A Phase 2, Single-arm Pathologist-blinded 48-week Study Using Liver Biopsy Specimens to Assess Copper Concentration and Histopathologic Changes in ALXN1840-treated Patients With Wilson Disease Followed by an up to 48-weeks Extension Period
Phase: PHASE2
Conditions: Wilson Disease
Sponsor: Alexion Pharmaceuticals, Inc.

Protocol Amendment 5 (Global) 
ALXN1840-WD-205 
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Alexion Confidential 
PROTOCOL TITLE PAGE 
Protocol Title: A Phase 2, single-arm, pathologist-blinded study using liver biopsy specimens to 
assess copper concentration and histopathologic changes in patients with Wilson disease who are 
treated with ALXN1840 for 48 weeks followed by an extension treatment period with 
ALXN1840 for up to an additional 48 weeks 
Protocol Number: ALXN1840-WD-205 
Amendment Number: 5 (Global) 
Compounds: ALXN1840 (bis-choline tetrathiomolybdate) 
Study Phase: 2 
Short Title: Copper concentration and histopathologic changes in liver biopsy in patients with 
Wilson disease who are treated with ALXN1840 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Legal Registered Address:  
121 Seaport Boulevard 
Boston MA, 02210 
USA 
Regulatory Agency Identifier Number(s) 
(XGUD&71XPEHUဨဨ 
,1'QXPEHU 
Approval Dates: 
Original Protocol 
20 Dec 2019 
Amendment 1 (Austria) 
07 May 2020 
Amendment 2 (Germany) 
03 Aug 2020 
Amendment 3 (Denmark) 
10 Aug 2020 
Amendment 4 (United Kingdom) 
23 April 2021 
Amendment 5 (Global) 
27 May 2022 
Alexion Signatory: 
Date 
Medical Monitor Name and Contact Information can be found in the Study Contact List. 
24-hour Emergency Contact: 
		

NCT #: NCT04422431

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INVESTIGATOR’S AGREEMENT 
I have read the Study ALXN1840-WD-205 protocol amendment 5 (Global) and agree to conduct 
the study in accordance with this protocol, all applicable government regulations, the principles 
of the ICH E6 Guidelines for Good Clinical Practice, and the principles of the World Medical 
Association Declaration of Helsinki. I also agree to maintain the confidentiality of all 
information received or developed in connection with this protocol.  
 
 
 
 
 
____________________________________ 
Printed Name of Investigator 
 
_____________________________________ 
Signature of Investigator 
 
_______________ 
Date 

Protocol Amendment 5 (Global) 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Amendment 5 (27 May 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union, the 
US Food and Drug Administration’s (FDA) regulation at 21 CFR part 312.30(b), and any 
applicable local regulations. 
Overall Rationale for the Amendment 
This amendment has been prepared to add the requirement for Alexion approval prior to 
increasing the dose of ALXN1840, to add labile-bound copper (LBC) and directly measured 
non-ceruloplasmin-bound copper (dNCC) as exploratory endpoints, and to add an exploratory 
endpoint for the daily mean area under the effect-time curve (AUEC) for dNCC. Administrative 
Change Letters since approval of the previous protocol have also been incorporated. Changes are 
summarized in the table below. 
Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or 
Clarifications 
Section 1.1, Synopsis; 
Section 3, Objectives and 
Endpoints; Section 8.1.2, 
Non-Ceruloplasmin-
Bound Copper 
Added as exploratory endpoints:  
• 
absolute and percent change in 
directly measured non-
ceruloplasmin-bound copper 
(dNCC) and labile-bound 
copper (LBC) from baseline to 
Week 48 
• 
daily mean area under the 
effect-time curve (AUEC) of 
dNCC from 0 to 48 weeks 
To align with other ALXN1840 
Phase 2 and 3 studies. 
Section 1.1, Synopsis, 
Drug Groups and 
Duration; Section 4.1 
Overall Design; Section 
4.3, Justification for Dose; 
Section 6.6 Dose 
Modification 
Addition of text to clarify that 
Alexion approval is needed to 
increase the dose of ALXN1840 
after an interruption or reduction.  
To enhance Alexion oversight of 
dose escalations. 
Section 1.2, Schema, 
Figure 1 
Figure corrected to remove 
mention of treatment-naïve 
patients. 
Treatment-naïve patients are not 
included in the study. 
Section 1.3 Schedule of 
Activities, Table 1 
Administer/dispense ALXN1840 
added at Week 48 for patients 
continuing into the Extension 
Period (including footnote ‘w’ 
“only for patients continuing into 
the Extension Period”). 
Patients continuing into the 
Extension Period require 
dispensation of ALXN1840 at the 
Week 48 visit of the Treatment 
Period. 
Footnote ‘o’ added to Week 48 
chemistry, coagulation, 
hematology panel, and urinalysis 
assessments 
To align with current protocol 
procedure. 

