after review of concerned clinical 
cases by and upon positive recommendation from the DMC, after Sponsor agreement 
and if the study is on temporary hold, after discussion with and agreement of the FDA.  
6.4 Patient Withdrawal Criteria 
Patients may withdraw their consent from participation in the study at any time, for any 
reason, during the trial.  
The Sponsor can terminate prematurely the trial at any time for futility or safety reasons, 
based upon Health Authorities’ request or DMC recommendation.  
6.5 Patient Withdrawal Procedures 
Patients will be informed that they have the right to withdraw from the study at any time, 
without prejudice to their medical care, and that they are not obliged to state their reasons. 
Any withdrawal will be documented in the eCRF and followed up by the Investigator. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 77 of 223 
If a patient withdraws or is withdrawn from the study, the reason for withdrawal will be 
recorded in the eCRF if available and all efforts must be made to complete and report the 
observations as thoroughly as possible.  
For any study withdrawal, all efforts should be made to conduct an Early Termination 
Visit. This visit should be performed within 4 weeks following the decision to withdraw and 
as described in Section 10 and recorded in the Early Termination eCRF.  
The extent of the termination visit will depend on whether the patient has received 
VTX-801 administration (even partial) or not; every effort should then be made to follow 
each patient who received at least a partial VTX-801 infusion for up to 5 years post-VTX-
801 administration with at least one phone call every 6 months to collect potential adverse 
events. 
If a patient fails to return for follow-up, attempts should be made to contact the patient to 
ensure the reason for not returning is not an AE. After 3 unsuccessful calls or emails, a 
certified letter will be sent; all attempts will be documented in source data and eCRF. For 
patients considered lost to follow-up, the eCRF must be completed up to the last visit 
performed. 
Ongoing AEs should be followed up in accordance with the procedures described in 
Section 9.2.7. 
Patients without evaluable Responder status evaluation may be replaced, as appropriate. 
6.6 Premature Termination or Suspension of the Study 
This study may be suspended or prematurely terminated for futility or for safety reasons, 
in the following circumstances: 
• Safety, i.e. determination of unexpected, significant, or unacceptable risk to the 
patients; 
• Futility, i.e. plans to modify, suspend or discontinue the development of VTX-801. 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators/Institutions, and the Regulatory Authority(ies) of the termination or 
suspension and the reason(s) for the termination or suspension. The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 78 of 223 
Sponsor or by the Investigator/Institution, as specified by the applicable regulatory 
requirement(s). 
Regardless of the reason for study termination, all patients having fully or partially 
received VTX-801 will have to complete the 5-year safety follow-up consisting of, at 
minimum, a call by the Investigator every 6 months to the patient. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 79 of 223 
7 VTX-801 TREATMENT, AUXILIARY TREATMENTS, DIET AND 
OTHER STUDY SPECIFICATIONS 
7.1 Wilson’s Disease Background Therapy  
Per enrollment criteria, all patients entering the study will already be on background WD 
therapy according to SoC therapy for WD (Schilsky et al, 2022; EASL, 2012); such 
treatment is referred to as “background WD therapy” in this study protocol (Enrollment 
criteria, Sections 5.2 and 5.3). Patients will be instructed to continue their background 
WD therapy upon entering the study and the dosing regimen should remain unchanged, 
unless requested otherwise: such treatment will be withdrawn or continued following the 
rules described in Section 4.6. Similarly, WD SoC therapy may be re-initiated following 
the rules described in Section 4.6 and may or may not be identical to background WD 
therapy, upon Investigator’s decision. 
Background WD therapy and WD SoC therapy in case of reinstitution will not be provided 
as part of the study. 
The Investigator will question patients for their compliance to background WD therapy at 
Screening (cf. Inclusion Criteria, Section 5.2) and also, during the periods when patients 
are requested to discontinue (Responder status, wash-out period) or reinstate WD 
medications. 
 Zinc Salt Treatments 
Any zinc salt formulation prescribed by the treating physician is acceptable. No wash-out 
period will be necessary for zinc-only treated patients around the radiocopper related 
assessments, since zinc salts are not expected to significantly interfere with the 
metabolism of IV-injected radiocopper. 
 Copper Chelator Treatments 
All D-penicillamine and trientine formulations approved in the patient country for the 
treatment of WD are acceptable as background WD therapy. Any other copper chelator 
is prohibited at enrollment. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 80 of 223 
Wash-out periods will need to occur for copper chelators around radiocopper related 
assessments, since they may chelate radiocopper and interfere with the evaluations 
(Section 10.2).  
7.2 Investigational Product: VTX-801 
Please refer to the VTX-801 IB and VTX-801 Pharmacy Manual for full details.  
 VTX-801 Description and Supply 
The investigational medicinal product (VTX-801) is a replication-deficient recombinant 
adeno-associated viral vector (rAAV) consisting of an AAV3B capsid containing a single-
stranded DNA genome carrying a shortened version of the ATP7B gene (ATP7B-
minigene). 
VTX-801 Solution for Infusion, 5.4 mL/vial, is supplied in its final formulation in a 10 mL 
closed vial. Each vial is for a single use in a single patient. A subsequent reconstitution 
will be performed on site. 
VTX-801 should be handled as a biohazardous product according to local regulations for 
biosafety level class 1 agents (BSL1). 
 Selection of VTX-801 Doses Used in the Study 
Starting VTX-801 dose: The initial VTX-801 dose has been selected primarily based 
upon non-clinical pharmacology and toxicology studies, as a balance between expected 
pharmacodynamics and safety. VTX-801(Anc80) 1.5E12VG/kg treatment is efficacious in 
6-week-old WD mice and is associated with ~11% of liver cells positive for miniATP7B 
transcripts; the same dose results in similar mRNA signal in healthy mice. To reach ~11% 
of liver cells expressing VTX-801 in NHPs, a dose of 5E12VG/kg of vector is necessary. 
Assuming liver transduction is equivalent between NHP and humans (based upon in vitro 
experiments in hepatocytes), the dose of 5E12VG/kg is considered potentially therapeutic 
in WD in patients. In addition, re-treatment of WD patients exposed to a sub-optimal 
VTX-801 dose may not be possible due to seroconversion to the AAV3B capsid. Based 
upon these considerations, as well as the safety profile in mice and NHPs, VTX-801 
5E12VG/kg is considered appropriate as a starting dose for the dose escalation. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 81 of 223 
VTX-801 dose increments during dose escalation: VTX-801 dose will be incremented 
by a factor of 3 between Cohorts 1 and 2; VTX-801 dose may be incremented by a factor 
of 2 between Cohorts 2 and 3. Therefore, the following will be used: 
o Cohort 1: 5E12 VG/kg  
o Cohort 2: 1.5E13 VG/kg 
o Cohort 3: 3E13 VG/kg 
Patients with BMI >30kg/m2: for patients with BMI >30 kg/m2, the dose will be calculated 
based upon an adjusted body weight determination that assumes a maximum permitted 
BMI of 30 kg/m2 for that patient respective height (actual).  
 VTX-801 Packaging and Labelling 
The packaging of VTX-801 is compliant with the IATA regulation for genetically modified 
organism (UN3245). VTX-801 will be labelled in accordance with applicable local 
regulatory requirements and applicable ICH Good Manufacturing Practice (GMP) and ICH 
GCP guidelines.  
VTX-801 is supplied in 10 mL vials in an individual package. Each vial is for a single use.  
 VTX-801 Storage and Stability 
Before reconstitution: 
Upon receipt, VTX-801 vials must be stored frozen at -60°C to -90°C (-76 ºF to -130 ºF) 
in a secured and temperature-controlled freezer as well as in a locked and restricted 
access storage facility under pharmacist supervision. 
After reconstitution: 
When reconstituted, with or without dilution in normal saline (0.9% sodium chloride), 
VTX-801 in the infusion bag for intravenous administration may be stored at ambient 
temperature prior to use but administration must be completed within 8 hours of the start 
of the first vial thaw.  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 82 of 223 
 VTX-801 Dosage, Preparation and Administration 
Quantity of VTX-801, final volume, infusion rate and duration of administration will depend 
on patient’s weight and cohort to which the patient has been assigned. However, for 
patients with BMI >30 kg/m2, the dose will be calculated based upon an adjusted body 
weight determination that assumes a maximum permitted BMI of 30 kg/m2 for that patient 
respective height (actual).  
Administration of VTX-801 will always be upon the Investigator written prescription at V5 
(D-1) and approved by the Sponsor. 
VTX-801 will be provided to the responsible pharmacist at the study site, who will handle 
and dispense study product in accordance with the VTX-801 Pharmacy Manual that 
includes the reconstitution protocol which is developed according to ICH GCP guidelines 
and applicable local laws. 
The VTX-801 will be administered as a single dose intravenous (IV) administration, at up 
to 3 different doses levels.  
The prepared volume of VTX-801 in Normal Saline (0.9% sodium chloride) is intended to 
be administered with the aid of an Infusion Pump. Recommendations for decontamination 
and destruction of the material used for IMP preparation and administration will be 
available in the VTX-801 Pharmacy Manual. 
7.2.5.1 Infusion Procedure 
VTX-801 infusions should be administered by appropriately qualified staff used to 
manage infusion associated reactions; resuscitation and safety equipment and 
procedures must be available throughout the end of the expected patient post-infusion 
safety follow up period. A 24/7 emergency medical coverage is also expected at site. 
• 
Fast patient overnight prior to VTX-801 administration and during administration; 
• 
The VTX-801 infusion administration should be started early in the morning in order 
to limit as much as possible the total duration of the fasting period; 
• 
In order to make sure that patients are well hydrated, small volumes of per os fluids 
only (no solid meals) are acceptable up to 2 hours before the infusion starts. 
Thereafter, only IV fluids should be given, as necessary; 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 83 of 223 
• 
Administer methylprednisolone 100 mg IV one hour before the VTX-801 infusion;  
• 
Have ready a keep-vein-open (KVO) port normal saline as a slow drip;  
• 
Measure pre-infusion blood pressure and heart rate;  
• 
Start VTX-801 infusion according to the VTX-801 Pharmacy Manual; 
• 
Measure blood pressure and heart rate every 15 min during the infusion, at the end of 
the infusion, 1 hour after the infusion and then every 4-hour until patient goes to sleep 
in the evening on the day of administration;  
• 
It is recommended that the patient also fasts for 2 hours after the administration for 
infusions shorter than 1 hour, but this time may be reduced for patients receiving 
longer infusions;  
Should the patient develop during or following the VTX-801 infusion clinical symptoms 
such as hypotension, fever, tachycardia, chills, rash or headache, this will be treated by 
standard methods used for infusion associated reactions; such methods may include (but 
are not limited to) slowing down the infusion rate to 50% of previous rate at the 
Investigator’s discretion. The infusion may be subsequently titrated back to the original 
rate, if tolerated by the patient. Additional therapeutic measures may include symptomatic 
treatment such as rehydration, acetaminophen (paracetamol), antihistamine and/or 
intravenous methylprednisolone administration. The infusion will be interrupted in the 
case of a CTCAE Grade 2 or 3 adverse event occurs (such as bronchospasm or 
anaphylaxis) (refer to Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0, 2017), and symptomatic measures will be implemented; when the situation 
has improved to Grade 1 or Grade 0 AE, the infusion of the IMP may resume, as long as 
the time elapsed since IMP thawing does not exceed 8 hours; if not, dosing will be 
permanently stopped for this patient. In the case of Grade 4 AE, the infusion will be 
stopped permanently in this patient (and cf. the stopping rules in Section 6.3). If the patient 
is at risk of vomiting following the VTX-801 infusion, the next day oral steroid (prednisone 
or prednisolone) may be replaced by an equivalent dose of IV methylprednisolone, as 
appropriate. 
Section 7.2.5.2 provides guidance for laboratory exams to be performed in case of severe 
event of IAR.  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 84 of 223 
7.2.5.2 Biochemical Analysis of Infusion-Associated Reactions by Laboratory 
Sampling 
In an effort to characterize the etiology should a severe event of IAR occur, an attempt 
should be made to collect blood samples for exploratory analysis as close as possible to 
the event, after acute clinical management steps have been taken. Note that these 
analyses will be tested locally at the site with fresh samples for optimal patient 
management; the choice of the tests for cytokines and complement (which will depend 
on local availability), sample volume and storage conditions should be checked in 
advanced with each site.  
Specifically, blood samples should be obtained for the following tests : 
• 
Cytokine panel, including but not limited to IL-6; measurements of other cytokines 
such as IL-10, IL-2, IFNγ, TNFα should be performed if available in the selected 
panel.  
• 
Complement assessment including at minimum C3 and C4; measurement of CH50 
(total hemolytic complement) and C5b-9 should be performed if available. 
• 
Liver biochemistry, creatinine, CRP, fibrinogen and complete blood count.  
• 
Any additional tests deemed necessary by the Investigator.  
On the day following the IAR, the tests outlined above should be repeated to evaluate if 
the inflammatory response has resolved. Liver biochemistry, creatinine, fibrinogen, and 
complete blood count follow-up testing should also be considered until resolution of the 
IAR and stabilization of the patient.  
 VTX-801 Accountability Procedures 
Records will be maintained of the delivery of VTX-801 vials to the study sites, the 
inventory at the study sites, the allocation to, and use of VTX-801 vials by each patient at 
the site, and the destruction or return of unused VTX-801 vials to the Sponsor. 
These records will include dates, quantities, batch numbers, expiry dates and the unique 
code numbers assigned to the study product and to the study patients.  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 85 of 223 
The Investigator will be responsible for ensuring the records adequately document that 
the patients are given the doses specified in the protocol and all VTX-801 received from 
the Sponsor is reconciled. 
  VTX-801 Compliance 
The assigned study product VTX-801, dosage, timing and mode of administration may 
not be changed. The number and duration of any interruptions of the infusion during 
administration will be recorded in the eCRF. 
As the single VTX-801 administration will be performed under direct medical supervision, 
patient non-compliance with treatment is not anticipated to be a significant issue. 
However, any departures from the intended regimen will be recorded in the eCRF. 
VTX-801 accountability and compliance will be documented throughout the study using 
study-specific dispensing and return record forms. 
7.3 Diluent for VTX-801 
The diluent for VTX-801 will be normal saline for infusion (0.9% sodium chloride in sterile 
water). The diluent will be supplied by the investigational sites.  
7.4 Radiocopper - [64Cu]CuCl2 
Please refer to the Radiocopper IB and Radiocopper Administration Manual for full 
details.  
 
 
 
 
 
 
 
 
 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 86 of 223 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
. 
 Radiocopper Description and Supply 
The radiocopper to be used (64CuCl2) has a half-life of 12.7 hours.  
The sterile ready-to-use injectable solution of radiocopper suitable for intravenous 
administration into humans will be provided to clinical sites. The administration 
instructions will be available in the Radiocopper Administration Manual.  
 Selection of the Radiocopper Dose for this Study 
For each administration of [64Cu]CuCl2 a delivered activity of 
 MBq was chosen. This 
administered activity represents the lowest reasonably achievable activity that will permit 
reliable radioanalysis of biological samples
  
A recent study by Sandahl et al, 2019 aimed to evaluate the diagnostic potential of 64CuCl2 
PET in WD management. The study evaluated the difference in hepatic copper 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 87 of 223 
metabolism in 8 healthy subjects, 5 healthy heterozygote subjects, and 9 WD patients 
after administration of radiocopper (71.2 ± 5.5 MBq). All subjects underwent 64Cu imaging 
by means of dynamic PET/CT of the liver (time 0-90 minutes) and static whole-body 
PET/CT (90 minutes and 20 hours after radiocopper administration). Human 64CuCl2 
PET/CT demonstrated increasing hepatic copper accumulation over a 20-hour period in 
patients with WD compared to healthy and heterozygote controls. 
 