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Section 1.3 Schedule of 
Activities, Table 1 and 
Table 2, Section 8.1.7, 
Imaging Techniques 
FibroScan noted as preferred 
method of transient elastography 
instead of required method. 
Other methods of transient 
elastography are permitted if 
FibroScan is not available. 
Section 1.3 Schedule of 
Activities, Table 2 
 
Footnote ‘f’ revised to 
“…..negative urine pregnancy test 
at each study visit.” 
To align with footnote ‘m’ in Table 
1. 
12-lead ECG deleted at EOS visit 
Not required. 
Extension Period Day 365 added 
to EOS visit 
Correction of typographical error. 
Administer/dispense ALXN1840 
deleted at Extension Period Day 
337. 
Extension Period Day 337 is the 
last visit in the Extension Period; 
treatment with ALXN1840 is 
complete. 
Section 5.1, Inclusion 
Criteria 
Inclusion criterion #1 for 
confirmation of diagnosis of 
Wilson disease changed to Leipzig 
score ≥ 4 (formerly > 4) and 
expanded to include historical test 
results. 
A historical diagnosis of Wilson 
disease is sufficient. The original 
criteria for diagnosis of Wilson 
disease will be recorded in a case 
report form. It is not necessary to 
repeat the diagnostic evaluation of 
Wilson disease for this protocol.  
Section 5.1, Inclusion 
Criteria; Section 8.3.5, 
Pregnancy; Section 10.4, 
Appendix 4, Pregnancy 
Information 
Contraception guidance updated to 
include duration of use and type; 
duration of pregnancy follow-up 
revised. 
To further define contraception and 
pregnancy follow-up requirements. 
Section 5.2, Exclusion 
Criteria 
Criterion #17 amended to exclude 
participation in another clinical 
study within 3 months (or 
5 half-lives of the administered 
investigational medicinal product, 
whichever is longer) prior to study 
start. 
More detailed language regarding 
exclusion of patients who 
participated in any interventional 
study prior to initiation of Study 
ALXN1840-WD-205. 
Section 6.5, Concomitant 
Therapy 
Standard of care treatment for 
Wilson disease added as prohibited 
medication during the Treatment 
and Extension Periods. 
Standard of care treatment for 
Wilson disease and ALXN1840 
should not be administered 
concomitantly. 
Section 6.6, Dose 
Modification, Table 6 
Addition of dose modification 
rules for increased triglycerides 
and total cholesterol. 
To include guidance on dose 
modifications in the event of 
increased triglycerides or total 
cholesterol. 
Section 8, Study 
Assessments and 
Procedures 
Liver biopsy text revised to “Liver 
biopsy is the last pre-dose baseline 
procedure to be completed and 
must be completed within 14 days 
prior to the first dose of 
ALXN1840” (formerly “a 
minimum of 14 days”). 
To align with text in Section 8.6. 

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Section 8.6, 
Pharmacodynamics 
Text updated to include all 
pharmacodynamic measures that 
will be evaluated. 
For clarification and completeness. 
10.1.1 Regulatory and 
Ethical Considerations  
Modified text to remove specific 
reference to regional guidance and 
listed as examples only. Included 
the European Regulation No 
536/2014 for clinical trials on 
medicinal products for human use 
as an example. 
To include a more general 
statement as not all regional 
guidances previously included are 
applicable in every region. 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests, 
Table 8, Clinical 
Chemistry 
Lipid profile (total cholesterol, 
LDL, HDL, and triglycerides 
added to the table of chemistry 
assessments. 
Routine tests added for 
completeness. 
Section 10.3, Appendix 3, 
Adverse Events, Reporting 
of Serious Adverse Events 
Deleted instructions for reporting 
via paper case report form. 
To align with current protocol 
procedure. 
Section 10.5, Genetics 
Retention of DNA sample changed 
from 10 years to 15 years. 
To align with Alexion standard. 
All sections 
Minor editorial updates and 
corrections. 
For clarification, and to ensure 
accuracy and consistency 
throughout the protocol. 
 
 

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TABLE OF CONTENTS 
PROTOCOL TITLE PAGE .............................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................3 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
1.1. 
Synopsis ......................................................................................................................11 
1.2. 
Schema ........................................................................................................................14 
1.3. 
Schedules of Activities ...............................................................................................14 
2. 
INTRODUCTION ......................................................................................................21 
2.1. 
Study Rationale ...........................................................................................................21 
2.2. 
Background .................................................................................................................21 
2.2.1. 
Wilson Disease ...........................................................................................................21 
2.2.2. 
ALXN1840 .................................................................................................................22 
2.3. 
Benefit/Risk Assessment ............................................................................................23 
2.3.1. 
Risk Assessment .........................................................................................................23 
2.3.2. 
Benefit Assessment .....................................................................................................25 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................25 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................26 
4. 
STUDY DESIGN .......................................................................................................28 
4.1. 
Overall Design ............................................................................................................28 
4.2. 
Scientific Rationale for Study Design ........................................................................28 
4.3. 
Justification for Dose ..................................................................................................29 
4.4. 
End of Study Definition ..............................................................................................30 
5. 
STUDY POPULATION .............................................................................................31 
5.1. 
Inclusion Criteria ........................................................................................................31 
5.2. 
Exclusion Criteria .......................................................................................................32 
5.3. 
Lifestyle Considerations .............................................................................................34 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................34 
5.3.2. 
Restrictions Relating to the Liver Biopsy ...................................................................34 
5.4. 
Screen Failures ............................................................................................................35 
6. 
STUDY DRUG ...........................................................................................................36 
6.1. 
Study Drugs Administered .........................................................................................36 

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6.2. 
Preparation/Handling/Storage/Accountability ............................................................36 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................37 
6.4. 
Study Drug Compliance .............................................................................................37 
6.5. 
Concomitant Therapy .................................................................................................37 
6.6. 
Dose Modification ......................................................................................................38 
6.7. 
Drug after the End of the Study ..................................................................................42 
7. 
DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..................................................................43 
7.1. 
Discontinuation of Study Drug ...................................................................................43 
7.1.1. 
Temporary Discontinuation ........................................................................................43 
7.1.2. 
Rechallenge .................................................................................................................43 
7.2. 
Patient Discontinuation/Withdrawal from the Study ..................................................43 
7.3. 
Lost to Follow-up .......................................................................................................44 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................46 
8.1. 
Efficacy Assessments .................................................................................................46 
8.1.1. 
Liver Biopsy Copper Content and Histologic Assessment .........................................46 
8.1.2. 
Non-Ceruloplasmin-Bound Copper ............................................................................47 
8.1.3. 
Model for End-Stage Liver Disease ...........................................................................47 
8.1.4. 
Modified Nazer Score .................................................................................................47 
8.1.5. 
Unified Wilson Disease Rating Scale (Parts I, II, and III) .........................................47 
8.1.6. 
Clinical Global Impression-Improvement Severity Scale and the Clinical 
Global Impression-Severity Improvement Scale ........................................................47 
8.1.7. 
Imaging Techniques ....................................................................................................48 
8.1.8. 
Quality of Life, Treatment Satisfaction, and Psychiatric Symptoms .........................48 
8.1.8.1. 
EuroQoL 5 Dimensions ..............................................................................................48 
8.1.8.2. 
Short Form Health Survey (SF-36) .............................................................................49 
8.1.8.3. 
Chronic Liver Disease Questionnaire .........................................................................49 
8.1.8.4. 
Treatment Satisfaction Questionnaire for Medication ................................................49 
8.1.9. 
Brief Psychiatric Rating Scale-24 ...............................................................................50 
8.2. 
Safety Assessments .....................................................................................................50 
8.2.1. 
Physical Examinations ................................................................................................50 
8.2.2. 
Vital Signs ..................................................................................................................50 
8.2.3. 
Electrocardiograms .....................................................................................................50 

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8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................51 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................51 
8.3. 
Adverse Events and Serious Adverse Events .............................................................52 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................52 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................52 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................52 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................53 
8.3.5. 
Pregnancy ...................................................................................................................53 
8.3.6. 
Adverse Events of Special Interest .............................................................................54 
8.4. 
Treatment of Overdose ...............................................................................................54 
8.5. 
Pharmacokinetics ........................................................................................................54 
8.6. 
Pharmacodynamics .....................................................................................................55 
8.7. 
Genetics ......................................................................................................................55 
8.8. 
Biomarkers ..................................................................................................................55 
8.9. 
Immunogenicity Assessments ....................................................................................55 
8.10. 
Medical Resource Utilization and Health Economics ................................................55 
9. 
STATISTICAL CONSIDERATIONS .......................................................................56 
9.1. 
Statistical Hypotheses .................................................................................................56 
9.2. 
Sample Size Determination ........................................................................................56 
9.3. 
Populations for Analyses ............................................................................................56 
9.4. 
Statistical Analyses .....................................................................................................57 
9.4.1. 
Efficacy Analyses .......................................................................................................57 
9.4.1.1. 
Treatment Period ........................................................................................................57 
9.4.1.2. 
Multiplicity Adjustment..............................................................................................58 
9.4.2. 
Safety Analyses ..........................................................................................................58 
9.4.3. 
Other Analyses ............................................................................................................58 
9.4.4. 
Interim Analyses .........................................................................................................59 
9.4.5. 
Extension Period Analyses .........................................................................................59 
9.5. 
Data Monitoring Committee .......................................................................................59 
9.6. 
Hepatic Adjudication Panel ........................................................................................59 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................60 