 
 
 
 
 
As summarized in Table 5, a total effective dose for patients in this study is estimated to 
be < 10 mSv, which is well below deterministic thresholds and corresponds to a minor to 
intermediate cumulative risk level based on ICRP Publication 62, 1992. 
A comprehensive review of radiocopper is contained in the IB supplied by Vivet 
Therapeutics. Investigators are to review this document prior to initiating this study. 
 Radiocopper Packaging and Labelling 
The labelling of the radiocopper ready-to-use solution for clinical use will comply with the 
applicable (local) laws and regulations. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 88 of 223 
 Radiocopper Dosage, Preparation and Administration  
During the study, each patient will receive on 3 separate occasions one intravenous 
administration of 
 MBq (±10%) radiocopper.  
Administration of radiocopper will take place under the supervision of an Investigator or 
designee. Before administration of the bolus, 10 mL of sterile sodium chloride solution 
(0.90% w/v of NaCl) will be injected to confirm that the intravenous access is intact. After 
administration of the bolus, the intravenous access will be flushed with 10 mL of the same 
solution. The Investigator or designee will check for extravasation (i.e. using a gamma 
camera or handheld probe) after each radiocopper injection. 
The time of administration of radiocopper will be recorded in the source data and eCRF. 
 Radiocopper Storage, Disposal and Accountability  
Upon receipt of the radiocopper, the responsible person will inspect the shipment and 
return the enclosed acknowledgement of receipt form duly completed and signed 
(date/time point of receipt must be noted). 
In accordance with applicable local Radiation Protection Regulations, the study site is 
responsible for all radiocopper received, processed, stored and disposed. Sites’ trained 
personnel will be responsible for storage in a locked container in the ‘hot room’ (a 
restricted access room) according to instructions provided by manufacturer. Only trained 
personnel will handle the radiocopper. 
After decay below the legal limit, all unused material radiocopper and packaging must be 
disposed by the site according to its standard operating procedure (SOP) on nuclear 
waste.  
The sites’ trained personnel will be responsible for the inventory and accountability of 
radiocopper. 
7.5 Immunosuppressive Regimens 
 
 
All treatments given as part of the immunosuppressive (IS) regimen will be supplied and 
reconciled by the study site in accordance with their local dispensing and accountability 
procedures. The products should be stored, handled and prepared in accordance with 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 89 of 223 
the manufacturer’s instructions. The Investigator will record patient compliance with the 
IS regimen in the eCRF. 
 Prophylaxis of IARs, Immune T-cell Response Against the AAV Capsid and 
  
In order to prevent potential IARs that may occur during or within 24 hours post-VTX-801 
infusion, a single injection of 100 mg of methylprednisolone will be administered 
intravenously prior to any VTX-801 infusion (see Section 7.2.5.1).  
Based upon recent published experience in AAV-based gene therapy trials, mitigation of 
the immune T-cell response against the AAV vector capsid will include oral steroid 
(prednisone or prednisolone) prophylaxis. Furthermore, Sirolimus will be added in order 
to improve such immune modulation regimen. Such a regimen may be useful to optimally 
mitigate the above effects, especially in the context of a liver disorder that may be more 
susceptible to developing reactions to hepatic viral infections. The rationale to use 
Sirolimus in this setting is the known effect on regulatory T-cells, which are essential to 
establish and maintain immune tolerance. Of interest, tacrolimus is currently used in a 
hemophilia AAV-based gene therapy (IV route) trial for the same purpose 
(ClinicalTrials.gov Identifier: NCT03369444). Furthermore, Sirolimus in combination with 
methylprednisolone and rituximab has also been safely co-administered with an AAV4 
vector in a phase I/II trial of intra-diaphragmatic gene transfer in children affected by 
Pompe disease (Corti et al, 2014). Mammalian target of rapamycin (mTOR) inhibitors 
have been shown to be effective and safe in adults and children following solid organ 
transplantation. Interestingly, prospective and retrospective data in pediatric patients (the 
most fragile population in this field) converted from calcineurin inhibitor therapy to mTOR 
inhibition suggest preservation of Immunomodulatory efficacy without adding significant 
risk of side effects (Ganschow et al, 2013 ).  
The IS regimen should be administered according to the protocol below, in line with drug 
labels. 
• Prevention of hypersensitivity reactions:  
 Methylprednisolone 100 mg will be administered IV one hour before the 
VTX-801 infusion.  
• Prevention of T-cell immune response against AAV capsid:  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 90 of 223 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 92 of 223 
 