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10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................60 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................60 
10.1.2. 
Financial Disclosure ...................................................................................................60 
10.1.3. 
Informed Consent Process ..........................................................................................61 
10.1.4. 
Data Protection ...........................................................................................................61 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................62 
10.1.6. 
Data Quality Assurance ..............................................................................................62 
10.1.7. 
Source Documents ......................................................................................................62 
10.1.8. 
Study and Site Start and Closure ................................................................................63 
10.1.9. 
Publication Policy .......................................................................................................63 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................64 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................66 
10.4. 
Appendix 4: Pregnancy Information ..........................................................................70 
10.5. 
Appendix 5: Genetics .................................................................................................74 
10.6. 
Appendix 6: Abbreviations .........................................................................................75 
10.7. 
Appendix 7: Protocol Amendment History ................................................................77 
11. 
REFERENCES ...........................................................................................................80 
 

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LIST OF TABLES 
Table 1: 
Schedule of Activities –Treatment Period ..................................................................16 
Table 2: 
Schedule of Activities – Extension Period .................................................................19 
Table 3: 
Potential Risks and Mitigation Strategy .....................................................................24 
Table 4: 
Study ALXN1840-WD-205 Objectives and Endpoints .............................................26 
Table 5: 
Study Drugs Administered .........................................................................................36 
Table 6: 
ALXN1840 Dose Modifications for Individual Patients ............................................39 
Table 7: 
Populations for Analyses ............................................................................................56 
Table 8: 
Protocol-Required Safety Laboratory Assessments ...................................................64 
 
LIST OF FIGURES 
Figure 1: 
Schema for Study ALXN1840-WD-205 ....................................................................14 
 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
A Phase 2, single-arm, pathologist-blinded study using liver biopsy specimens to assess copper 
concentration and histopathologic changes in patients with Wilson disease who are treated with 
ALXN1840 for 48 weeks followed by an extension treatment period with ALXN1840 for up to 
an additional 48 weeks 
Short Title:  
Copper concentration and histopathologic changes in liver biopsy in patients with Wilson disease 
who are treated with ALXN1840 
Rationale: 
This study is being conducted to assess the effect of ALXN1840 on changes in liver copper (Cu) 
concentration and liver histopathology in patients with Wilson disease (WD). Currently available 
standard of care (SoC) medications (ie, trientine, penicillamine, and zinc) control excess free Cu 
in the blood, but do not consistently reduce Cu overload in the liver. Conversely, 
tetrathiomolybdate (the active ingredient in ALXN1840) has been shown to reduce liver Cu 
stores in animal models (Suzuki, 1993; Suzuki, 1994; Suzuki, 1995; Ogra, 1995a; Ogra, 1995b; 
Ogra, 1996). 
Accumulation of Cu in the liver leads to an increased risk of tissue and organ damage. Limited 
available data obtained from serial liver biopsies in patients with WD indicate that liver Cu 
concentration remains elevated, with no consistent reduction of liver Cu over time in patients 
treated with SoC beyond the first year (Medici, 2006; Scheinberg, 1987; Cope-Yokoyama, 2010; 
Gibbs, 1990). The impact of ineffective decoppering with SoC medications can be seen in 
patients with WD who discontinue treatment for WD, who are at risk for rapid progression to 
liver failure (Maselbas, 2010; Dziezyc, 2014). Unlike penicillamine or trientine, ALXN1840 can 
enter hepatocytes and compete with metallothionein to bind intracellular Cu (Suzuki, 1993). 
Copper bound to the tetrathiomolybdate complex is excreted into the bile, promoting net 
negative excretion of Cu from the liver (Ogra, 1995b). In the Long-Evans Cinnamon rat model 
of WD, treatment with tetrathiomolybdate leads to rapid reduction in liver Cu concentration 
(Suzuki, 1995).  
The principal aim of this study is to evaluate the effect of ALXN1840 on reduction of liver Cu 
concentration at Week 48 of treatment compared with baseline in patients with WD who have 
been previously treated with SoC (ie, trientine, penicillamine, or zinc) for at least 1 year. 
Molybdenum concentration will also be assessed in the liver. 

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Objectives and Endpoints 
Objectives 
Endpoints 
Treatment Period 
Primary 
To evaluate change in liver copper (Cu) 
concentration following treatment with ALXN1840 
at Week 48 in patients with Wilson disease (WD) 
Change from baseline to Week 48 in liver Cu 
concentration 
Secondary 
To assess change in liver histopathology following 
treatment with ALXN1840 
Change from baseline to Week 48 in steatosis, 
inflammation, and fibrosis  
To evaluate the safety of ALXN1840 in patients 
with WD 
Adverse events (AEs), vital signs, ECGs, clinical 
laboratory data, and physical examination data 
To evaluate pharmacokinetics (PK) of ALXN1840 
• 
ALXN1840 PK profiles in plasma at Week 6 
(Day 43) and Week 36 (Day 253), of which 
ALXN1840 PK are measured as total molybdenum 
(Mo) and plasma ultrafiltrate (PUF) Mo 
• 
Pre-dose trough ALXN1840 concentrations in plasma 
at each study site visit 
• 
ALXN1840 concentrations in the liver biopsy 
specimen.  
To evaluate the effects of ALXN1840 on clinical 
symptoms 
Change from baseline in Clinical Global Impression-
Improvement (CGI-I) Scale and the Clinical Global 
Impression-Severity (CGI-S) Scale  
Exploratory 
To explore the effects of ALXN1840 on hepatic 
status 
Change from baseline to Week 48 in: 
• 
Model for End Stage Liver Disease (MELD) score 
• 
Modified Nazer score  
To assess changes in liver fibrosis and steatosis 
using non-invasive techniques 
Liver stiffness by magnetic resonance (MR) elastography 
and transient elastography (Vibration-Controlled Transient 
Elastography/FibroScan), MR-proton density fat fraction 
(PDFF) 
To explore changes in mitochondrial ultrastructure 
of the liver at Week 48 
Change from baseline to Week 48 in mitochondrial 
ultrastructure by electron microscopy 
To explore the change in Cu deposition in the eye at 
Week 48 
Change from baseline to Week 48 in in Cu deposition in 
the eye by optical coherence tomography 
To explore the change in pharmacodynamic (PD) 
and biomarkers with ALXN1840 treatment at 
Week 48 
• 
Absolute and percent change in plasma total and PUF 
Cu and calculated non-ceruloplasmin-bound Cu 
(cNCC) concentrations, as well as directly measured 
NCC (dNCC), labile-bound Cu (LBC), ceruloplasmin 
(Cp) and Cp-bound Cu (CpC) from baseline to Week 
48 
• 
Daily mean area under the effect-time curve (AUEC) 
of dNCC from 0 to 48 weeks 
To explore the effects of ALXN1840 on quality of 
life at Week 48 
Change from baseline to Week 48 in quality of life 
measures of: 
• 
EuroQoL 5 Dimensions (EQ-5D) 
• 
Short form-36 (SF-36) 
• 
Chronic Liver Disease Questionnaire (CLDQ) 
To assess treatment satisfaction of ALXN1840 at 
Week 48 
Treatment Satisfaction Questionnaire for Medication-9 
(TSQM-9) 
To explore the effects of ALXN1840 on neurologic 
and psychiatric symptoms 
Change from baseline to Week 48 in: 
• 
Brief Psychiatric Rating Scale-24 (BPRS-24) 
• 
Unified Wilson Disease Rating Scale (UWDRS) 