 
. DMC data monitoring will 
continue and the committee will be informed should any adverse events of interest, 
especially ALT increases, occur after the end of the IS regimen; therefore, the most 
up-to-date safety information will be taken into account in the DMC evaluation and 
recommendation for dose escalation at the next dose level (cf. DMC Charter).  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 93 of 223 
 Mitigation of Overt Transaminase Increase 
7.5.2.1 Surveillance of transaminase increase 
During the post-administration follow-up period, each patient will follow a comprehensive 
surveillance plan monitoring liver biochemistry, including ALT. Instances of ALT ≥ 1.5 x 
baseline (in any laboratory in charge of analysis) up to 9 months post-VTX-801 infusion 
should be reported to the Sponsor within 24 hours of the laboratory value being available; 
reporting is via data entry into the clinical trial database. Laboratory alerts will also be put 
in place where possible. Due to the unknown timing of the potential rise in hepatic 
transaminases, unscheduled visits and blood/urine samples may be necessary to 
evaluate safety and/or potential or suspected loss of efficacy.  
7.5.2.2 Reporting, management and search for etiology of transaminase increase  
In case an ALT increase ≥ 1.5 x baseline is observed between Week 2 and Month 9 post-
VTX-801 administration, and within 24 hours of awareness, the Investigator will enter 
the AE into the eCRF and discuss with the Sponsor medical monitor (or delegate) the 
appropriateness of initiating reactive steroid treatment. 
If the above-mentioned transaminase increase is ALT or AST ≥ 5x ULN (consistent with 
suspected DILI criteria listed in Section 6.3), a DILI form will be completed and reported 
as outlined in Section 9.6. A liver biopsy will be performed as soon as possible (if possible, 
within 24-48 hours), in order to assess the results of the liver biopsy and the respective 
transaminase elevation for causality through HAC adjudication; furthermore, testing of 
liver biochemistry should be repeated within 48 to 72 hours to confirm the abnormalities 
and the patient should be placed in close monitoring and followed until normalization or 
stabilization. Note that DILIs will be evaluated as per current guidelines: Clinical Practice 
Guidelines: Drug-induced liver injury, EASL, 2019 and Guidance for Industry Drug-
Induced Liver Injury: Premarketing Clinical Evaluation, FDA guideline, 2009. 
If the decision is taken to initiate reactive steroid treatment: 
- 
An unscheduled sampling for IFN-gamma ELISpot to AAV3B capsid and 
miniATP7B transgene assays will be taken, ideally before steroid reactive 
treatment initiation. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 94 of 223 
- 
The investigator will perform the evaluation for an alternative etiology for liver 
disease (other than T-cell immune response to VTX-801), including:  
o acute viral hepatitis (immediate testing): 
- 
PCR for HSV, CMV, EBV, HCV 
- 
serology for HAV: HAV IgM  
- 
HBV testing: HBsAg and if positive HBV DNA  
- 
serology for HEV (IgG and IgM) and HEV RNA 
o alcoholic and autoimmune hepatitis: ANA, SMA, and anti-LKM1 auto-
antibodies, as well as total IgG testing, 
o hepatobiliary disorders other than WD,  
o cardiovascular causes,  
o concomitant treatments.  
- 
Reactive steroid treatment: without awaiting all results of the above-mentioned 
evaluations and within 24 hours of receiving the ALT results ≥ 1.5x baseline, if no 
contra-indication has been identified, the patient will be administered oral steroid 
(prednisolone or prednisone) 1 mg/kg per day for 1 week (maximum dose 
60 mg/day), tapered down by 10 mg every week until complete withdrawal 
(whatever the ALT response to reactive prednisolone treatment), replacing the 
prednisolone dose scheduled for T-cell immune response prophylaxis (cf. Section 
7.5.1). Should the schedule of the reactive steroid treatment result in a shorter 
course of treatment than the planned prophylactic steroid treatment, then the 
course of reactive steroids will be prolonged so that it is not shorter (the taper will 
be adjusted by the investigator according to medical judgement). This approach is 
based upon the Clinical Practice Guidelines published by the European 
Association for the study of the Liver on treatment of autoimmune hepatitis, a T-
cell mediated disease of the liver commonly controlled by a steroid course both at 
diagnosis and during relapses (EASL, 2015).  
- 
The DMC will be informed and based on the whole information received, it will 
provide its recommendation to maintain the (altered) regimen or not. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 95 of 223 
- 
In case testing is positive for viral hepatitis, any steroid treatment will be stopped 
or tapered immediately and sirolimus treatment (if still ongoing) will be stopped 
immediately. 
7.5.2.3 HAC assessments and recommendation for patient management 
Data regarding suspected DILI events will be provided to the HAC for adjudication via 
sending of a completed suspected DILI form along with all additional information received 
from site. These events will be followed up as AEs of special interest (AESI; see 
Section 9.6).  
In instances where a liver biopsy was taken, the HAC will assess the liver biopsy report 
for causality and provide its assessment and recommendation to the DMC on whether to 
maintain the reactive steroid regimen or not, and the DMC will then provide their own 
(prevailing) recommendation. 
7.5.2.4 Long-term follow-up  
Patients will then be followed long-term (at least 12-24 months) by monitoring liver 
enzymes to ensure their normalization or stabilization, as well as to ensure the clinical 
status of the patient is stable or normal; in this case, unscheduled biological sampling 
may be added to the planned assessments, as necessary.  
7.6 Other Concomitant Medications/Treatments  
 Contraception 
“Highly-effective” methods of contraception are recommended. A highly-effective method 
of birth control is defined in ICH M3(R2) as one that results in a low failure rate (i.e., less 
than 1 percent per year) when used consistently and correctly, such as implants, 
injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual 
abstinence, or a vasectomized partner (the vasectomized partner must have received 
medical assessment of the surgical success). Note: Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
• Male patients must be willing to use two methods of contraception from the day of 
the first radiocopper injection through 6 months following VTX-801 infusion and also 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 96 of 223 
for the week following the W36 radiocopper injection. Male patients must also not 
donate sperm. All sexually active male patients must use a condom and those with 
female partners of childbearing potential must require their partner to use an additional 
form of adequate contraception as approved by the Investigator, such as an 
established form of hormonal contraceptive, a diaphragm or cervical/vault cap, IUD, 
or sponge with spermicide.  
• Female patients of childbearing potential must be willing to use two methods of 
contraception from signing the informed consent through one week after W36 
radiocopper injection. If using oral contraception, it must have remained unchanged 
for ≥ 3 months prior to inclusion. Female patients using oral contraception should 
refrain from changing their contraception regimen during the study (in accordance with 
inclusion criterion #5, Section 5.2); any change must be recorded in the eCRF. 
• Note: contraception is warranted for both genders after the administration of VTX-801 
as a gene therapy product for 6 months; thereafter, males can stop contraception and 
restart only during Week 36 radiocopper explorations, while females will continue 
contraception up to Week 36 included, in order to prevent any fetal exposure to 
ionizing radiations during Week 36 explorations.  
 Drug Interactions and Prohibited Medications  
Use of known hepatotoxic agents should be avoided as much as possible during the 
course of the clinical trial. 
Sirolimus is known to be a substrate for both cytochrome P-450 3A4 (CYP3A4) and P-
glycoprotein (P-gp). Inducers of CYP3A4 and P-gp may decrease Sirolimus 
concentrations whereas inhibitors of CYP3A4 and P-gp may increase Sirolimus 
concentrations (Rapamune US label and SPC).  
Strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, 
voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of CYP3A4 and 
P-gp are contraindicated during the Sirolimus treatment period. Alternative agents with 
lesser interaction potential with Sirolimus should be considered. 
The dosage of Sirolimus and/or the following co-administered drug may need to be 
adjusted: 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 97 of 223 
• Drugs that could increase Sirolimus blood concentrations: bromocriptine, 
cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, HIV-protease 
inhibitors (e.g., ritonavir, indinavir), metoclopramide, nicardipine, troleandomycin, 
verapamil.  
• Drugs and other agents that could decrease Sirolimus concentrations: 
carbamazepine, phenobarbital, phenytoin, rifapentine, St. John’s Wort (Hypericum 
perforatum).  
• Drugs with concentrations that could increase when given with Sirolimus: 
verapamil. 
• Since Sirolimus has been shown to increase blood lipids (Rapamune US label and 
SPC), the Sirolimus dose may need to be adjusted during the transient Sirolimus 
treatment in patients with abnormal values or treated for hyperlipidemia at 
baseline; such adjustment will be made by the Investigator, in consultation with the 
Sponsor, and will be based upon the routine monitoring of hyperlipidemia in the 
patient, trying to maintain Sirolimus level within the target range as far as possible. 
• Immunosuppressants may affect response to vaccination. Vaccination with live 
vaccine within 30 days before Sirolimus administration is prohibited (cf. Exclusion 
Criteria) up to and including Week 14. The use of non-live vaccines, including for 
COVID-19 or seasonal flu, should be avoided within 2 weeks before Sirolimus 
initiation and up to the end of the Sirolimus treatment. For this reason, if a patient 
is to be vaccinated, according to local recommendations, he/she is encouraged to 
do it before enrolling into the trial. 
• Sirolimus with other drugs known to cause angioedema, such as ACE-inhibitors, 
may increase the risk of developing angioedema; therefore, in case a patient would 
develop new angioedema during the coadministration period, the ACE inhibitor will 
be temporarily replaced by a different medication until the end of the Sirolimus 
administration period, if possible; if not possible, the Sirolimus regimen will be 
interrupted. 
• Since cases of abnormal wound healing have been reported in patients treated 
with Sirolimus, the Investigator will evaluate the risk/benefit of the continuation of 
Sirolimus treatment in case of significant wound (surgical intervention that cannot 
be postponed or accident). 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 99 of 223 
8 STUDY PROCEDURES AND EVALUATIONS 
8.1 Clinical Evaluations 
 Demographics and Medical History 
Demographic and baseline characteristic data will be collected on all patients. Relevant 
medical history/baseline medical conditions including substances usages will be recorded 
in the eCRF. 
Medical history includes Leipzig score (EASL, 2012) from historical records and ATP7B 
genotype. ATP7B genotype is to be assessed from Screening 1, V1A sample, for patients 
without historical genotyping available from a CLIA-certified laboratory. Note: Due to the 
extended time needed to obtain genotyping results, ERC review and patient inclusion and 
treatment may occur before receiving genotyping results, provided that Leipzig score ≥ 4 
based upon the other parameters. 
 Prior and Concomitant Medications  
Prior and concomitant medications (including background WD therapy) will be recorded 
(prescription medications, over-the-counter and herbal remedies).  
Reasonable effort will be made to determine and record all relevant prior treatments (e.g. 
prescription medications, over-the-counter and herbal remedies) or procedures (e.g. 
operative procedures, radiologic tests, biopsies, etc.) received by the patients within 
1 month before Screening until administration of VTX-801. All available WD treatment 
history will be recorded. 
Assessment of eligibility during Screening visits will include a review of permitted and 
prohibited medications. 
Concomitant treatments (e.g. prescription medications, over-the-counter and herbal 
remedies) or procedures (e.g. operative procedures, radiologic test, biopsies, etc.) 
received by the patient will be recorded from VTX-801 administration to last patient study 
visit included.  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 100 of 223 
 Physical Examination 
The physical examination will include: general appearance, skin, head and neck, eyes-
ears-nose-throat, lymph node palpation, lungs, chest, abdomen, extremities, and 
neurological function. 
In the absence of any abnormal findings, the physical examination will be reported 
“normal” for all items in the eCRF. 
Height and BMI will be recorded at screening only. 
Weight will be recorded at each visit that includes physical examination. On Visit 5 
occurring the day before VTX-801 administration only weight will be recorded.  
 Vital Signs 
Vital signs include systolic and diastolic blood pressures (BP), pulse (P), respiratory rate 
(RR), temperature (°C), and should be taken after the patient has been resting supine or 
upright for 5 minutes. 
Additionally, blood pressure and heart rate will be regularly measured during the safety 
follow up period related to VTX-801 administration: 
• prior to VTX-801 administration 
• at 15-minute intervals during the VTX-801 administration duration (+/- 3 min) 
• at the end of the administration  
• 1 hour after the end of the administration (+/- 10 min) 
• and then at 4-hour intervals until night sleep (+/- 15 min) 
All abnormalities should be clearly documented.  
 Electrocardiogram 
12-lead ECG will be recorded; each ECG recording will be retained in the patient’s file 
and uploaded to the vendor’s portal for central reading (refer to Image Acquisition 
Guidelines). ECG recordings will be reviewed locally by the Investigator or delegate for 
immediate action if needed. In addition, ECG will be analyzed systematically by a central 
reading vendor based on following parameters: heart rate, QRS axis, PR interval, QRS 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 101 of 223 
duration and QT and QTc (Fridericia (primary) and Bazett formulas). In case of 
discrepancy between local and central interpretation, central reading and interpretation 
will prevail. 
Patients will be in a lying position for 5 minutes prior to the measurements. ECGs will be 
evaluated and classified as normal/abnormal. In case of “abnormal”, the abnormality has 
to be described.  
 Ophthalmology 
A slit lamp eye examination will be performed, and abnormalities will be documented, in 
particular the presence or absence of a Kayser-Fleischer ring. Additional gross 
ophthalmic abnormalities, if any detected at examination, will be reported as well.  
Examination can be performed any time from Baseline V2 to before the day of 
radiocopper administration as long as results are available before the day of radiocopper 
administration. 
 Questionnaires 
The Unified Wilson's Disease Rating Scale (UWDRS) and Mini-International 
Neuropsychiatric Interview (M.I.N.I.) will be used to assess neurological and psychiatric 
symptoms at Screening 1 and 2 (UWDRS part II and III only), baseline (excepted M.I.N.I), 
Weeks 12, 36 and 52 in Year 1 and, at 6 months and 12 months visits in Years 2 to 5. 
The Montreal Cognitive Assessment (MoCA) will be performed at Screening 2 to exclude 
patients having dementia or moderate to severe cognitive impairment. 
The Symbol Digit Modality Test (SDMT) and Stroop Test will be used to assess executive 
functions at baseline, W12, W52 and every 12 months visits in Years 2 to 5. 
The M.I.N.I Screening 2 results will be used as baseline data. Baseline UWDRS, Stroop 
and SDMT can be performed any time from Baseline V2 to the day before radiocopper 
administration as long as results are available before the day of radiocopper 
administration. 
UWDRS will be conducted by a trained neurology specialist and M.I.N.I., MoCA, SDMT 
and Stroop Test by a trained medical doctor or designee, ideally the same Healthcare 
Provider (HCP) will conduct the same assessment(s) throughout the study. At least two 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 102 of 223 
appropriate staff representatives for each site will be trained to administer the 
questionnaires to allow for a replacement, as needed. 
In a situation where a patient cannot reliably report a change in symptoms, a capable 
caregiver will be involved in providing assessments regarding changes in mood or 
function. The same caregiver should provide the assessments at each visit, if possible. 
 Abdominal MRI, Liver MR Elastography  
Abdominal MRI (to detect any gross abnormalities) and MR liver elastography will be 
performed either at Screening 1 (V1A) or Screening 2 (V1B) (to also include MRI for liver 
volume) and Week 52 (end of Year 1) and at each 12-month visit of Years 2 to 5. In case 
of initial screening failure, the abdominal MRI and MR liver elastography, if any, may be 
re-used for re-screening if no longer than two months have elapsed between screening 
assessments.  
The abdominal MRI and MR liver elastography results at Screening 1 or 2 will be used as 
baseline data. 
• The elastography must be performed in at least a 4-hour fasted state. 
All the abdominal MRI and MR liver elastographies will be analyzed by a central reading 
vendor. 
In case of contraindication to abdominal MRI and MR elastography, these will be replaced 
by non-centralized hepatic ultrasound and Vibration-controlled transient elastography 
(Fibroscan®), respectively. If performing Fibroscan®, both liver stiffness and CAP score 
should be collected at the site. Any AEs will be collected. 
In case where the site is equipped with MRI but not MR elastography, vibration-controlled 
transient elastography should be used instead of the MR elastography. In any case, the 
Sponsor should be notified of the change. 
 Brain MRI 
Brain MRI will be performed at Screening 1 or 2 and at the 12-month visit of Year 3 (V52), 
and at the end of the 5-Year follow up. In case of initial screening failure, the brain MRI, 
if any, may be re-used for re-screening if no longer than two months have elapsed 
between screening assessments.  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 103 of 223 
The results at Screening 1 or 2 will be used as baseline data. 
Brain MRI will be analyzed by a central reading vendor. 
In case of contraindication to brain MRI, it will be neither performed nor replaced. 
 Central and Local Laboratories for Standard Clinical Evaluations 
Several blood and urine samples will be taken throughout the study for analysis at either 
the site (“Local”) or Central Laboratories. 
Local Laboratory data will be entered into the eCRF by the site. In case of discrepancy 
between Local and Central Laboratory data for a same visit, Central Laboratory data will 
prevail. 
The instructions for sample collection, specimen preparation, handling, storage and 
shipping are described in the Central Laboratory Manual. 
The main Central Laboratory will provide the site with the corresponding kits to support 
the management of all samples, from preparation of sampling to sending samples to 
respective Central Laboratories. 
 Central Laboratory Standard Evaluations 
Table 7 lists the standard parameters to be analyzed by the Central Laboratory. Please 
refer to Table 8 for the Liver Biochemistry Panel sampling frequency and the Schedule of 
Events for the related time points. 
 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 105 of 223 
triglycerides and total cholesterol is included at Screening 1, Screening 2, Week 4 and 
Week 8. 
Each patient will have a comprehensive surveillance plan which monitors liver enzymes 
and liver function tests post administration of VTX-801. It will include a test at each visit 
occurring either on site or at home (home nurse) and twice a week sampling between 
Week 4 and Week 12. Additionally, availability of laboratory results will be optimized in 
order to ensure quick Investigator accessibility to the results (less than 3 days) to make 
a decision on further action. 
Furthermore, reports of abnormal ALT (defined as ≥ 1.5 x baseline) will also be made 
available to Sponsor within 24 hours of the laboratory value being available (cf. Section 
7.5.2).  
Remnant blood and urine samples may be used for future biomarker explorations 
(excluding any genotyping) as data emerges; this will be the subject of an optional 
approval by patients in the informed consent (tick box). 
Table 8 outlines the frequency of sampling of liver biochemistry parameters after VTX-801 
administration, including both locally and centrally analyzed samples. 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 110 of 223 
• An additional NAb test will be performed shortly before VTX-801 administration 
(Day 1, Visit 6), then 1 month after VTX-801 administration (Week 4, Visit 10) and 
at the end of the 1-year follow up (Visit 46). 
 Genotyping 
Patients will have a sample taken for genotyping at or before Screening 1, in case biallelic 
pathogenic or likely pathogenic ATP7B variants have not been already identified in a 
CLIA-certified laboratory as part of their medical history (see Section 8.1.1).  
Note: Due to the extended time needed to obtain genotyping results, ERC review and 
patient inclusion and treatment may occur before receiving genotyping results, provided 
that Leipzig score ≥ 4 based upon the other parameters. 
 Viral Vector Shedding  
In order to detect and follow up the presence of the AAV in different substrates (blood, 
urine, saliva, feces), samples will be collected at specific patient visits until 3 consecutive 
samples are negative for the concerned substrate after VTX-801 administration: 
• Mandatory:  
• Baseline (starting after last radiocopper sampling and stopping within 24 hours 
before VTX-801 administration; note that permitted window for VTX-801 is +7D 
during which period viral vector shedding samples can be taken) 
• Day 2 post-VTX-801 administration, Week 2 and Week 4 site visits 
• Based on results: Discontinuation of sampling (for a given substrate) once 3 
consecutive samples are negative (≤quantification limit). Site will be informed of the 
shedding results as soon as possible in order to avoid performing unnecessary 
sampling for a given substrate. 
• During each of the Week 12 and Week 36 period of 4 consecutive visits (V26 to V29 
and V39 to V42 respectively), only 1 sample per substrate will be taken per period and 
if applicable. 
For the shedding samples related to feces, all efforts will be done to get the required 
number of feces samples as per protocol, considering the uncertainty related to patient’s 
bowel movements. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 113 of 223 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 114 of 223 
8.3 Total Blood Volume 
The maximal total volume of blood to be taken per patient during the entire course of the 
study will be as follows: 1,488 mL Refer to Appendix 17.1. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 115 of 223 
9 ASSESSMENT OF SAFETY 
9.1 Specification of Safety Parameters 
The safety of the study intervention will be assessed through the recording, reporting and 
analyzing of baseline medical conditions, AEs, general physical examination, laboratory 
tests, and vital signs data. The timing and frequency of safety assessments are described 
in Section 9.2.6. 
9.2 Adverse Events 
 Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in the form of signs, symptoms, 
abnormal laboratory findings, or disease that emerges or worsens during an interventional 
clinical study with an IMP or NIMP, regardless of causal relationship and even if no IMP 
or NIMP has been administered. 
Worsening of a pre-existing medical condition, (e.g., migraine headaches, gout) is to be 
considered an AE if there is either an increase in severity, frequency, or duration of the 
condition or an association with significantly worse outcomes. 
 Severity of Adverse Events 
AEs will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0, 2017 grading system. The CTCAE v5 grading criteria must be used 
when available for an AE. Only when CTCAE v5 grading criteria are not available for a 
specific AE, will the Investigator assess the severity of the AE based on the following 
definitions:  
• Grade 1 (mild): the patient is aware of the event or symptom, but the event or 
symptom is easily tolerated. 
• Grade 2 (moderate): the patient experiences sufficient discomfort to interfere 
with or reduce his or her usual level of activity. 
• Grade 3 (severe): the patient is unable to carry out usual activities due to 
significant impairment of functioning. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 116 of 223 
• Grade 4 (life-threatening): the patient’s life is at risk from the event. 
• Grade 5 (fatal): the event results in the patient’s death. 
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
 Causality Assessment 
The Investigator will determine whether or not, in his/her opinion, the AEs are related to 
VTX-801 according to the following definitions: 
Relationship to VTX-801 
• Unrelated: The AE is temporally independent of study product and/or the event 
appears to be explained by another etiology  
• Unlikely related: The AE has a time to drug intake that makes a relationship 
improbable (but not impossible) and/or disease or other drugs provide plausible 
explanations 
• Possibly related: The AE has a reasonable time sequence to administration 
of the drug, but could also be explained by concurrent disease or other drugs 
or chemicals. Information on drug withdrawal may be lacking or unclear 
• Probably related: The AE has a reasonable time sequence to administration 
of the drug, is unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information (if applicable) is not required to fulfil this 
definition 
• Definitely related: The AE occurred in a plausible time relationship to drug 
administration, and cannot be explained by concurrent disease or other drugs 
or chemicals. The response to withdrawal of the drug (dechallenge) should be 
clinically plausible. The event must be definitive pharmacologically or 
phenomenologically. A satisfactory rechallenge procedure (if applicable) may 
be utilized if necessary 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 117 of 223 
• In addition, the Investigator will also determine whether the AEs are definitely, 
probably, possibly, unlikely related or unrelated with the study procedures and 
radiocopper. 
• Relationship assessments will be captured in the eCRF in all cases. 
The DMC will also review all liver and neuropsychiatric TEAEs (on an ad-hoc basis if they 
meet the SAE/AESI or Stopping Rules criteria and at patient level/cohort level review for 
all other events) and provide supplemental causality assessment in addition to 
Investigator assessment. These assessments must be submitted to the FDA for review, 
either as individual case safety reports (for SUSARs) or as aggregate reports (for all other 
events). 
The liver and neuropsychiatric serious TEAEs will be reported to the DMC (within 24 
hours) and expeditiously adjudicated by the HAC in case of suspected DILI or by the DMC 
in case of neuropsychiatric TEAE (if possible, within 48 hours). All SUSAR will be reported 
to the FDA and the other concerned Regulatory Authorities as per regulatory timeline (7 
to 15 days). 
 Abnormal Laboratory Test Values and Other Objective Measurements 
Abnormal laboratory findings and other objective measurements such as vital signs and 
ECGs, should NOT routinely be captured and reported as AEs as they will be collected 
and analyzed separately in the eCRF. However, abnormal laboratory findings and other 
objective measurements which (i) meet the criteria for a SAE or (ii) result in early 
discontinuation or in treatment being interrupted, (iii) require medical intervention or (iv) 
are considered clinically significant should be captured and reported in the AE pages of 
the eCRF. 
If reporting an abnormal laboratory finding in the AE pages of the eCRF, a clinical 
diagnosis should be recorded rather than the abnormal value itself, if available (for 
example “anemia” rather than “decreased RBC count” or “hemoglobin = 10.5 g/dL”). 
 Eliciting Adverse Events 
AEs will be obtained by the Investigator at scheduled or unscheduled study visits, 
following physical examination, based on information spontaneously provided by the 
patient and/or through questioning. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 118 of 223 
To elicit AEs, simple questions with minimal connotations should be used as the initial 
questions at all evaluation points during the study. For example: 
• How have you felt since your last visit? 
• Have you had any health problems since you were here last? 
In the case that a patient was seen by a health care professional other than the 
Investigator (e.g., at a different institution) concerning an AE, every effort should be made 
by the Investigator to contact the treating physician in a timely manner in order to obtain 
all necessary information and report the event appropriately. 
 Recording Adverse Events 
As quality and precision of acquired AE data is of key importance, the Investigator should 
use the AE definitions provided in above sections and observe the following guidelines 
when completing the AE pages of the eCRF: 
• Whenever possible, recognized medical terms should be used to describe AEs rather 
than colloquialisms (for example, ‘influenza’ rather than ‘flu’), and abbreviations should 
be avoided. 
• AEs should be described using a specific clinical diagnosis rather than component 
signs or symptoms, if this is available (for example, ‘congestive heart failure’ rather 
than ‘dyspnea, rales and cyanosis’). However, signs and symptoms considered 
unrelated to an identified disease or syndrome should be reported as individual AEs 
in the eCRF. 
• AEs occurring secondary to other events (e.g., sequelae or complications) should be 
identified by the primary cause. A primary AE, if clearly identifiable, generally 
represents the most accurate clinical term to record in the AE pages of the eCRF. 
Additional guidance can be found in the eCRF completion conventions provided by the 
Sponsor. 
An Adverse Event (AE) is any untoward medical occurrence in a study subject which is 
temporally associated with the use of a medicinal product or study conduct, regardless of 
its potential relationship to the medicinal product or study conduct. An AE, therefore, can 
be any unfavorable or unintended sign, including any abnormal laboratory finding, 
symptom, or disease (new or exacerbated), whether or not related to the IMP or study 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 119 of 223 
conduct. AEs should be followed-up in accordance with the procedures described in 
Section 9.2.7. 
AEs will be captured differently in the eCRF depending on the date of onset and causality 
assessment (per Investigator’s judgment) as described below: 
Table 16 
Capture of Adverse Events in the eCRF 
AE onset date 
Types of AEs to be captured in the eCRF 
From signing the ICF, including 
Screening 1 and until start of 
Screening 2 
• Only AEs considered to be possibly, probably or 
definitely related to the study procedures  
From Screening 2 included until 
1-year post VTX-801 infusion 
visit included 
• All AEs 
After the 1-year post infusion 
visit until completion of the 
5-year follow-up visit included 
• All AEs except those AEs incontrovertibly 
unrelated to VTX-801, radiocopper and study 
procedures  
After the 5-year follow up period • Only SAEs considered to be possibly, probably or 
definitely related to VTX-801 
Abbreviations: AE= Adverse Event; eCRF= electronic Case Report Form; ICF= Informed Consent form; SAE= Serious 
Adverse Event.  
Note: The above table refers to newly onset AEs. Follow-up details regarding the AEs 
previously entered into the eCRF will be captured regardless of the type of AE. (Refer to 
Section 9.2.7). 
 Follow-up of Adverse Events 
Follow-up of AEs is defined as follows: 
• The AEs which occur after signing the ICF and up to completion of the 5-Year follow-
up period after VTX-801 administration will be recorded in the AE pages of the eCRF 
per the criteria defined above. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 120 of 223 
• All AEs that were previously captured in the eCRF, and all SAEs, will be followed until 
resolution or until the Investigator assesses them as ‘chronic’ or ‘stable’. 
• If the Investigator becomes aware of a SAE, including death, after the 5-Year follow-
up period and the SAE is considered by the Investigator to be possibly, probably or 
definitely related to the study product, it will be reported to the designated CRO safety 
group in accordance with Section 9.3.2. 
Taking the above post-treatment safety surveillance reporting requirements into account, 
AE follow-up information data will be recorded in the AE pages of the eCRF up until Last 
Patient Last Visit. 
After Last Patient Last Visit and 2 weeks prior to any data lock, the status of all 
outstanding ongoing AEs will be checked and any up-to-date change made in the eCRF. 
At that stage, as considered appropriate by the Sponsor, follow-up information will 
continue to be requested from the Investigator on specific AEs (and in any case all SAEs 
considered possibly, probably or definitely related to the study product by the Investigator) 
although related details will not be recorded in the eCRF beyond database lock. 
9.3 Serious Adverse Events 
 Definition of Serious Adverse Event 
A SAE is defined as an AE which meets one of the following criteria: 
• Results in death. 
• Is life-threatening (defined as a patient at immediate risk of death at the time of the 
event). 
• An event requiring inpatient hospitalization or prolongation of existing 
hospitalization.  
Note: In general, hospitalization signifies that a person has been detained (usually 
overnight) at a hospital or emergency ward for observation and/or treatment. Emergency 
room visits which do not result in admission to the hospital should be evaluated for one 
of the other serious outcomes (e.g., life-threatening; required intervention to prevent 
permanent impairment or damage; other serious, medically important event).  
• Results in a persistent or significant disability/incapacity. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 121 of 223 
Note: The term significant disability/incapacity means a substantial disruption of a 
person’s ability to conduct normal life functions, i.e., the AE resulted in a significant, 
persistent or permanent change, impairment, damage or disruption in the patient’s body 
function/structure, physical activities and/or quality of life. 
• Is a congenital anomaly or birth defect in the case of pregnancy. 
• Any other important medical event that may not result in death, be life threatening, 
or require hospitalization, may be considered a serious adverse experience when, 
based upon appropriate medical judgment, the event may jeopardize the patient 
and may require medical or surgical intervention to prevent one of the outcomes 
listed above. 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 inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the above criteria. An AE of severe intensity 
might not necessarily be considered serious. For example, persistent nausea for several 
hours may be considered severe, but not a SAE. Conversely, a stroke resulting in only a 
limited degree of disability may be considered mild, but would be a SAE. 
SAEs will be: 
• Recorded in the eCRF if the criteria described in Section 9.2.6 (Table 15) are met. 
• Reported in accordance with the procedures described in Section 9.3.2. 
• Followed until resolution, stabilization or until determined to be chronic by the 
Investigator. 
• Reviewed and evaluated by the Investigator. 
 Reporting of Serious Adverse Events and Adverse Events of Special 
Interest 
Any SAE meeting the criteria described in Section 9.2.6 (Table 15), any AESI meeting 
the definitions in Section 9.6, or any event applicable to the study Stopping Rules must 
be entered into the eCRF within 24 hours of first awareness of the event by study 
personnel. A causality assessment must be provided at the time of reporting and a 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 122 of 223 
narrative should also be provided. Any SAEs experienced after the 5-Year follow up 
period should be reported to the designated CRO designee safety group if the Investigator 
has assessed that the SAE is possibly, probably or definitely related to IMP 
administration.  
Entry of an SAE/AESI (or updated SAE/AESI information) into the eCRF will trigger an 
automatic alert to the designated CRO Safety group (Aixial). 
If the EDC system is not available, SAEs/AESIs should be reported by emailing or faxing 
a completed paper SAE/AESI Report Form to the designated CRO safety group within 24 
hours of site awareness. The SAE/AESI may be reported by telephone; however, this 
must be followed up within 24 hours with either a completed paper SAE/AESI Report 
Form (if EDC system is still not available) or by recording it into the eCRF (if EDC 
becomes available in the meantime). Additionally, it may be necessary for the designated 
CRO safety group to communicate with the Investigator if additional information is 
required. Note: when EDC becomes available, the SAE/AESI Report must still be entered 
in the eCRF despite the paper SAE Form being submitted. 
During both business and non-business hours, the email address, telephone and fax 
numbers listed below can be used to notify the designated CRO safety group. If a paper 
SAE/AESI Report Form is submitted via email or fax and no acknowledgement is received 
within one working day, the report should be re-submitted. 
Reportable Events Hotline: 
Aixial Group CRO (formerly Cmed) 
Email: 
 
 
 
 
 