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Objectives 
Endpoints 
Extension Period 
All patients will continue to receive ALXN1840 in the 48-week Extension Period. 
All safety and efficacy parameters will be measured as detailed above at Week 48 in the Extension Period, except 
for liver biopsy, which will not be performed in the Extension Period. 
Overall Design: 
This is a Phase 2, open-label, pathologist-blinded, multicenter study designed to evaluate the 
change in liver Cu concentration at Week 48 compared with baseline in adult patients with WD 
treated with ALXN1840 at doses up to 30 mg once a day (QD) who have been treated for at least 
1 year with SoC (ie, penicillamine, trientine, or zinc). This study will include a Screening Period, 
Treatment Period, and an optional 48-week Extension Period.  
In the Treatment Period, efficacy and safety will be assessed for ALXN1840 at Week 48 in 
patients with WD who are aged 18 years and older. 
Patients who complete the Treatment Period will be offered the opportunity to participate in a 
48-week Extension Period to evaluate the long-term safety and efficacy of ALXN1840. All 
patients will continue to receive ALXN1840 at doses up to 30 mg/day during the Extension 
Period. Note that there will be no liver biopsies during the Extension Period. 
This study is pathologist-blinded for the assessments of liver histology samples. 
Disclosure Statement: This is an open-label, single-arm study with outcome assessor-masking 
for the assessments of liver histology samples.  
Number of Patients: 
Approximately 28 patients will be enrolled into the study globally, such that approximately 
24 evaluable patients complete the 48-week Treatment Period.  
Drug Groups and Duration: 
On Day 1 of the Treatment Period, patients will receive ALXN1840. Patients will be initiated at 
15 mg once daily, then the dose will be increased to 30 mg once daily at Week 6. 
In case of drug tolerability issues, the dose of ALXN1840 may be reduced or temporarily 
interrupted. Such dose changes must be discussed with the Alexion Medical Monitor and 
documented in the study record. Any subsequent dose increases must be approved by Alexion. 
The planned study duration is approximately 100 weeks, including an up to 4-week Screening 
Period. A liver biopsy will be performed during the Screening Period within 14 days prior to the 
first dose of study drug, followed by a 48-week Treatment Period, which starts on the day of first 
dose of study drug, and an optional 48-week Extension Period.  
Data Monitoring Committee: An independent Data Monitoring Committee (DMC), comprising 
experts in relevant fields with no direct relationship to the study, will be appointed by Alexion. 
As detailed in a Charter (maintained separately from the study protocol), the DMC will review 
and monitor study data for safety, effectiveness, and study conduct, and make recommendations 
regarding study continuation, changes to the study population, and/or modification to study 
procedures.  

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Hepatic Adjudication Panel: A separate, independent Hepatic Adjudication Panel, both 
comprising experts in relevant fields, will be appointed by Alexion. The specific responsibilities 
for this Panel are described in a Charter (maintained separately from the study protocol). 
1.2. 
Schema 
A schematic view of the study design is provided in Figure 1. 
Figure 1: 
Schema for Study ALXN1840-WD-205 
  
  
1.3. 
Schedules of Activities 
The Schedule of Activities (SoA) for the Screening and Treatment Periods is provided in 
Table 1. In the Screening Period, the liver biopsy should be performed after all other screening 
activities have been completed, including imaging, and the patient has met all inclusion and no 
exclusion criteria. 
The Day 337 (Week 48) visit is the end of the Treatment Period and the beginning of the 
Extension Period (ie, the Week 48 visit and the Extension Period Day 1 visit will occur on the 
same day). All assessments for the Week 48 visit and the liver biopsy must be performed before 
the first dose of ALXN1840 on Day 1 of the Extension Period. Dosing of ALXN1840 on 
Extension Period Day 1 marks the beginning of the Extension Period. Patients who do not enter 
the Extension Period will discontinue dosing at Week 48 following the second liver biopsy and 
will have a final study visit for safety follow up at Day 365 (Week 52) of the Treatment Period.  
The SoA for the Extension Period is provided in Table 2.  
On study visit days where laboratory sampling is planned, patients will be asked to withhold any 
doses of ALXN1840 due to be taken prior to their visit, to allow laboratory samples to be taken 
pre-dose. 
Laboratory specimen handling and processing instructions will be provided in the study 
laboratory manual. Blood samples should not be collected from a heparinized line.  

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Unscheduled visits that occur outside the protocol-specified visits are permitted at the discretion 
of the Investigator. Procedures, tests, and assessments conducted during unscheduled visits will 
be performed at the discretion of the Investigator. 
 

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Table 1: 
Schedule of Activities –Treatment Period 
 
Screening 
Treatment Period 
UNSa 
Follow-Upb 
Day 
-28 to -1 
1c 
8d 
15d 
29c 
43c 
57c 
85c 
127c 
169c 
211d 
253c 
295d 
337c / 
ETe 
 
365 
Week 
-4 to 0 
 
1 
2 
4 
6 
8 
12 
18 
24 
30 
36 
42 
48 
 
52 
Window (days) 
  
 
±3 
±7 
±3 
±7 
 
±7 
Obtain informed consent 
(written or electronic) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review eligibility criteria 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyg and 
demographic parametersh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WD medication history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Abbreviated physical 
examinationi 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
  
 
 
Vital signsj 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
12-lead ECG 
X 
 
 
 
 
X  
 
 
 
 
 
 
 
X 
  
 
FSHk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/hepatitis B and C testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA sample 
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testm 
X 
X 
  