All additional follow-up evaluations must be reported within 24 hours of site awareness, 
following the same processes. The Sponsor is responsible for complying with applicable 
regulatory reporting requirements for SAEs and, where necessary, for ensuring the 
relevant authorities are notified (see Section 9.4). The Investigator will ensure the 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 123 of 223 
appropriate IRBs/IECs are notified of the SAE in accordance with ICH GCP and local 
regulatory requirements. 
9.4 Regulatory Reporting of Safety Events 
Following notification from the Investigator, the Sponsor and/or its designee (CRO) will 
report adverse events which are both serious and unexpected (not previously described 
in the reference safety information in the approved IB) and that are possibly, probably or 
definitely related with the IMP (otherwise known as SUSARs) to the FDA, EMA, other 
concerned Regulatory Authorities, IRB/IECs and Investigators within the required 
timelines as specified in 21 CFR Part 312.32, EU Directive 2001/20/EC, the European 
Commission’s “Detailed guidance on the collection, verification, and presentation of 
adverse event/reaction reports arising from clinical trials on medicinal products for human 
use” (CT-3, June 2011), ICH GCP Guidelines and other applicable national regulatory 
requirements. Typically, fatal and life-threatening SUSARs must be reported within 7 
calendar days and all other SUSARs must be reported within 15 calendar days. All SAEs 
designated as not related to the IMP, will be reported to the concerned Regulatory 
Authorities, and IRB/IECs at least annually in a summary format.  
Additionally, adverse events may occur during a clinical trial which do not fall within the 
definition of a SUSAR and thus are not subject to the reporting requirements for SUSARs, 
even though they may be relevant in terms of patient safety. Examples are new adverse 
events related to the conduct of a trial or the development of an IMP likely to affect the 
safety of patients such as:  
• A SAE which could be related with the trial procedures and which could modify the 
conduct of the trial. 
• A significant hazard to the patient population such as lack of efficacy of an IMP 
used for the treatment of a life-threatening disease. 
• A major safety finding from a newly completed animal study (such as 
carcinogenicity). 
• A temporary halt of a trial for safety reasons, e.g. in accordance with Stopping 
Rules (see Section 6.3); or if the trial is conducted with the same IMP in another 
country by the same Sponsor, recommendations of the DMC, if any, where 
relevant for the safety of patients. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 124 of 223 
These adverse events/observations are not to be reported as SUSARs, but they might 
require other action, such as urgent safety measures and their notification, substantial 
amendments, or early termination of the trial, and shall be reported in accordance with 
applicable local regulations and guidelines. 
In addition, the liver and neuropsychiatric serious TEAEs will be reported to the DMC 
(within 24 hours of awareness) and expeditiously adjudicated by the HAC in case of 
suspected DILI or by DMC in case of neuropsychiatric TEAE (if possible, within 48 hours). 
If the SAE is also unexpected, i.e., a SUSAR, this SAE must be timely reported to FDA 
and the other concerned Regulatory Authorities as per regulatory requirements (within 7 
to 15 calendar days). The DMC will review all liver and neuropsychiatric TEAEs and 
provide supplemental causality assessment in addition to PI assessment and these 
assessments must be submitted to FDA for review. In addition, all TEAEs, irrespective of 
causality and grade, will be submitted in the Clinical Study Report. 
9.5 Reporting of Pregnancy 
In case of unexpected ongoing pregnancy in a female study participant at the time of 
radiocopper related assessments, despite the contraceptive measures, the radiocopper 
administration and assessments should not be performed and the Sponsor will be 
notified. 
If any female partner of a male patient who has been exposed to VTX-801 becomes 
pregnant and the presumed date of conception falls after the date VTX-801 or 
radiocopper was administered then the pregnancy will be documented, based on 
information provided by the patient, subject to specific written consent provided by the 
pregnant partner. Taking into consideration the presumed date of conception, all 
pregnancies that occur after VTX-801 or radiocopper exposure and during the entire 
study following VTX-801 infusion will be recorded in the eCRF. 
For female patients, all pregnancies that occur after ICF signature will be recorded in the 
eCRF. Any pregnancy occurring after VTX-801 or radiocopper exposure will be followed 
up for outcome. 
Any pregnancy (either female study participants or female partners of male study 
participants) must be followed up to determine course and outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 125 of 223 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Consent to report information regarding pregnancy outcome will be obtained from the 
female partners of male study participants.  
Although pregnancy itself is not considered an AE, it must be reported in the same 
timelines as a SAE, but by using the paper Pregnancy Notification Form. The form must 
be completed and forwarded via email or fax to the designated CRO safety group using 
the email address or fax number listed in Section 9.3.2 within 24 hours of the Investigator 
becoming aware of the pregnancy.  
If the outcome or course of the pregnancy involves a SAE (e.g., a congenital anomaly) 
then the SAE Form should be completed in addition to the updated Pregnancy Notification 
Form. Spontaneous abortions and congenital birth defects should always be reported as 
SAEs (see Section 9.3.1). 
9.6 Adverse Event of Special Interest  
A serious or non-serious event of scientific and medical concern specific to a Vivet 
Therapeutics’ product or program, for which ongoing monitoring and rapid communication 
by the Investigator to the Sponsor and CRO can be appropriate. Such an event might 
warrant further investigation in order to characterize and understand it. 
AESIs are reportable to the designated Aixial DSPV group from the time of VTX-801 
administration regardless of seriousness or causality. Upon receipt, these AEs will be 
captured in the safety database, targeted follow-up queries will be sent to sites, and 
source documentation will be sent to the DMC and / or HAC (as outlined in the respective 
study committee charters).  
The AESIs for this study (defined at any timepoint in the study after VTX-801 
administration) are: 
• 
DILI as defined in Section 6.3. 
• 
ALT ≥ 1.5 x Baseline. 
• 
Neurological, psychiatric or behavioral AEs (either new or worsening from baseline).  
• 
Copper deficiency as defined in Section 9.7. 
• 
CTCAE Grade 3 or 4 AEs triggering stopping criteria (defined in Section 6.3). 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 126 of 223 
• 
Newly diagnosed malignancy after VTX-801 administration if not reported as SAE 
(see Section 6.3). 
• 
Biochemical deterioration after WD background treatment withdrawal (see 
Section 4.6). 
• 
Other events identified in medical review of special interest as agreed by the 
Sponsor medical monitor. 
Any confirmed or suspected AESIs will be closely monitored by the Investigator and 
reported to the designated CRO and Vivet following the same procedure as for SAEs, as 
described in Section 9.3.2. 
9.7 Copper Deficiency Detection and Management 
In case a patient would develop copper deficiency at any time during the trial, the following 
rules will apply: 
Criteria suggesting overtreatment: 
• 24h urinary Cu < 20 µg/day (after 2 days chelator wash-out if on chelators or 
dual chelator and zinc therapy) 
• Absolute Neutrophil Count < 1,000/µL 
• CuEXC < 0.40 µ/mol/L  
If the patient meets any of the criteria listed above, 24h urinary Cu should be done or 
repeated (after 2 days chelator wash-out if on chelators or dual chelator and zinc therapy) 
and a blood cell count will be performed. If the CBC shows anemia, a peripheral blood 
smear analysis including corrected reticulocyte count will also be performed. 
• If new value of 24h urinary Cu < 20 µg/day, overtreatment is confirmed  
o For patients on SoC treatment, SoC treatment should cease 
o For patients off SoC treatment:  
- 
if 24h urinary Cu < 20 µg/day and patient is neutropenic or has 
sideroblastic anemia, or develops symptoms consistent with 
copper deficiency myelopathy (see below), then Cu replacement 
is warranted. Initial treatment will be with Copper Gluconate 2 mg 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 127 of 223 
per os, three times a day for 7 days (Huff et al, 2007). Length of 
treatment and dose adjustment will depend on response and will 
be guided by the site Investigators and the DMC; 
- 
if 24h urinary Cu < 20 µg/day but without neutropenia or 
sideroblastic anemia, then the patient is expected to rebalance Cu 
stores through dietary intake and Cu replacement is not required. 
• If new value of 24h urinary Cu ≥ 20 µg/day, no treatment change is required.  
Other signs including confirmed sideroblastic anemia, pancytopenia and posterior cord 
syndrome are late complications. Suspicion of copper deficiency should prompt a formal 
neurological exam looking for findings of copper deficiency myelopathy (posterior cord 
syndrome), and if abnormal, imaging of the spine by MRI to assess for demyelination, or 
other evaluation(s) deemed appropriate by a neurology consultant.  
Any patient who develops copper deficiency will be monitored closely and carefully until 
normalization or stabilization of biochemical abnormalities and clinical symptoms, if 
present. 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 128 of 223 
10 STUDY SCHEDULES 
The study is divided into 4 periods, each associated with a specific Schedule of Events 
Table, as follows: 
Table 1 
The Screening period. 
Table 2 
Baseline, VTX-801 administration and follow-up to and including Week 12. 
Table 3 
Follow-up until completion of Year 1 period post-VTX-801 administration 
(Week 13 to Week 52). 
Table 4 
Years 2-5 follow-up period post-VTX-801 administration. 
The Study Schedules of Events include several visit categories, as follows: 
Site visit 
The visit occurs at site.  
It is either an “outpatient” or “inpatient” visit. 
Outpatient visit 
The patient comes to and leaves the hospital the same day without 
being hospitalized. 
Inpatient visit 
The patient comes to the hospital and is hospitalized for as long as 
it is required. 
Home nurse visit The visit will take place either at the patient’s home, performed by 
a “home nurse” to collect samples or at site at the Investigator’s 
discretion and with the patient’s agreement. This type of visit can 
be planned for all types of assessments/retests (for which the home 
nurse is qualified and trained accordingly) as needed. 
When samples are taken by the home nurse, they will be sent to 
the central lab, unless otherwise agreed in writing between the site 
and Sponsor. 
Phone calls 
Four phone calls are planned instead of site visits. At the discretion 
of the Investigator, these visits can occur on site. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 129 of 223 
- Two phone call during which patient will be informed by the 
Investigator about their Responder status and associated actions. 
- Two phone call or a video consultation during which Investigator 
will check patient health and occurrence of any AE since the last 
visit. 
 
Visits, Weeks and Months numbering: 
• The Study Day 1/ Week 1 starts from administration of VTX-801.  
• Flexibility of up to 7 additional days for VTX-801 administration is allowed if 
needed in order to comply with radiocopper production constraints or to 
accommodate the sites and/or patients. Initiation of the Sirolimus treatment 
 
 will then need to be shifted 
accordingly (start 7 days prior to VTX-801 administration). 
• As such, any visit with a Day, Week or Month with no negative number refers 
to timing after VTX-801 administration (for example: Day 8; Week 2). 
10.1 Visits 1A and 1B: Screening Period 
 Visit 1A - Screening 1 
Refer to Table 1 Summary of Schedule of Events: Screening 
Visit 1A 
Minimum 6 to 8 
weeks before 
Screening 2 
Screening 1 Outpatient visit Cross-reference 
Signed and dated informed consent 
Section 14.3 
Demographics, medical history and Leipzig score (taken from 
historical records) 
Section 8.1.1 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 130 of 223 
ATP7B genotype (mandatory for those patients without an 
historical genotyping available from a CLIA-certified laboratory) 
Note: Due to the extended time needed to obtain genotyping 
results, ERC review and patient inclusion and treatment may occur 
before receiving genotyping results, provided that Leipzig score ≥ 
4 based upon the other parameters 
Section 8.2.2 
UWDRS part II and III, M.I.N.I  
Section 8.1.7 
Vital signs  
Section 8.1.4 
Weight and height recording, Body Mass index 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Brain MRI (to be performed at V1A (Screening 1) or V1B 
(Screening 2) 
Section 8.1.9 
Abdominal MRI including liver volume; Liver MR elastography. 
Elastography (to be performed in a > 4 hours fasted state)  
Note: These assessments are to be performed either at V1A 
(Screening 1) or V1B (Screening 2)  
Section 8.1.8 
Central Laboratory: blood/urine biochemistry with lipid panel, 
hematology; Coagulation.  
Fasting conditions are required for the lipid panel. 
Section 8.1.11 
Central laboratory: Hematology 
Section 8.1.11 /  
Table 7 
Central Laboratory: Liver panel biochemistry 
Section 8.1.11 /  
Table 7 
Ceruloplasmin (enzymatic assay and nephelometry), CuEXC, 
REC and total Cu. 
Section 8.1.13  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 131 of 223 
24-hour urinary copper 
Section 8.1.13  
Anti-AAV3B capsid neutralizing antibodies 
Section 8.2.1 
Local laboratory urine drug test screen: amphetamines, cocaine, 
opiates, phencyclidine. 
Section 8.1.12 
Adverse events 
Section 9.2 
Prior medications, including background WD therapy history 
Section 8.1.2 
 
 Visit 1B - Screening 2 
The duration of Screening 2 sampling is about up to 5 weeks. The screening will occur 
from Day -49 to Day -14 (+/- 5 days) to assess eligibility. 
Laboratory values and alcohol consumption details during the past year for patient 
eligibility will be those from Screening 2 assessments (V1B); if laboratory results fall 
outside study entry criteria on initial assessment, they may be repeated, only after 
Sponsor approval is granted. If needed, retest samples for standard exams (hematology, 
blood/liver biochemistry, urinalysis) can be assayed locally at the site or using a home 
nurse visit.  
In case of initial screening failure, the liver biopsy, if already collected, may be re-used 
for re-screening if not older than 3 months. 
In order to fulfil inclusion criterion #7 (Section 5.3), stable laboratory parameters used to 
assess copper metabolism, i.e, 24-hour urinary copper, free serum copper, such as non-
ceruloplasmin copper (NCC) or CuEXC, as well as liver enzymes, hemoglobin, and white 
blood cell count should be stable (no significant change), on at least 2 occasions 
assessed 6 to 8 weeks apart prior to enrollment (ERC assessment). The interval may be 
extended beyond 8 weeks for logistical reasons. As a consequence, the first 
corresponding sampling will occur at Screening 1 and the second sampling will occur at 
Screening 2 at the latest. 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 132 of 223 
Refer to Table 1 Summary of Schedule of Events: Screening 
Visit 1B 
Day -49 to 
Day -14 
Screening 2 
Outpatient visit Cross-reference 
Eligibility (inclusion/exclusion criteria) 
Section 5 
Medical history 
Section 8.1.1 
UWDRS part II and III, M.I.N.I, MoCA 
Section 8.1.7 
Vital signs  
Section 8.1.4 
Physical examination, weight and BMI calculation  
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Brain MRI  
Note: Only to be performed at V1B (Screening 2) if not already 
performed at V1A (Screening 1) 
Section 8.1.9 
Abdominal MRI including liver volume; Liver MR elastography. 
Elastography to be performed in a > 4 hours fasted state  
Note: Only to be performed at V1B (Screening 2) if not already 
performed at V1A (Screening 1) 
Section 8.1.8 
ECG 
Section 8.1.5 
Urine pregnancy test (for Women of Childbearing Potential 
[WOCBP] only) 
Section 8.1.11 
Viral serology  
Section 8.1.11 
Tuberculosis test (QuantiFERON®-TB Gold)  
Section 8.1.12 
Alpha-fetoprotein 
Section 8.1.12 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 133 of 223 
Central Laboratory: blood/urine biochemistry with lipid panel, 
hematology; Coagulation  
Fasting conditions are required for the lipid panel. 
Section 8.1.11 
Central Laboratory: Liver panel biochemistry 
Section 8.1.11 
Ceruloplasmin (enzymatic assay and nephelometry), CuEXC, 
REC and total Cu  
Section 8.1.13 
24-hour urinary copper  
Section 8.1.13 
Anti-AAV3B capsid neutralizing antibodies 
Section 8.2.1 
Local laboratory urine drug test screen: amphetamines, 
cocaine, opiates, phencyclidine,  
Section 8.1.12 
Liver biopsy (All efforts should be made to collect liver biopsies 
for each patient as described in the schedule of events. However, 
for the dose escalation cohorts only, if a patient declines to have 
liver biopsies taken, these can be replaced with Fibroscan®. 
Should Fibroscan® be used instead of liver biopsy at Screening, 
this should be implemented for the rest of the study, to ensure 
consistency for the longitudinal analysis). 
Section 8.2.5 
Adverse events  
Section 9.2 
Prior medications, including background WD therapy history 
Section 8.1.2 
 
10.2 Visits 2-5: Baseline and Pre-VTX-801 Period 
Duration: 4 study visits within a period of 7 days: 
• Visit 2; Baseline: 1-day outpatient visit, which will also include the initiation of 
Sirolimus treatment 
. 
• Flexibility of up to 7 additional days for VTX-801 administration is allowed if 
needed in order to comply with radiocopper production constraints or to 
accommodate the sites and/or patients. As a consequence, initiation of the 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 134 of 223 
Sirolimus treatment 
 will then 
need to be shifted accordingly (start 7 days prior to VTX-801 administration). 
• No visits for 3 days. 
• Visits 3-4-5: a 3-day in- or outpatient visit period during 
 
. 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
(Note permitted visit windows are allowed for some assessments; refer to Table 2 and its footnotes) 
Visit 2 
Day -7 
Baseline 
Outpatient visit Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Serum pregnancy test (for WOCBP only) 
Section 8.1.12 
Central Laboratory: blood/urine biochemistry; hematology; 
coagulation 
Section 8.1.11 
Central Laboratory: Liver biochemistry panel 
Section 8.1.11  
Local Laboratory: Liver biochemistry panel 
Section 8.1.12 
Calculation of MELD, APRI, FIB4 by CRO 
Table 11 
Ceruloplasmin (enzymatic assay and nephelometry), CuEXC, 
total Cu, REC, RAC, ANCC, CRP 
Section 8.1.13  
ELISA and IFN-gamma ELISpot  
Section 8.2.4 
Ophthalmology: slit lamp examination. It can be performed from 
Baseline V2 to the day before radiocopper administration as long 
as results are available before the day of radiocopper 
administration.  
Section 8.1.6 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 135 of 223 
UWDRS, SDMT and Stroop Test 
They can be performed from Baseline V2 to the day before 
radiocopper administration as long as results are available before 
the day of radiocopper administration. 
Section 8.1.7 
Adverse events  
Section 9.2 
Prior medications 
Section 8.1.2 
 Sirolimus treatment 
Section 7.5 
 
 
For patients on copper chelator:  
• Patients are to be informed to start the wash-out period 
without copper-chelator treatment 3 days before radiocopper 
injection until the end of the radiocopper investigations. 
• The 24-hour urine copper sample will start 48 hours after 
initiation of the chelator wash-out period and will end prior to 
radiocopper administration.  
 