 
X 
  
X 
X 
X 
X 
  
X 
  
X 
  
X 
Chemistry, coagulation, 
hematology panel, and 
urinalysisn 
Xo 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Xp 
 
X 
Screening ultrasound (before 
liver biopsy) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRE, transient elastography 
(FibroScan preferred), MR-
PDFF  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
  
 
Optical coherence tomography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
  
 
Liver biopsy (see Section 5.3.2) 
X 
  
 
 
 
 
 
 
 
 
 
 
 
X 
  
 
Plasma PK/PD/biomarker 
samplesq 
 
X 
  
 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
  
 
24-hour uriner 
 
X 
  
 
X 
  
 
X 
  
X 
  
X 
  
X 
  
 
UWDRSs,t 
 
X 
  
 
 
 
 
 
 
 
 
 
 
X 
  
 
CGIs 
 
Xu 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
EQ-5Ds 
 
X 
  
 
 
 
 
 
 
X 
  
 
 
X 
  
 
TSQM-9s 
X 
 
 
 
 
 
 
 
 
 
  
 
 
X 
  
 

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Screening 
Treatment Period 
UNSa 
Follow-Upb 
Day 
-28 to -1 
1c 
8d 
15d 
29c 
43c 
57c 
85c 
127c 
169c 
211d 
253c 
295d 
337c / 
ETe 
 
365 
Week 
-4 to 0 
 
1 
2 
4 
6 
8 
12 
18 
24 
30 
36 
42 
48 
 
52 
Window (days) 
  
 
±3 
±7 
±3 
±7 
 
±7 
SF-36s 
 
X 
  
 
 
 
 
 
 
X 
  
 
 
X 
  
 
CLDQs 
 
X 
  
 
 
 
 
 
 
X 
  
 
 
X 
  
 
BPRS-24s 
 
X 
  
 
 
 
 
 
 
X 
  
 
 
X 
  
 
AE, concomitant medication, and 
non-pharmacologic 
therapy/procedurev 
  
Administer/dispense 
ALXN1840w 
 
X 
  
 
X 
X 
X 
X 
X 
X 
  
X 
  
Xw 
 
 
Note: Patients who complete the 48-week period of treatment will be offered the opportunity to participate in an up to 48-week Extension Period in which they will continue to 
receive ALXN1840. 
a Unscheduled study visits may occur at any time during the study and may include any study procedures (including dispensing of ALXN1840) as deemed 
necessary by the Investigator. These visits may or may not be completed by a home healthcare nurse, where applicable, depending on the purpose of the 
unscheduled visit.  
b Follow up visit procedures (Day 365) will be performed only for patients who do not enter the Extension Period and will be the EOS visit for these patients. 
c Assessments on Day 1 and other study visit days where laboratory sampling is planned should be performed pre-dose.  
d Weeks 1, 2, 30, and 42 (Days 8, 15, 211, and 295) assessments will be performed via a safety phone call. CGI-I and CGI-S, and UWDRS should be performed 
as soon as possible (as considered appropriate by the Investigator) if a neurological AE is reported. Investigators can perform additional study assessments or 
laboratory testing at their discretion. 
e For patients continuing in the Extension Period, assessments at the Day 337 (Week 48) visit in the Treatment Period will be used as the Extension Period Day 1 
assessments. 
f Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened up to 2 times after agreement on required repeated 
assessments with the Alexion Medical Monitor. 
g Demographic parameters include age and sex. Race and ethnicity will be collected only where allowable per local regulations. 
h Wilson disease history will include details of any previous liver biopsies performed and treatment received.  
i Abbreviated physical examination consists of a body system relevant examination based upon Investigator judgment and patient symptoms. At least 1 body 
system must be checked for an abbreviated examination. 
j Vital signs include heart rate, blood pressure, respiration rate, temperature, height (Day 1 only; without shoes), and weight. 
k Follicle-stimulating hormone will only be performed for post-menopausal females. 
l The DNA sample is optional and can be collected at any time on or after Day 1; the sample will only be taken if the patient has provided informed consent 
(written or electronic) for this procedure. 
m Serum and urine pregnancy tests will only be performed for females of childbearing potential. Female patients of childbearing potential must not be pregnant 
and not breastfeeding, and must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at each subsequent study visit. Positive 
urine pregnancy results must be confirmed by a serum pregnancy test. 