 
For Visits 3-4-5, patients from expansion cohort (only) will be hospitalized, stay at a 
unit with clinical support or other location approved by the 
 
 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visit 3 
Day -3 
Pre VTX-801 
In or Out-
patient visit 
Cross-reference 
Vital signs 
Section 8.1.4 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 136 of 223 
Physical examination 
Section 8.1.3 
Sirolimus 
Section 7.5 
Sirolimus level test: sampling for blood trough concentration 4-5 
days after starting treatment with Sirolimus  
Section 7.5 
 
 
24-hour urinary copper (to end prior to radiocopper 
administration) 
Section 8.1.13 
 
 
Radiocopper administration (around 9 am) 
Section 7.4 
  
 
 
 
 
 
 
 
 
Adverse events  
Section 9.2 
Prior medications 
Section 8.1.2 
 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visit 4 
Day -2 
Pre VTX-801 
In or Out-
patient visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Sirolimus 
Section 7.5 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 137 of 223 
 
 
  
 
 
 
 
 
 
 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visit 5 
Day -1 
Pre VTX-801 
In or Out-
patient visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Weight 
Section 8.1.3 
Sirolimus 
Section 7.5 
 
 
 
 
  
 
 
 
 
 
 
 
Vector shedding: blood, urine, saliva, feces - mandatory 
Vector shedding: At Day -1 baseline starting after last radiocopper sampling Section 8.2.3 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 138 of 223 
and within 24 hours before VTX-801, taking into account +7D window for 
administration. These assessments are to be performed either at V5 or V6. 
Adverse events  
Section 9.2 
Prior medications 
Section 8.1.2 
10.3 Visit 6: Day 1, Week 1 
This is the first day of the inpatient period related to VTX-801 administration. The 
patient will then be hospitalized overnight and will be discharged on the following day. 
If the patient’s medical status post-VTX-801 administration necessitates a prolonged 
hospitalization, please refer to Section 9.3 Serious Adverse Events. 
Flexibility of up to 7 additional days for VTX-801 administration is allowed if needed in 
order to comply with radiocopper production constraints or to accommodate the sites 
and/or patients. 
Home nurse collected samples for liver biochemistry panel may be sent to the Central 
Laboratory instead of to the Local laboratory. 
 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visit 6 
Day 1 + 7 
days 
VTX-801 
Inpatient visit 
Cross-reference 
Special instructions: 
Patient will be fasted overnight prior to VTX-801 administration 
and during administration. 
It is recommended that the patient also fasts for 2 hours after the 
administration for infusions shorter than 1 hour but this time may 
be reduced for patients receiving longer infusions.  
The VTX-801 infusion administration should be started early in 
the morning in order to limit as much as possible the total 
duration of the fasting period.  
Section 7.2 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 139 of 223 
Vital signs before, during and after VTX-801 administration: 
- 
before VTX-801 administration 
- 
at 15-minute intervals during the VTX-801 administration 
(+/- 3 min) 
- 
at the end of the infusion 
- 
1 hour after the end of infusion (+/- 10 min) 
- 
and then at 4-hour intervals until night sleep (+/- 15 min) 
Section 8.1.4 
ECG performed prior to VTX-801 administration 
Section 8.1.5 
Anti-AAV3B capsid neutralizing antibodies sampling prior to 
VTX-801 administration 
Section 8.2.1 
Sirolimus  
Section 7.5 
 
 
Methylprednisolone administered IV one hour before VTX-801 
Section 7.5.1 
  
 
 
 
 
 
 
 
 
 
 
For patients on chelator therapy: patient restarts WD treatment 
 
Vector shedding: blood, urine, saliva, feces - mandatory 
Vector shedding: At Day -1 baseline starting after last radiocopper sampling 
and within 24 hours before VTX-801, taking into account +7D window for 
administration. These assessments are to be performed either at V5 or V6. 
Section 8.2.3 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 140 of 223 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
VTX-801 administered  
Section 7.2 
10.4 Visit 7: Day 2, Week 1: Post-VTX-801 Administration 
This is the second day of a 2-day inpatient period related to VTX-801 administration. 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visit 7 
Day 2 
VTX-801 
Inpatient visit 
Cross-reference 
Vital signs  
Section 8.1.4 
Physical examination 
Section 8.1.3 
Local laboratory: Liver biochemistry panel 
Section 8.1.12 
Vector shedding: blood, urine, saliva, feces - mandatory 
Note: vector shedding sampling is to occur at every site scheduled visit 
until 3 consecutive concerned samples are negative (at or below 
quantification limit) 
Section 8.2.3 
Sirolimus 
Section 7.5 
 
 
Oral steroid (Prednisone or Prednisolone) 
Section 7.5.1 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 141 of 223 
10.5 Visits 8-46: Follow-up Until End of Year 1 Post-VTX-801 Administration 
 Visit 8 (Day 8 ± 2 days)  
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visit 8 
D8 ± 2 days 
Follow-up 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: Hematology 
Section 8.1.11 
Central Laboratory: Liver biochemistry panel 
Section 8.1.11 
Local laboratory: Liver biochemistry panel 
Section 8.1.12 
Vector shedding: blood, urine, saliva, feces - mandatory 
Note: at all visits until end of year 1, as applicable, vector shedding 
sampling is to occur at every site scheduled visit until 3 consecutive 
concerned samples are negative (at or below quantification limit) 
Section 8.2.3 
Sirolimus 
Section 7.5 
Sirolimus level test: sampling for blood trough concentration after 
7 to 14 days according to local practice 
Section 7.5 
 
 
Oral steroid (Prednisone or Prednisolone) 
Section 7.5.1 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 142 of 223 
 Visit 9 (Day 15 ± 2 days) 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visit 9 
D15 ± 2 days 
Follow-up 
Home nurse 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Local Laboratory: Liver biochemistry panel 
Section 8.1.12 
Sirolimus  
Section 7.5 
 
 
Oral steroid (Prednisone or Prednisolone) 
Section 7.5.1 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 Visit 10 (Week 4 ± 2 days) 
Importantly, from Week 4 to Week 12 inclusive post VTX-801 administration, liver function 
tests will be performed twice a week. 
Additionally, in the case that an ALT increase ≥ 1.5 x baseline between Week 4 and Month 
6 post-VTX-801 administration occurs despite the immunosuppressive regimen 
(Section 7.5), site has to specifically refer to Section 7.5.2 for guidance.  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 143 of 223 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visit 10 
Week 4 ± 2 days Follow-up 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: Blood/urine biochemistry with lipid panel; 
hematology; coagulation  
Fasting conditions are required for the lipid panel. 
Section 8.1.11 
Central Laboratory: Liver biochemistry panel 
Section 8.1.11 
Local laboratory: Liver biochemistry panel 
Section 8.1.12 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC, CRP 
Section 8.1.13 
Anti-AAV3B capsid neutralizing antibodies 
Section 8.2.1 
Vector shedding: blood, urine, saliva, feces - mandatory 
Note: at all visits until end of year 1, as applicable, vector shedding 
sampling is to occur at every site scheduled visit until 3 consecutive 
concerned samples are negative (at or below quantification limit) 
Section 8.2.3 
ELISA and IFN-gamma ELISpot  
Section 8.2.4 
Sirolimus 
Section 7.5 
Sirolimus level test: sampling for blood trough concentration 28 
days after starting treatment with Sirolimus 
Section 7.5 
 
 
Oral steroid (Prednisone or Prednisolone) 
Section 7.5.1 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 144 of 223 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 Visits 11-17 (Weeks 4, 5, 6 and 7 ± 2 days) 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visits 11-17 
Weeks 4, 5, 6, 7 
± 2 days 
Follow-
up 
Home nurse 
visits 
Cross-reference 
Vital signs 
Section 8.1.4 
Local Laboratory: Liver biochemistry panel (twice per week) 
Section 8.1.12  
Sirolimus 
Section 7.5 
 
 
Oral steroid (Prednisone or Prednisolone) 
Section 7.5.1 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
Visit 16, Week 6: A call or a video consultation between 
Investigator and patient (check for patient health and for the 
occurrence of any adverse event since the last visit) 
 
 Visit 18 (Week 8 ± 2 days) 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visit 18 
Week 8 ± 2 days 
Follow-
up 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 145 of 223 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: Liver and lipid biochemistry panels 
Fasting conditions are required for the lipid panel. 
Section 8.1.11 
Local Laboratory: Liver biochemistry panel  
Section 8.1.12 
Vector shedding: blood, urine, saliva, feces - mandatory 
Note: at all visits until end of year 1, as applicable, vector shedding 
sampling is to occur at every site scheduled visit until 3 consecutive 
concerned samples are negative (at or below quantification limit). 
Section 8.2.3 
ELISA and IFN-gamma ELISpot  
Section 8.2.4 
Sirolimus 
Section 7.5 
Sirolimus level test: sampling for blood trough concentration 8 
weeks days after starting treatment with Sirolimus 
Section 7.5 
 
 
Oral steroid (Prednisone or Prednisolone) 
Section 7.5.1 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 Visits 19-25 (Weeks 8, 9, 10 and 11 ± 2 days) 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visits 19-25 
Weeks 8, 9, 10, 
11 ± 2 days 
Follow-
up 
Home nurse 
visits 
Cross-reference 
Vital signs 
Section 8.1.4 
Local Laboratory: Liver biochemistry panel (twice per week) 
Section 8.1.12 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 146 of 223 
Sirolimus 
Section 7.5 
 
 
Oral steroid (Prednisone or Prednisolone): last dose at the end 
of Week 8 unless continued in the case of overt transaminase 
increase 
Section 7.5.1 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 Visits 26-29 (Week 12) 
Only for the expansion cohort: the patient is to be hospitalized, stay at a unit with 
clinical support or other location approved by the Sponsor 
 
 
Refer to Section 10.2, Visit 2 for the wash-out instructions for patients on copper chelators 
or dual chelator and zinc therapy:  
Refer to Section 7.6.3, for expansion cohort only,
 
 
The 2 samples of Week 12 for “Liver biochemistry panel” will occur at site as much as 
possible. For example, at Visit 26 collecting the first sample is mandatory, with the second 
sample collected at Visit 28 or Visit 29. 
If the second sample cannot occur at site, it should be collected at the home nurse visit 
planned after end of hospitalization within Week 12 (Visit 30). 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visit 26 
Week 12 ± 5 
days 
Follow-
up 
In or Out-
patient visit 
Cross-reference 
Vital signs 
Section 8.1.4 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 147 of 223 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Urine pregnancy test (for WOCBP only) 
Section 8.1.12 
Central Laboratory: Blood/urine biochemistry; hematology; 
coagulation 
Section 8.1.11 
Central Laboratory: Liver biochemistry panel 
Section 8.1.11 
Local Laboratory: Liver biochemistry panel (twice per week) 
Section 8.1.12 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC 
Section 8.1.13 
24-hour 
urinary 
copper 
(to 
end 
prior 
to 
radiocopper 
administration) 
For patients on copper chelator:  
• Patients are to be informed to start the wash-out period 
without 
copper-chelator 
treatment 
3 
days 
before 
radiocopper injection and until the end of the radiocopper 
investigations. 
• The 24-hour urine copper sample will start 48 hours after 
initiation of the chelator wash-out period and will end prior 
to radiocopper administration 
Section 8.1.13 
Vector shedding: blood, urine, saliva, feces 
Note: at all visits until end of year 1, as applicable but only at this visit 
during this period of 4 consecutive visits (V26 to V29). 
Section 8.2.3 
ELISA and IFN-gamma ELISpot  
Section 8.2.4 
ECG 
Section 8.1.5 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 148 of 223 
UWDRS, M.I.N.I., SDMT and Stroop Test  
Section 8.1.7 
 
 
 
 
  
 
 
 
 
 
 
  
 
Sirolimus 
 
Section 7.5 
 
 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Visit 27 
Week 12 
Follow-up 
In or Out-
patient visit 
Cross-reference 
Vital signs 
Section 8.1.4 
 
 
  
 
 
 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 150 of 223 
 
The patient will leave the hospital after following assessments: 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
This visit is for the expansion cohort only. 
Visit 29 
Week 12  
Follow-up 
In or Out-patient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Local Laboratory: Liver biochemistry panel (only if not done at 
Visit 28) 
Section 8.1.12 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sirolimus administration 
 
Section 7.5 
 
 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 151 of 223 
 Visits 30 and 31 (Weeks 12 and 13 ± 3 days) 
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
Note: Visit 30 will not occur (including recording vital signs) if the liver biochemistry 
sample is collected at either Visit 28 or Visit 29 at site 
Visits 30-31 
Weeks 12,13  
± 3 days 
Follow-
up 
Home nurse 
visits 
Cross-reference 
Vital signs 
Section 8.1.4 
Local Laboratory: Liver biochemistry panel (only if not done at 
either Visit 28 or 29) 
Section 8.1.12 
Sirolimus administration 
 
Section 7.5 
 
 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 Visit 32 (Week 14 + 2 days) 
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
Note: Time window at W14 may be increased beyond 2 days to accommodate the DMC 
review process. 
Visit 32 
Week 14  
+ 2 days 
Follow-up 
Phone call 
Cross-reference 
Vital signs (only if visit occurs on site) 
Section 8.1.4 
Investigator 
informs 
the 
patient 
about 
his/her 
“Responder/Insufficient Responder” status and associated 
consequences: 
• withdrawal or continuation of the WD SoC therapy  
Section 4.5 / 
Section 4.6 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 152 of 223 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 
Visits 33-35 (Weeks 15, 16 and 20 ± 3 days) 
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
Visits 33-35 
Weeks 15, 16, 
20 ±3 days 
Follow-
up 
Home nurse 
visits 
Cross-reference 
Vital signs 
Section 8.1.4 
Local Laboratory: Liver biochemistry panel  
Section 8.1.12 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
Additional for Visit 35, Week 20 only: 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC and CRP 
Section 8.1.13 
24-hour urinary copper  
Section 8.1.13 
Visit 35, Week 20: A call or a video consultation between 
Investigator and patient (check for patient health and for the 
occurrence of any adverse event since the last visit) 
 
 
Visit 36 (Week 24 ± 3 days) 
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
Visit 36 
Week 24 ± 3 
days 
Follow-
up 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 153 of 223 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11 
Central Laboratory: Liver biochemistry panel 
Section 8.1.11 
Local Laboratory: Liver biochemistry panel 
Section 8.1.12 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, Exchangeable Cu, ANCC 
Section 8.1.13 
24-hour urinary copper 
For patients on copper chelator:  
• Patients have to be reminded to have a 72-hour period 
without copper-chelator treatment: 
- 
48 hours prior starting sampling of urine, 
- 
And during the 24 hours of urine collection. 
• They will restart their copper-chelator treatment only after 
the last sampling of the 24-hour urine collection. 
Section 8.1.13 
Vector shedding: blood, urine, saliva, feces - mandatory 
Note: at all visits until end of year 1, as applicable, vector shedding 
sampling is to occur at every site scheduled visit until 3 consecutive 
concerned samples are negative (at or below quantification limit) 
Section 8.2.3 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Ophthalmology: slit lamp examination  
Section 8.1.6 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 154 of 223 
 
Visits 37-38 (Weeks 28 and 32 ± 3 days) 
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
Visits 37-38 
Weeks 28 and 
32 ±3 days 
Follow-
up 
Home nurse 
visits 
Cross-reference 
Vital signs 
Section 8.1.4 
Local Laboratory: Liver biochemistry panel  
Section 8.1.12 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 
Visits 39-42 (Week 36) 
Only for the expansion cohort: the patient is to be hospitalized, stay at a unit with 
clinical support or other location approved by the Sponsor
 
 
. 
If it does not occur, the patient will only attend one visit (Visit 39) as 
 
  
Refer to Section 10.2, Visit 2 for the wash-out instructions for patients on copper chelator.  
Refer to Section 7.6.3, for expansion cohort only, on patient to be given 
 
 
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
Visit 39 
Week 36 ± 5 
days 
Follow-
up 
In or Out-
patient visit 
Cross-reference 
Vital signs 
Section 8.1.4 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 155 of 223 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Urine pregnancy test (WOCBP) 
Section 8.1.11 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11 
Central Laboratory: Liver biochemistry panel 
Section 8.1.11 
Local Laboratory: Liver biochemistry panel 
Section 8.1.12 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC 
Section 8.1.13 
24-hour 
urinary 
copper 
(to 
end 
prior 
to 
radiocopper 
administration)  
For patients on copper chelator:  
• Patients are to be informed to start the wash-out period 
without 
copper-chelator 
treatment 
3 
days 
before 
radiocopper injection and until the end of the radiocopper 
investigations. 
• The 24-hour urine copper sample will start 48 hours after 
initiation of the chelator wash-out period and will end prior 
to radiocopper administration. 
Section 8.1.13 
Vector shedding: blood, urine, saliva, feces 
Note: at all visits until end of year 1, as applicable but only at this visit 
during this period of 4 consecutive visits (V39 to V42). 
Section 8.2.3 
UWDRS, M.I.N.I. 
Section 8.1.7 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 156 of 223 
Radiocopper administration (around 9 am) if applicable 
Section 7.4 
  
 
 
 
 
 
 
  
 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
Visit 40 
Week 36  
Follow-up 
In or Out-
patient visit 
Cross-reference 
Vital signs 
Section 8.1.4 
 
 
  
 
 
 
 
 
 
 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 157 of 223 
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
Visit 41 
Week 36  
Follow-up 
In or Out-
patient visit 
Cross-reference 
Vital signs 
Section 8.1.4 
 
 
  
 
 
 
 
 
 
 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 
The patient will leave the hospital after following assessments: 
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
This visit is for the expansion cohort only. 
Visit 42 
Week 36  
Follow-
up 
In or Out-
patient visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Local Laboratory: Liver biochemistry panel 
Section 8.1.12 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 158 of 223 
 
  
 
 
 
 
 
 
  
 
 
 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 
Visit 43 (Week 38) 
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
Note: The time window at W38 may be increased beyond 2 days to accommodate the 
DMC review process. 
Visit 43 
Week 38 +2 
days 
Follow-up 
Phone call 
Cross-reference 
Vital signs (only if visit occurs at site) 
Section 8.1.4 
If the patient underwent the Week 36 radiocopper related 
assessments, Investigator informs the patient about his/her 
“Responder/Insufficient Responder” status and associated 
consequences: 
• withdrawal, continuation or restart of the WD SoC therapy  
Section 4.5 / 
Section 4.6 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 159 of 223 
 
Visits 44-45 (Weeks 40 and 44 ± 3 days) 
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
Visits 44-45 
Weeks 40 and 
44 ±3 days 
Follow-
up 
Home nurse 
visits 
Cross-reference 
Vital signs 
Section 8.1.4 
Local Laboratory: Liver biochemistry panel  
Section 8.1.12 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
Additional for Visit 45, Week 44 only: 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC and CRP 
Section 8.1.13 
24-hour urinary copper: only for “Responders” at that time and 
as such, not on SoC treatment. 
Section 8.1.13 
 
Visit 46 (Week 52 ± 7 days) 
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
Visit 46 
Week 52 ± 7 
days 
Follow-
up 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11 
Central Laboratory: Liver biochemistry panel 
Section 8.1.11 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 160 of 223 
Local Laboratory: Liver biochemistry panel 
Section 8.1.12 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC, CRP 
Section 8.1.13 
Vector shedding: blood, urine, saliva, feces - mandatory 
Note: at all visits until end of year 1, as applicable, vector shedding 
sampling is to occur at every site scheduled visit until 3 consecutive 
concerned samples are negative (at or below quantification limit) 
Section 8.2.3 
24-hour urinary copper  
For patients on copper chelator:  
• Patients have to be reminded to have a 72-hour period 
without copper-chelator treatment: 
- 
48 hours prior starting sampling of urine, 
- 
And during the 24 hours of urine collection. 
• They will restart their copper-chelator treatment only after 
the last sampling of the 24-hour urine collection. 
Section 8.1.13 
Anti-AAV3B capsid neutralizing antibodies 
Section 8.2.1 
ECG 
Section 8.1.5 
Ophthalmology: slit lamp examination  
Section 8.1.6 
UWDRS, M.I.N.I., SDMT and Stroop Test 
Section 8.1.7 
Abdominal MRI and liver MR elastography. Elastography to be 
performed in a > 4-hour fasted state 
Section 8.1.8 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 161 of 223 
Liver biopsy (All efforts should be made to collect liver biopsies 
for each patient as described in the schedule of events. However, 
for the dose escalation cohorts only, if a patient declines to have 
the liver biopsies taken, these can be replaced with Fibroscan®. 
Should Fibroscan® be used instead of liver biopsy at Screening, 
this should be implemented for the rest of the study, to ensure 
consistency for the longitudinal analysis).  
Section 8.2.5 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
10.6 Visits 47-50: Follow-up (Year 2) 
Note concerning 24-hour urinary copper for patients on copper chelator:  
• Patients have to be reminded to have a 72-hour period without copper-chelator 
treatment: 
- 
48 hours prior starting sampling of urine, 
- 
And during the 24 hours of urine collection. 
• 
They will restart their copper-chelator treatment only after the last sampling of the 
24-hour urine collection 
 Visit 47 (Year 2, Month 3 ± 14 Days) 
Refer to Table 4 Summary of Schedule of Events: Years 2 to 5 Follow Up 
Visit 47 
Study Month 15 
± 14 Days 
Follow-up 
Year 2 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 162 of 223 
Central Laboratory: Liver biochemistry panel  
Section 8.1.11 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC 
Section 8.1.13 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 163 of 223 
 Visit 48 (Year 2, Month 6 ± 14 Days) 
Refer to Table 4 Summary of Schedule of Events: Years 2 to 5 Follow Up 
Visit 48 
Study Month 18 
± 14 Days 
Follow-
up  
Year 2 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11 
Central Laboratory: Liver biochemistry panel  
Section 8.1.11 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC 
Section 8.1.13 
24-hour urinary copper 
Section 8.1.13 
UWDRS, M.I.N.I  
Section 8.1.7 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 Visit 49 (Year 2, Month 9 ± 14 Days) 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 164 of 223 
Refer to Table 4 Summary of Schedule of Events: Years 2 to 5 Follow Up 
Visit 49 
Study Month 21 
± 14 Days 
Follow-up 
Year 2 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11 
Central Laboratory: Liver biochemistry panel  
Section 8.1.11 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC 
Section 8.1.13 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 Visit 50 (Year 2, Month 12 ± 14 Days) 
Refer to Table 4 Summary of Schedule of Events: Years 2 to 5 Follow Up 
Visit 50 
Study Month 24 
± 14 Days 
Follow-up 
Year 2 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11 
Central Laboratory: Liver biochemistry panel  
Section 8.1.11 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 165 of 223 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC  
Section 8.1.13 
24-hour urinary copper 
Section 8.1.13 
UWDRS, M.I.N.I, SDMT and Stroop Test  
Section 8.1.7 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Abdominal MRI and liver MR elastography. Elastography to be 
performed in a > 4-hour fasted state.  
Section 8.1.8 
ECG 
Section 8.1.5 
Ophthalmology: slit lamp examination  
Section 8.1.6 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
10.7 Visits 51-52: Follow-up (Year 3) 
Note concerning 24-hour urinary copper for patients on copper chelator:  
• 
Patients have to be reminded to have a 72-hour period without copper-chelator 
treatment: 
- 
48 hours prior starting sampling of urine, 
- 
And during the 24 hours of urine collection. 
• 
They will restart their copper-chelator treatment only after the last sampling of the 24-
hour urine collection. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 166 of 223 
 Visit 51 (Year 3, Month 6 ± 14 Days) 
Refer to Table 4 Summary of Schedule of Events: Years 2 to 5 Follow Up 
Visit 51 
Study Month 30 
± 14 Days 
Follow-up 
Year 3 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11 
Central Laboratory: Liver biochemistry panel  
Section 8.1.11 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC  
Section 8.1.13 
24-hour urinary copper 
Section 8.1.13 
UWDRS, M.I.N.I  
Section 8.1.7 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 Visit 52 (Year 3, Month 12 ± 14 Days) 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 167 of 223 
Refer to Table 4 Summary of Schedule of Events: Years 2 to 5 Follow Up 
Visit 52 
Study Month 36 
± 14 Days 
Follow-up 
Year 3 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11  
Central Laboratory: Liver biochemistry panel  
Section 8.1.11  
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC  
Section 8.1.13 
24-hour urinary copper 
Section 8.1.13 
UWDRS, M.I.N.I, SDMT and Stroop Test 
Section 8.1.7 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Brain MRI 
Section 8.1.9 
Abdominal MRI and liver MR elastography. Elastography to be 
performed in a > 4-hour fasted state.  
Section 8.1.8 
ECG 
Section 8.1.5 
Ophthalmology: slit lamp examination  
Section 8.1.6 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 168 of 223 
Liver biopsy (All efforts should be made to collect liver biopsies 
for each patient as described in the schedule of events. However, 
for the dose escalation cohorts only, if a patient declines to have 
the liver biopsies taken, these can be replaced with Fibroscan®. 
Should Fibroscan® be used instead of liver biopsy at Screening, 
this should be implemented for the rest of the study, to ensure 
consistency for the longitudinal analysis). 
Section 8.2.5 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
10.8 Visits 53-54: Follow-up (Year 4) 
Note concerning 24-hour urinary copper for patients on copper chelator:  
• Patients have to be reminded to have a 72-hour period without copper-chelator 
treatment: 
- 
48 hours prior starting sampling of urine, 
- 
And during the 24-hour urine collection. 
• They will restart their copper-chelator treatment only after the last sampling of the 
24-hour urine collection. 
 Visit 53 (Year 4, Month 6 ± 14 Days) 
Refer to Table 4 Summary of Schedule of Events: Years 2 to 5 Follow Up 
Visit 53 
Study Month 42 
± 14 Days 
Follow-up 
Year 4 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 169 of 223 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11 
Central Laboratory: Liver biochemistry panel  
Section 8.1.11 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC  
Section 8.1.13 
24-hour urinary copper 
Section 8.1.13 
UWDRS, M.I.N.I  
Section 8.1.7 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 Visit 54 (Year 4, Month 12 ± 14 Days) 
Refer to Table 4 Summary of Schedule of Events: Years 2 to 5 Follow Up 
Visit 54 
Study Month 48 
± 14 Days 
Follow-up 
Year 4 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11  
Central Laboratory: Liver biochemistry panel  
Section 8.1.11  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 170 of 223 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC  
Section 8.1.13 
24-hour urinary copper 
Section 8.1.13  
UWDRS, M.I.N.I, SDMT and Stroop Test 
Section 8.1.7 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Abdominal MRI and liver MR elastography. Elastography to be 
performed in a > 4-hour fasted state.  
Section 8.1.8 
ECG 
Section 8.1.5 
Ophthalmology: slit lamp examination  
Section 8.1.6 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
10.9 Visits 55-56: Follow-up (Year 5) 
Note concerning 24-hour urinary copper for patients on copper chelator:  
• Patients have to be reminded to have a 72-hour period without copper-chelator 
treatment: 
- 
48 hours prior starting sampling of urine, 
- 
And during the 24-hour urine collection. 
• They will restart their copper-chelator treatment only after the last sampling of the 
24-hour urine collection. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 171 of 223 
 Visit 55 (Year 5, Month 6 ± 14 Days) 
Refer to Table 4 Summary of Schedule of Events: Years 2 to 5 Follow Up 
Visit 55 
Study Month 54 
± 14 Days 
Follow-up 
Year 5 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11  
Central Laboratory: Liver biochemistry panel  
Section 8.1.11  
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC  
Section 8.1.13 
24-hour urinary copper 
Section 8.1.13  
UWDRS, M.I.N.I  
Section 8.1.7 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Adverse events  
Section 9.2 
Concomitant medications 
Section 8.1.2 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 172 of 223 
 Visit 56 (Year 5, Month 12, ± 14 Days) – End of Study Visit 
Refer to Table 4 Summary of Schedule of Events: Years 2 to 5 Follow Up 
Visit 56 
Study Month 60 
± 14 Days 
Follow-up 
Year 5 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: Blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11  
Central Laboratory: Liver biochemistry panel  
Section 8.1.11  
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC  
Section 8.1.13 
24-hour urinary copper 
Section 8.1.13  
UWDRS, M.I.N.I, SDMT and Stroop Test 
Section 8.1.7 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Abdominal MRI and liver MR elastography. Elastography to be 
performed in a > 4-hour fasted state.  
Section 8.1.8 
ECG 
Section 8.1.5 
Ophthalmology: slit lamp examination  
Section 8.1.6 
Brain MRI 
Section 8.1.9 
Adverse events  
Section 9.2 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 173 of 223 
Concomitant medications 
Section 8.1.2 
10.10 Early Termination Visit 
If a patient withdraws or is withdrawn prematurely, the following assessments and 
procedures should be performed according to patient and visit status and recorded in the 
Early Termination eCRF.  
This is an outpatient visit and it should be performed within 4 weeks following the decision 
to withdraw. Priority of assessments will be those related to safety (vital signs; physical 
examination; blood/urine biochemistry/hematology/ coagulation; liver biochemistry panel; 
adverse events), the other listed assessments will occur if possible or applicable. 
Importantly, ongoing AEs should be followed up in accordance with the procedures 
described in Section 9.2.7. 
If a patient discontinues between enrollment (Visit 2) and before administration of 
VTX-801, the Early Termination visit will contain: 
Refer to Table 2 Summary of Schedule of Events: Baseline to Week 12 
Early Termination visit: If occurring prior 
to VTX-801 administration 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Central Laboratory: blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11  
Central Laboratory: Liver biochemistry panel  
Section 8.1.11  
ECG 
Section 8.1.5 
Adverse events 
Section 9.2 
Concomitant medications 
Section 8.1.2 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 174 of 223 
Reason for early termination 
 
 
If a patient discontinues after administration of VTX-801 (even partial) and before 
completing the Year 1 follow up, the visit will be the one planned at the end of Year 1.  
Refer to Table 3 Summary of Schedule of Events: Weeks 13 to 52 (End of Year 1) 
Early Termination visit: If occurring after 
VTX-801 administration; before end of 
Year 1 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 
Central Laboratory: blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11  
Central Laboratory: Liver biochemistry panel  
Section 8.1.11  
Local Laboratory: Liver biochemistry panel  
Section 8.1.12  
ECG 
Section 8.1.5 
Adverse events 
Section 9.2 
Concomitant medications 
Section 8.1.2 
Reason for early termination 
 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC 
Section 8.1.13 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 175 of 223 
24-hour urinary copper  
Section 8.1.13  
Anti-AAV3B capsid neutralizing antibodies 
Section 8.2.1 
ELISA and INF-gamma ELISpot  
Section 8.2.4 
Vector shedding: blood, urine, saliva, feces - mandatory 
Note: at all visits until end of year 1, as applicable, vector shedding 
sampling is to occur at every site scheduled visit until 3 consecutive 
concerned samples are negative (at or below quantification limit) 
Section 8.2.3 
Abdominal MRI and liver MR elastography. Elastography to be 
performed in a > 4-hour fasted state 
Section 8.1.8 
Ophthalmology: slit lamp examination  
Section 8.1.6 
UWDRS, M.I.N.I., SDMT and Stroop Test 
Section 8.1.7 
 
Additionally, every effort should then be made to follow each patient for up to 5 years 
post-VTX-801 administration with at least one phone call every 6 months to collect 
potential adverse events. 
If a patient discontinues after completing the Year 1 follow up visits, the Early Termination 
visit will be the one planned at the end of Year 5.  
 
Refer to Table 4 Summary of Schedule of Events: Years 2 to 5 Follow Up 
Early Termination visit: If occurring after 
completion of Year 1 follow-up 
Outpatient 
visit 
Cross-reference 
Vital signs 
Section 8.1.4 
Physical examination 
Section 8.1.3 
Alcohol consumption 
Section 7.7 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 176 of 223 
Central Laboratory: blood/urine biochemistry; hematology; 
Coagulation 
Section 8.1.11  
Central Laboratory: Liver biochemistry panel  
Section 8.1.11  
ECG 
Section 8.1.5 
Adverse events 
Section 9.2 
Concomitant medications 
Section 8.1.2 
Reason for early termination 
 
Calculation of MELD, APRI, FIB4 by CRO 
Section 8.1.14 
Table 11 
Ceruloplasmin (enzymatic assay and nephelometry), total Cu, 
REC, RAC, CuEXC, ANCC 
Section 8.1.13 
24-hour urinary copper 
Section 8.1.13  
Abdominal MRI and liver MR elastography. Elastography to be 
performed in a > 4-hour fasted state  
Section 8.1.8 
Ophthalmology: slit lamp examination  
Section 8.1.6 
Brain MRI 
Section 8.1.9 
UWDRS, M.I.N.I., SDMT and Stroop Test 
Section 8.1.7 
 
Additionally, every effort should then be made to follow each patient for up to 5 years 
post-VTX-801 administration with at least one phone call every 6 months to capture 
potential adverse events. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 177 of 223 
10.11 Unscheduled Visit 
Unscheduled visits may be necessary during the study, especially for safety monitoring 
purposes and/or repeat safety assessments or in case of potential or suspected loss of 
efficacy.  
All unscheduled study visits, procedures, examinations, clinical laboratory evaluations 
etc., will be noted in the patient’s medical record and the eCRF including: 
• Reason for visit/procedure 
• Procedures, examinations, clinical laboratory evaluations, as applicable 
• Follow-up 
• Adverse events  
• Concomitant treatments 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 178 of 223 
11 STATISTICAL CONSIDERATIONS 
The study statistical analysis plan (SAP) will be developed and finalized before the first 
interim data lock. Full details of the analysis to be performed will be included in the SAP. 
This Section is a summary of the planned statistical analyses at the time of protocol 
development. 
A separate SAP will be developed specifically for the safety reviews to be conducted by 
the DMC. 
11.1 Sample Size Considerations 
Sample size has not been determined based upon statistical calculations. The sample 
size of up to approximately 16 patients, with approximately 4 patients per cohort, was 
chosen based on scientific judgment to have sufficient replication to meet the study 
objectives.  
The best efforts will be made to enroll at least 1 patient of each gender in each cohort of 
4.  
11.2 Planned Interim Analyses 
An interim analysis is planned before the final analysis and will cover the first patient first 
visit to 1 year after last patient has been treated with VTX-801. 
The final analysis will cover all study data. 
In addition, safety reviews will be conducted by the DMC. These will include patient-level, 
cohort-level and ad-hoc data reviews. The objective of these reviews will be to provide 
recommendations relating to patient safety and Responder status. 
An additional interim analysis may occur during the study if considered necessary by the 
Sponsor.  
11.3 Analysis Sets 
The Safety Analysis Set will include all patients who received at least part of the VTX-801 
dose. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 179 of 223 
The Pharmacodynamics Analysis Set will include all patients who received at least part 
of the VTX-801 dose and who have at least one post-baseline pharmacodynamics 
assessment (free serum Cu (CuEXC and ANCC), REC, RAC, total serum Cu, 24-hour 
urinary Cu and serum ceruloplasmin by enzymatic activity assay and by nephelometry). 
The Efficacy Analysis Set will include all patients who received at least part of the 
VTX-801 dose and who have at least one post-baseline radiocopper assessment. 
Other Analysis Sets may be defined in the SAP, as necessary.  
11.4 Statistical Methodology 
All statistical analyses will be descriptive, there will be no hypothesis testing. Continuous 
variables will be summarized using descriptive statistics (n, mean, standard deviation, 
median, minimum, and maximum). Categorical variables will be summarized showing the 
number and percentage (n, %) of patients within each classification. 
 Demographics and Medical History  
Demographic and baseline measurements will be summarized using standard descriptive 
methods. 
 Extent of Exposure 
A by-patient listing of the date and time of IMP administration and the dose administered 
will be presented. 
 Concomitant Medications 
All concomitant medications administered, including steroids and Sirolimus treatment, will 
be presented in a data listing. Concomitant medications may be summarized 
descriptively, by therapeutic class and preferred term, as warranted by the data. 
 Safety Analyses 
Safety evaluations will be based on the incidence, severity and type of AEs, and on 
changes in the patient’s physical examination findings, vital signs, clinical laboratory 
results (hematology, biochemistry and coagulation), urine tests results, ECG, brain MRI, 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 180 of 223 
abdominal MRI, liver MR elastography, and viral vector shedding findings. Safety results 
will be presented for all patients in the Safety Analysis Set. 
11.4.4.1 Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
System Organ Class (SOC), High-Level Group Term (HLGT), High Level Term (HLT), 
Preferred Term (PT), and Lower-Level Term (LLT) will be attached to the clinical 
database. 
AEs will be summarized based on the date of onset for the event. Summaries (number 
and percentage of patients) of treatment-emergent AEs will be provided by SOC and PT, 
by dose cohort and overall. 
Treatment-emergent adverse event is defined as any AE that emerges during or after 
IMP administration having been absent pre-treatment or worsens relative to the pre-
treatment state.  
Events that are considered possibly, probably or definitely related to the IMP, deaths, 
SAEs, and AEs resulting in IMP discontinuation will also be tabulated by SOC and PT. 
A tabulation will also be provided that summarizes at least treatment-emergent and 
treatment-related AEs (possibly, probably or definitely related) by maximum severity (i.e., 
CTCAE grade). 
Duration of AEs will also be investigated as appropriate. 
All AEs, including treatment-emergent and non-treatment-emergent AEs, will be listed in 
patient data listings. 
11.4.4.2 Laboratory Evaluations 
Summaries of clinical laboratory data from central laboratories, including transaminase 
results, will be provided using descriptive statistics. No inferential statistics will be 
provided. Quantitative values and change from baseline in quantitative values will be 
summarized by dose cohort and overall. Listings of all laboratory results and reference 
ranges will be provided.  
Graded laboratory abnormalities, including for transaminases, will be defined using the 
grading scheme based on NCI CTCAE v5 and summarized by dose cohort and overall. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 182 of 223 
 
 (e.g., 
sample size, arithmetic mean, % coefficient of variation, standard deviation, median, 
minimum, and maximum). 
 
e.g., sample size, arithmetic and geometric 
mean, % coefficient of variation, standard deviation, median, minimum, and maximum).  
 
 
 
Time to SOC withdrawal, need for SOC adjustments, need for reinstatement of SoC after 
withdrawal and whether response occurs at the pre-study SoC dose and time to copper 
deficiency and whether correction occurs will be listed and summarized, by dose cohort 
using appropriate descriptive statistics. 
 Other Analyses 
All other study endpoints will be analyzed for all patients of the Safety Analysis Set using 
appropriate descriptive statistics, by dose cohort and planned visit: 
• Humoral and cellular immune responses to VTX-801: in vitro neutralizing antibody 
(NAb) anti-AAV3B capsid assay, ELISA against AAV3B capsid and miniATP7B, 
IFN-gamma ELISpot to AAV3B capsid and miniATP7B 
• MELD, APRI, FIB4 scores 
• Scores/diagnosis from the M.I.N.I.  
• Scores from SDMT and Stroop Test 
• Total score from the UWDRS part I, II and III 
Descriptive statistics will include absolute values, changes from baseline and percent 
change from baseline, as appropriate. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 183 of 223 
11.5 Changes to the Planned Statistical Methods 
Changes to the planned statistical methods will be documented in the clinical study 
report(s). 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 184 of 223 
12 STUDY OPERATIONS 
12.1 Study Sites 
 Investigational Sites 
Sites will be selected to participate in this research after completion of feasibility and 
qualification assessments. Investigational sites will use their patient records/databases to 
identify potential patients for the study. Investigational sites will implement detailed patient 
identification, management and retention plans. 
A selection of the investigational sites (termed “Infusion sites”) will be allowed to perform 
all study procedures including radiocopper related administration, radiocopper 
assessments and VTX-801 infusion. 
The other investigational sites (termed “non-infusion sites”) will be allowed to perform all 
study procedures except for the inpatient stays where radiocopper-related administration 
and assessments and VTX-801 infusion will be performed. 
Radiocopper administration and related assessments and VTX-801 infusion for patients 
enrolled at non-infusion sites will be performed at the infusion sites. 
 Referral Sites 
The Sponsor may select patient identification centers (“Referral sites”) to identify potential 
patients from their records/databases and to refer them to one of the participating 
Investigational sites, including cross-border referrals. Study activity at Referral sites will 
be limited to refer potential patients to the corresponding Investigational site. In case there 
is a need for Referral country regulatory/ethics committee submission, the Referral sites 
may be involved accordingly. 
 Home Nurses 
As described in Section 10 and the schedule of assessments, at the discretion of the 
Investigator and if agreed to by the patient, some visits may be conducted at the patient’s 
home by a home nurse. This type of visit can be planned for all types of 
assessments/retests (for which the home nurse is qualified and trained accordingly) as 
needed. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 185 of 223 
If home nurse visits are to be conducted instead of site visits as described in Section 10 
and the schedule of assessments, this will be agreed in advance by the Investigator, 
patient and Sponsor. Home nurses will operate under a written agreement with the 
Investigational site and will fully uphold patient confidentiality. Samples collected by the 
home nurse may be processed by the Central Laboratory. All study data will be 
transferred to the Investigational site. 
12.2 Study Monitoring 
During the course of the study, a CRA will conduct routine site visits (both on site and 
remotely) to review protocol compliance, compare eCRF entries with individual patient’s 
original source documents (accessed by the Investigator), assess product accountability 
and ensure the study is conducted according to applicable regulatory requirements. The 
review of the patient’s original medical records shall be performed in a manner which 
ensures patient confidentiality is maintained. 
The Investigator shall permit the CRA to review study data as frequently as deemed 
necessary to ensure that data are recorded in an adequate manner and that protocol 
adherence is satisfactory. 
The Investigator may not enroll patients into the study until authorization is given by the 
Sponsor, or their designee, Aixial, which would typically be after completion of a 
successful Site Initiation Visit (SIV) by the CRA to conduct a detailed training of the 
protocol and eCRF, and confirmation that the site’s essential regulatory documents have 
been verified. 
12.3 Source Documents 
Each participating site shall maintain appropriate medical and research records for this 
trial, in compliance with ICH GCP and regulatory and institutional requirements for the 
protection of patient confidentiality.  
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, 
hospital records, clinical and office charts, laboratory notes, memoranda, patients’ 
memory aids or evaluation checklists, pharmacy dispensing records, recorded data from 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 186 of 223 
automated instruments, recorded audio tapes of counseling sessions, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, X-rays, and patient files and 
records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.  
The eCRF is not a source document.  
 Access to Source Data and Documents 
The Investigator/institution shall provide direct access to all relevant data and records to 
the CRA, auditors, the Sponsor’s authorized representatives, designated agents of the 
Sponsor, IRB, and Health Authorities, as required, for study-related monitoring, audits, 
inspections, IRB/EC review and regulatory inspection. An infusion site may need to 
provide access to patient records to a non-infusion site. 
12.4 Data Handling and Record Keeping 
The Investigator is responsible for ensuring the accuracy, completeness, legibility and 
timeliness of the source data. Data collection is the responsibility of the clinical trial staff 
at the site under the supervision of the Investigator.  
The Sponsor and/or its designated CRO, will provide training and guidance to 
Investigators on recording trial data in the eCRF. 
 Data Capture Methods 
Clinical data (including AEs, concomitant medications, safety assessments and outcome 
measures) will be entered by the site staff into a 21 CFR Part 11-compliant data capture 
system provided by the designated CRO. The data capture system includes password 
protection and internal quality checks, such as automatic range checks, to identify data 
appearing inconsistent, incomplete or inaccurate.  
Any diagnostic and/or laboratory data collected by a central vendor will be stored 
electronically in the central vendor’s database system. Data will subsequently be 
transferred to the Sponsor and/or its designated CRO, for inclusion into data collected in 
the EDC system. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 187 of 223 
CRO personnel will be responsible authorizing access to the EDC system for Investigator-
designated site staff.  
 Study Site Responsibilities 
All data requested on the eCRF must be recorded. Data will be transcribed by authorized 
personnel at the study site from the source documents into the eCRF for enrolled patients 
(i.e., all patients who have signed the ICF). All information on the eCRF must be traceable 
to these source documents. All electronic entries (including any changes or updates) will 
be traceable through the system. Only the Investigator or authorized staff may enter or 
modify data in the database using their unique password and User Identification. The 
Investigator must certify that the data entered in the eCRFs are complete and accurate 
by electronically signing the eCRF.  
Data must be transcribed in the eCRF within 5 working days of the source data recording. 
In certain cases, i.e. ahead of cohort and patient level DMC meetings data used for 
decision making must be transcribed within 2 working days. 
Any SAE meeting the criteria described in Section 9.2.6, Table 15 must be entered into 
the eCRF within 24 hours of first awareness of the event by study personnel. 
Although pregnancy itself is not considered an AE, it must be entered in the eCRF in the 
same timelines as a SAE (within 24 hours of the Investigator becoming aware of the 
pregnancy). 
 Data Management Responsibilities 
The Aixial Data and Analytics department will serve as the Statistical and Data 
Management Center for this study and will be responsible for data management, quality 
review, analysis and reporting of the study data. 
Data management staff at Aixial will review the data in the eCRFs according to their 
internal SOPs and systematically validate the data using appropriate electronic checks in 
addition to relevant manual checks. For any errors identified in the data, Aixial will 
generate a formal query to be addressed by the investigational site staff within the EDC 
system. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 188 of 223 
For classification purposes, concomitant medications, AEs and medical history entered 
into the eCRF will be coded using relevant medication and medical term dictionaries. 
These will be specified in the study-specific Data Management Quality Plan. 
 Study Records Retention and Archiving 
After the trial is completed, the Investigator will receive or download an electronic file with 
the eCRFs of the patient data for the site for archiving at the investigational study site. No 
records will be destroyed without the written consent of the Sponsor, if applicable.  
Essential documents should be retained for a minimum of two years after the last approval 
of a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least two years have elapsed since the 
formal discontinuation of clinical development of the investigational product. However, 
these documents should be retained for a longer period if required by the applicable local 
requirements. 
ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 189 of 223 
13 QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 Quality Management Systems 
This study shall be conducted in accordance with the provisions of the Declaration of 
Helsinki and all revisions thereof, and in accordance with USA FDA regulations (CFR, 
Sections 312.50 and 312.56) and with ICH GCP. 
The Sponsor and Aixial shall implement and maintain quality control (QC) and quality 
assurance (QA) procedures with written SOPs to ensure the study is conducted and data 
are generated, documented and reported in compliance with the protocol, ICH GCP, US 
CFR Title 21 and other applicable regulatory requirements. 
All participating sites are required to have written procedures in place for assuring the 
quality of the research being conducted, including, but not limited to:  
• How data will be evaluated for compliance with the protocol and for accuracy in 
relation to source documents.  
• The documents to be reviewed (e.g., eCRFs, clinic notes, product accountability), who 
is responsible, and the frequency for reviews.  
• Methods of training for staff, and methods of tracking such training. 
13.2 Audit 
The Sponsor may conduct audits of clinical research activities in accordance with internal 
SOPs to evaluate compliance with the principles of GCP and ICH related guidelines. 
Health Authorities may also wish to conduct an inspection (during the study or after its 
completion). Should an inspection be requested by Health Authorities, the Investigator 
must inform the Sponsor immediately that such request has been made. 
The Investigator will permit such audits by Sponsor or Health Authorities and facilitate 
them by providing access to the relevant source documents. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 190 of 223 
13.3 Protocol Amendment 
Any substantial change or addition to the protocol can only be made in a written protocol 
amendment that must be approved by the Sponsor, Health Authorities and the IRB/IEC 
prior to implementation. 
Only amendments that are intended to eliminate an apparent immediate hazard to 
patients may be implemented without prior approval, provided the Health Authorities and 
the concerned IRB/IEC are subsequently notified by written protocol amendment.  
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any patient included in 
this study, even if this action represents a deviation from the protocol. In such cases, the 
Sponsor’s designated CRO, Aixial, should be informed and AE/SAE reporting 
requirements followed as appropriate. 
13.4 Protocol Deviation 
The Investigator may not deviate from the protocol without a written protocol amendment 
having been established and approved by the IRB/IEC and the concerned Health 
Authorities, when applicable, except when necessary to eliminate immediate hazards to 
the patient or when the change(s) involve(s) only logistical or administrative aspects of 
the study. Any deviations may result in the patient having to be withdrawn from the study 
or render that patient non-evaluable. 
A protocol deviation is any non-compliance with the clinical trial protocol, ICH-GCP 
requirements, or all Study Plans and Manuals. The non-compliance may be either on the 
part of the patient, the Investigator, or the study site staff. As a result of deviations, 
corrective actions are to be developed by the site and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 5 
working days of the scheduled protocol-required activity. All deviations must be promptly 
reported to Aixial and the Sponsor.  
All deviations from the protocol must be documented in study patient source documents. 
Protocol deviations must be sent to the local IRB/EC per their guidelines. The Investigator 
and his/her staff are responsible for knowing and adhering to their local guidelines. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 191 of 223 
14 ETHICS/PROTECTION OF HUMAN PATIENTS 
14.1 Ethical Standard 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations 
(including European Directive 2001/20/EC, US CFR Title 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
Records that may reveal the identities of patients must be well protected, with 
consideration given to confidentiality and the right to privacy. 
Each Principal Investigator will sign this protocol and complete, sign and date the FDA 
1572 form (or an equivalent document) prior to conducting any study-related activities. 
Each Principal Investigator and Sub-Investigator will complete, sign and date the 
Financial Disclosure Form (or an equivalent document) to declare any financial or other 
competing interests. Participating Investigators will receive protocol training either at the 
SIV or via attendance at an Investigator Meeting. 
14.2 Institutional Review Board / Independent Ethics Committee 
Before initiating the study, the Investigator/institution should obtain approval/favorable 
opinion from the IRB/EC for the trial protocol, written ICF, ICF updates, patient recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
patients. The IRB/IEC shall be appropriately constituted and perform its functions in 
accordance with FDA, EU, ICH GCP, and local requirements as applicable. 
Prior to study start, the Investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents 
and all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to the CRA, auditors, the Sponsor’s QA representatives, 
designated agents of the Sponsor, IRBs/IECs, and Regulatory Authorities as required. If 
an inspection of the clinical site is requested by a Regulatory Authority, the Investigator 
must inform the Sponsor immediately that this request has been made. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 192 of 223 
14.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the patient’s agreeing to participate 
in the study and continues throughout the patient’s study participation. Written 
documentation of informed consent is required prior to any performance of study 
procedures. 
A site-specific, IRB/EC-approved ICF, describing in detail the study treatments and 
procedures, visit schedule, restrictions and risks and possible benefits, will be given to 
the patient during a clinic visit. The patient will be asked to read and review the document. 
The Investigator will explain the research study to the patient and answer any questions 
that may arise. The patient should have the opportunity to discuss the study with others 
if they wish and should be given adequate time to consider their decision before to 
agreeing to participate. If the patient agrees to participate, he/she will sign and date the 
ICF with the Investigator. A copy of the signed informed consent document will be given 
to the patient to keep. 
The patient may withdraw consent at any time throughout the course of the trial without 
affecting their legal rights or incurring loss of benefits to which they are otherwise entitled. 
The rights and welfare of the patient will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in 
this study, or by withdrawal of consent.  
 Exclusion of Women, Minorities, and Children  
Women and minorities may be eligible to participate. Participants must meet all of the 
inclusion criteria listed in Section 5.2 and none of the exclusion criteria listed in 
Section 5.3 to be eligible to participate. Only adults (aged 18-65 years at the time of 
signing the informed consent form) will be enrolled at this early stage of VTX-801 
development; children, a relevant population in WD, are to be evaluated at a later stage, 
after gaining experience in adults and evaluating safety. 
14.4 Patient Confidentiality 
Patient confidentiality is strictly held in trust by the participating Investigators, their staff, 
home nurses and the Sponsor(s) and their agents. This confidentiality is extended to 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 193 of 223 
cover testing of biological samples and genetic tests in addition to the clinical information 
relating to participating patients. 
The study protocol, documentation, data, and all other information generated will be held 
in strict confidence. No information concerning the study or the data will be released to 
any unauthorized third party without prior written approval of the Sponsor. 
The study monitor or other authorized representatives of the Sponsor may inspect all 
documents and records required to be maintained by the Investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
patients in this study. The clinical study site will permit access to such records. 
14.5 Treatment Plan in The Event of Study Discontinuation 
In the event the study is prematurely discontinued, arrangements will be made for the 
patients’ care to continue according to local standard clinical practice. Any patient will 
have an Early Termination visit scheduled and the assessments listed in Section 10.10 
performed.  
For any patient administered the IMP, even partially, every effort will be made to follow 
up the patient for up to 5 years post-IMP administration with at least one phone call every 
6 months.  
14.6 Future Use of Stored Specimens 
Samples will not be labelled with information that directly identifies the patient but will be 
coded with the identification number for the patient. 
Collected samples may be transferred for analysis to the Sponsor, or to other laboratories 
working for the Sponsor. 
Biological samples will be stored for the time established by regulatory requirements or 
destroyed after the final clinical study report has been finalized if storage is not required.  
Some samples require long term storage after the study ends.  
There might be a new request for these samples to be used for purposes related to the 
QA of the laboratory tests described in this protocol, in which case they will be used for 
this purpose. This may include the assessment of the quality of current tests, the 
maintenance or improvement of these tests, the development of new test methods for the 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 194 of 223 
markers described in this protocol, as well as making sure that new tests are comparable 
to previous methods and work reliably. 
If study results suggest that further investigations using stored biological samples are 
warranted, these tests might be carried out on an exploratory basis. In addition, biological 
samples may be used by the Sponsor or their research partners for further research that 
is not related to the disease or the product under study. This testing will be done on 
anonymized samples (meaning that any identification linking the patient to the sample is 
destroyed). Patients will be asked to check a box on the informed consent form for this 
optional testing and refusal of consent will not affect their possibility of participating in the 
study. 
14.7 Insurance 
The Sponsor has established an insurance policy for the total anticipated duration of the 
study, covering the participants with respect to the risks involved in taking part in this 
study in accordance with this protocol. In the case of injury or disability deriving from 
participation in the study, patients are requested to inform the Investigator or his/her staff 
responsible for the study at the institution without delay. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 195 of 223 
15 PUBLICATION POLICY 
The Sponsor shall retain the ownership of all data. When the study is complete the 
Sponsor shall arrange the analysis and tabulation of data. A clinical study report shall 
then be prepared, which may be used for publication, presentation at scientific meetings 
or submission to Regulatory Authorities. All proposed publications based on this study 
must be subject to the Sponsor's approval requirements. 
As per local requirements, the study will be registered with publicly searchable databases 
including ClinicalTrials.gov. A summary of the study results will be published on the 
ClinicalTrials.gov and EUDRACT websites.  

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 196 of 223 
16 LITERATURE REFERENCES 
 
1. EMA guideline, 2009 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-follow-patients-
administered-gene-therapy-medicinal-products_en.pdf 
 
2. EMA guideline, 2017 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-
identify-mitigate-risks-first-human-early-clinical-trials-investigational_en.pdf 
 
3. FDA guideline, 2020 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/long-term-
follow-after-administration-human-gene-therapy-products 
 
4. FDA guideline, 2018 
https://www.fda.gov/media/115172/download 
 
5. FDA guideline, 2009 
https://www.fda.gov/media/116737/download 
 
6. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, 2017 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_5x7.pdf 
 
7. Dietary Guidelines for Americans, 2015-2020 
https://health.gov/sites/default/files/2019-09/2015-2020_Dietary_Guidelines.pdf. 
Accessed on 23Sept2020 
 
8. Ala et al, 2007 
Wilson’s Disease. Lancet 2007; 369: 397-408. 
 
9. Beinhardt et al, 2014 
Long-term Outcomes of Patients with Wilson Disease in a large Austrian Cohort. Clinical 
Gastroenterology and Hepatology 2014;12:683-689. 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 197 of 223 
10. Binks, 2021 
“Symposium on Toxicities and limitations of gene therapy: The challenges of DMD Gene 
therapy Clinical trials”. Presented on May 12 2021 at the ASGCT 2021 meeting. 
Accessed on 30-July-2021 https://annualmeeting.asgct.org/program/day-two. 
 
11. Brewer, 2015 
The Modern Treatment of Wilson’s Disease. J Gastrointest Dig Syst 5:312. 
doi:10.4172/2161-069X.1000312. 
 
12. Chand et al, 2021 
Thrombotic Microangiopathy Following Onasemnogene Abeparvovec for Spinal 
Muscular Atrophy: A Case Series. J Pediatr 2021 Apr;231:265-268. doi: 
10.1016/j.jpeds.2020.11.054. 
 
13. Choe et al, 2020 
A population-based epidemiology of Wilson's disease in South Korea between 2010 and 
2016. Sci Rep. 2020 Aug 20;10(1):14041. 
 
14. Cillo et al, 2020 
Immunosuppressive regimens for adult liver transplant recipients in real-life practice: 
consensus recommendations from an Italian Working Group. Hepatol Int 2020;14:930–
943. 
 
15. Corti et al, 2014 
B-cell depletion is protective against anti-AAV capsid immune response: a human 
subject case study. Molecular Therapy — Methods & Clinical Development 2014;1: 
14033. doi:10.1038/mtm.2014.33. 
 
16. Członkowska et al, 2018b 
Accuracy of the radioactive copper incorporation test in the diagnosis of Wilson disease. 
Liver Int. 38 (10); 1860-1866. 
 
17. Członkowska et al, 2022 
Seven decades of clinical experience with Wilson's disease: Report from the national 
reference centre in Poland. Eur J Neurol. 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 198 of 223 
18. Daniel-Robin et al, 2022 
Epidemiology, treatment and burden of Wilson disease in France: A 10-year analysis of 
the national health insurance database. Clin Res Hepatol Gastroenterol.  
 
19. D'Antiga et al, 2021, European Society of Gene and Cell Therapy Congress 
Adeno-associated virus vector mediated gene therapy for Crigler Najjar syndrome: 
results of safety and efficacy from the dose escalation phase of the CareCN clinical trial. 
Abstract 0R77. 
 
20. Duan, 2018 
Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy. Mol 
Ther. 2018 Oct 3;26(10):2337-2356. doi: 10.1016/j.ymthe.2018.07.011. Epub 2018 Jul 
17. PMID: 30093306 Free PMC article. Review. 
 
21. EASL, 2012 
EASL Clinical Practice Guidelines: Wilson’s disease. Journal of Hepatology 2012 vol. 
56:671–685. 
 
22. EASL, 2015 
EASL Clinical Practice Guidelines: Autoimmune hepatitis. Journal of Hepatology 2015 
vol. 63:971–1004. 
 
23. EASL, 2019 
EASL Clinical Practice Guidelines: Drug-induced liver injury. Journal of Hepatology 2019 
vol. 70(6):1222-1261. 
 
24. Ganschow et al, 2013  
Growing experience with mTOR inhibitors in pediatric solid organ transplantation. 
Pediatr Transplantation 2013: 17: 694–706. 
 
25. George et al, 2017 
Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. NEJM; 
377:2215-2227. 
 
26. Gibbs et al, 1980 
Biliary excretion of copper in Wilson’s disease. Lancet 1980; Sep 6: 538-539. 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 199 of 223 
27. Gil-Farina et al, 2016 
Recombinant AAV Integration Is Not Associated With Hepatic Genotoxicity in Nonhuman 
Primates and Patients. Mol Ther. 2016 Jun;24(6):1100-1105. doi: 10.1038/mt.2016.52. 
 
28. Guillou et al, 2022  
Fatal thrombotic microangiopathy case following adeno-associated viral SMN gene 
therapy. Blood Adv 26;6(14):4266-4270. 
 
29. Hill et al, 1986 
Treatment of Wilson's disease with zinc. II. Validation of oral 64copper with copper 
balance. Am J Med Sci. 1986 Dec;292(6):344-9. 
 
30. Huff et al, 2007 
Copper Deficiency Causes Reversible Myelodysplasia. American Journal of Hematology 
2007; 82:625-630. 
 
31. ICRP Publication 62, 1992 
Radiological Protection in Biomedical Research, A Report of Committee 3 Adopted by 
the International Commission on Radiological Protection, Nov 1992. Pergamon Press. 
 
32. Kamath et al, 2001 
A model to predict survival in patients with end-stage liver disease. Hepatology 2001 
Feb;33(2):464-70. doi: 10.1053/jhep.2001.22172. 
 
33. Kumar, 2006 
Copper deficiency myelopathy. Mayo Clin Proc. 2006 Oct;81(10):1371-84. 
 
34. Maselbas et al, 2010 
Persistence with treatment in patients with Wilson disease. Neurologia i Neurochirurgia 
Polska 2010; 44, 3: 260–263. 
 
35. Maselbas et al, 2019 
Persistence with treatment for Wilson disease: a retrospective study. BMC Neurology 
2019;19:278. 
 
36. Mathews, 1954 
The absorption and excretion of radiocopper in hepatolenticular degeneration (Wilson’s 
Disease). J. Neurol. Psychiat. 17, 242. 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 200 of 223 
 
37. Mendell et al, 2021 
Current Clinical Applications of In Vivo Gene Therapy with AAVs  
Mol Ther - 2021 Feb 3;29(2):464-488. doi: 10.1016/j.ymthe.2020.12.007. Epub 
2020 Dec 10.  
 
38. Merle et al, 2007 
Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort 
study. Gut. 2007;56(1):115‐120. doi:10.1136/gut.2005.087262. 
 
39. Morales et al, 2020 
Broader Implications of Progressive Liver Dysfunction and Lethal Sepsis in Two Boys 
following Systemic High-Dose AAV. Mol Ther 2020 Aug 5;28(8):1753-1755. doi: 
10.1016/j.ymthe.2020.07.009. Epub 2020 Jul 16.  
 
40. Nathwani et al, 2017 
Advances in Gene Therapy for Hemophilia. Hum Gene Ther. 2017 Nov;28(11):1004-
1012. doi: 10.1089/hum.2017.167. 
 
41. Ohmori, 2020 
Advances in gene therapy for hemophilia: basis, current status, and future perspectives. 
Int J Hematol - 2020 Jan;111(1):31-41. doi: 10.1007/s12185-018-2513-4. Epub 2018 
Aug 6. 
 
42. Park et al, 2017 
Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis 
and Noninvasive Measurement of Steatosis in Patients With Biopsy-Proven 
Nonalcoholic Fatty Liver Disease. Gastroenterology. 2017 Feb;152(3):598-607.e2. doi: 
10.1053/j.gastro.2016.10.026. Epub 2016 Oct 27. PMID: 27911262; PMCID: 
PMC5285304 
 
43. Pavletic et al, 2015 
Exercise-induced elevation of liver enzymes in a healthy female research volunteer. 
Psychosomatics. 2015;56(5):604-606) 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 201 of 223 
44. Pettersson et al, 2007 
Muscular exercise can cause highly pathological liver function tests in healthy men. Br J 
Clin Pharmacol 2007; 65:2; 253–259. DOI:10.1111/j.1365-2125.2007.03001. 
 
45. Philippidis, 2022 
Novartis Confirms Deaths of Two Patients Treated with Gene Therapy Zolgensma. Hum 
Gene Ther 2022 Sep;33(17-18):842-844. doi: 10.1089/hum.2022.29216.bfs 
 
46. Pipe et al, 2017 
101HEMB01 Is a Phase 1/2 Open-Label, Single Ascending Dose-Finding Trial of 
DTX101 (AAVrh10FIX) in Patients with Moderate/Severe Hemophilia B That 
Demonstrated Meaningful but Transient Expression of Human Factor IX (hFIX). Blood 
2017;130: 3331. 
 
47. Poujois et al, 2020 
Liver transplantation as a rescue therapy for severe neurologic forms of Wilson disease. 
Neurology, 2020 May;26;94(21): e2189-e2202; doi: 10.1212/WNL. 
 
48. Rangarajan et al, 2017  
AAV5–Factor VIII Gene Transfer in Severe Hemophilia A. NEJM; 377:2519-2530. 
 
49. Sandahl et al, 2019 
Evaluation of human Copper metabolism and the diagnosis of Wilson disease by 64CuCl2 
positron emission tomography. Abstract (2019). 
 
50. Scheinberg et al, 1987 
The Use of Trientine in Preventing the Effects of Interrupting Penicillamine Therapy in 
Wilson's Disease. N Engl J Med 1987; 317:209-213. doi: 
10.1056/NEJM198707233170405. 
 
51. Schilsky, 2017 
Wilson Disease. Diagnosis, Treatment, and Follow-up. Clin Liver Dis 21 (2017); 755-
767. 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 202 of 223 
52. Schilsky et al, 2022 
A multidisciplinary approach to the diagnosis and management of Wilson disease: 2022 
practice guidance on Wilson disease from the American Association for the Study of 
Liver Diseases. Hepatology. 2022;00:1-49. doi: 10.1002/hep.32801 
 
53. Shieh et al, 2020  
Re : “Moving Forward After Two Deaths in a Gene Therapy Trial of Myotubular 
Myopathy” by Wilson and Flotte. Hum Gene Ther. 2020;31(15-16):787. 
doi:10.1089/hum.2020.217  
 
54. Shieh, 2021 - European Society of Gene and Cell Therapy Congress 
ASPIRO Gene Therapy Trial In X-Linked Myotubular Myopathy (XLMTM): Update on 
Preliminary Efficacy and Safety Findings. Abstract INV32. 
 
55. Sini et al, 2012 
Non-invasive assessment of hepatic fibrosis in a series of patients with Wilson's 
Disease. Dig Liver Dis. 2012 Jun;44(6):487-91. doi: 10.1016/j.dld.2011.12.010 
 
56. Smith et al, 2022 
Pre-existing humoral immunity and complement pathway contribute to immunogenicity of 
adeno-associated virus (AVV) vector in human blood. Front. Immunol.2022 Sep 16; 13. 
https://doi.org/10.3389/fimmu.2022.999021 
 
57. Solovyev et al, 2020 
Biomedical copper speciation in relation to Wilson's disease using strong anion 
exchange chromatography coupled to triple quadrupole inductively coupled plasma 
mass spectrometry. Anal Chim Acta. 2020 Feb 15;1098:27-36. doi: 
10.1016/j.aca.2019.11.033. Epub 2019 Nov 15. PMID: 31948584. 
 
58. Sterling et al, 2006 
Development of a simple noninvasive index to predict significant fibrosis in patients with 
HIV/HCV coinfection. Hepatology 2006 Jun;43(6):1317-25. doi: 10.1002/hep.21178. 
 
59. Stove et al, 2018 
Measurement of sirolimus concentrations in human blood using an automated 
electrochemiluminescence immunoassay (ECLIA): a multicenter evaluation, Clinical 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 203 of 223 
Chemistry and Laboratory Medicine (CCLM), 2018; 56(5):764-775. doi: 10.1515/cclm-
2017-0583. 
 
60. Strickland et al, 1971 
Metabolic studies in Wilson's disease. Evaluation of efficacy of chelation therapy in 
respect to copper balance. Am J Med. 1971 Jul;51(1):31-40. 
 
61. Tauxe et al, 1966 
Radiocopper studies in patients with Wilson's disease and their relatives. Am J Med. 
1966 Sep;41(3):375-80. 
 
62. Tedesco‐Silva et al, 2019 
Optimizing the clinical utility of sirolimus‐based immunosuppression for kidney 
transplantation. Clin Transplant. 2019 Feb;33(2):e13464. doi: 10.1111/ctr.13464. 
 
63. Tenenbaum et al, 2003 
Evaluation of risks related to the use of adeno-associated virus-based vectors. Curr 
Gene Ther. 2003 Dec;3(6):545-65. 
 
64. Vierling et al, 1978 
Incorporation of radiocopper into ceruloplasmin in normal subjects and in patients with 
primary biliary cirrhosis and Wilson's disease. Gastroenterology, Volume 74, Issue 4, 
Pages 652–660. 
 
65. Vivet Therapeutics, 2021 
VTX-801_CLN_002 study, "COMET". Copper balance study of a single intravenous 
injection of [64Cu]copper dichloride in adult healthy volunteers, including Wilson´s 
Disease heterozygotes. Clinical Study Report; January 2021. 
 
66. Walker et al, 2018 
Liver Transplant Can Resolve Severe Neuropsychiatric Manifestations of Wilson 
Disease: A Case Report. Experimental and Clinical Transplantation 2018;5: 620-624. 
 
67. Walshe, 2003 
Wilson’s disease: the importance of measuring serum caeruloplasmin non-
immunologically. Ann Clin Biochem 2003; 40: 115–121. 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 204 of 223 
68. Wang et al, 2015 
Comparative Study of Liver Gene Transfer With AAV Vectors Based on Natural and 
Engineered AAV Capsids. Mol Ther. 2015 Dec; 23(12): 1877–1887. 
 
69. Woimant et al, 2019 
Monitoring of Medical Therapy and Copper End Points. Wilson Disease - Chapter 22, 
2019; 223-232. 
 
70. Zhong-Hua Lin et al, 2011 
Performance of the aspartate aminotransferase‐to‐platelet ratio index for the staging of 
hepatitis C‐related fibrosis: An updated meta‐analysis. Hepatology 2011; 53(3):726-736. 
 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 205 of 223 
17 APPENDICES 
 
 
 

 
 
Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023  
 
Author: Aixial Group CRO 
 
MSSOP002/F1; Version 1.0 01NOV2016                 CONFIDENTIAL                  Page 211 of 223 
17.2 Modelling and Simulation 
 
 

Investigational Product: VTX-801 
Protocol VTX-801_CLN_001 
Version: 9 dated 07 AUG 2023 
Author: Aixial Group CRO 
MSSOP002/F1; Version 1.0 01NOV2016 
  CONFIDENTIAL   
  Page 223 of 223 
17.3 Low-copper Diet 
Low-copper diet, from Schilsky et al, 2022 (AASLD): Foods with very high concentrations 
of copper (shellfish, nuts, chocolate, mushrooms, and organ meats) generally should be 
avoided, at least in the first year of treatment. Diets deficient in copper may delay the 
onset of the disease and control disease progression, but dietary management is not 
sufficient to treat patients.