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n The MELD and modified Nazer scores will be calculated by a central laboratory. 
o In addition to screening samples submitted to the central laboratory, additional samples for coagulation and hematology tests are to be performed at a local 
laboratory within 3 days before the liver biopsy, to assure the safety of the liver biopsy. 
p Plasma samples will be obtained from the blood samples collected pre-dose on the day of all study visits. Patients should be instructed not to take their dose of 
ALXN1840 on the morning of scheduled study visits so that PK/PD/Biomarker samples are collected at pre-dose trough: total and PUF Mo (PK), total and PUF 
Cu, NCC (PD), Cp, and CpC (biomarker). At the Week 6 (Day 43) and Week 36 (Day 253) visits, serial blood samples will be collected for plasma 
PK/PD/Biomarker concentrations at the following time points: pre-dose at 0 hour, and at 2- and 4-hours post-dose. 
q For the 24-hour urine sample, 500 mL will be considered the minimum acceptable sample size. Any amount < 500 mL will not be tested due to an insufficient 
sample collection. Urine collected will be used for 24-hour creatinine, Mo and Cu. Dispense container for 24-hour urine collection during the Screening Period, 
Day 1, and Day 57 (Week 8), Day 127 (Week 18), Day 169 (Week 24), and Day 253 (Week 36). 
r The UWDRS is scheduled to be performed at Day 1 and Day 337 (Week 48) only but can also be performed as appropriate if a neurological adverse event is 
reported. 
s Can be performed up to 7 days before Day 1, at the discretion of the Investigator. 
t CGI-I is not performed at Day 1, only CGI-S. 
u Adverse event, concomitant medication, and non-pharmacologic therapy/procedure are to be collected from signing of the ICF. 
v Appropriately trained study staff will instruct patients on how to correctly dose themselves, including any changes to the dosing regimen. ALXN1840 will not 
be dispensed or administered at the Early Termination Visit. 
w ALXN1840 dispensed/administered only for patients continuing into the Extension Period. 
 
Abbreviations: AE = adverse event; BPRS = Brief Psychiatric Rating Scale-24; CGI = Clinical Global Impression; CGI-I = Clinical Global Impression-
Improvement Scale; CGI-S = Clinical Global Impression-Severity Scale; CLDQ = Chronic Liver Disease Questionnaire; Cp = ceruloplasmin; Cp-C = 
ceruloplasmin-bound copper; Cu = copper; EOS = End of Study; EQ-5D = EuroQoL 5 Dimensions; ET = Early Termination; FSH = follicle-stimulating 
hormone; MELD = Model for End-Stage Liver Disease; Mo = molybdenum; MRE = magnetic resonance elastography; MR-PDFF = magnetic resonance-proton 
density fat fraction; NCC = non-ceruloplasmin bound copper; PD = pharmacodynamic; PK = pharmacokinetic; SF-36 = Short Form 36; SoC = standard of care; 
TSQM-9 = Treatment Satisfaction Questionnaire for Medication-9; UNS = unscheduled; UWDRS = Unified Wilson Disease Rating Scale; WD = Wilson Disease. 

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Table 2: 
Schedule of Activities – Extension Period  
Extension Period 
UNSa 
ET 
EOS 
Extension Period Day 
1b,c 
85 
169 
253 
337 
 
 
365 
Window (days) 
±7 
±7 
 
 
±7 
Physical examination 
X 
  
  
  
X 
 
X 
X 
Abbreviated physical examinationd 
  
X 
X 
X 
  
 
  
  
Vital signse 
X 
X 
X 
X 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
X 
 
X 
 
Pregnancy testf 
X 
X 
X 
X 
X 
 
X 
X 
Chemistry, coagulation, and hematology panel 
and urinalysisg 
X 
X 
X 
X 
X 
 
X 
X 
24-hour urineh 
X 
 
X 
 
X 
 
 
 
MRE, transient elastography (FibroScan 
preferred), MR-PDFF 
X 
 
 
 
X 
 
 
 
Optical coherence tomography 
X 
 
 
 
X 
 
 
 
Plasma PK/PD/Biomarker samplesi 
X 
X 
X 
X 
X 
 
X 
 
UWDRSj 
X 
 
 
 
X 
 
X 
 
CGI 
X 
 
X 
 
X 
 
X 
 
EQ-5D 
X 
 
X 
 
X 
 
X 
 
TSQM-9 
X 
 
  
 
X 
 
X 
 
SF-36 
X 
 
X 
 
X 
 
X 
 
CLDQ 
X 
 
  
 
X 
 
X 
 
BPRS 
X 
 
X 
 
X 
 
X 
 
AE, concomitant medication, and 
non-pharmacologic therapy/procedure 
 
Administer/dispense ALXN1840k 
X 
X 
X 
X 
 
 
 
 
Note: Patients who complete the 48-week Treatment Period will be offered the opportunity to participate in an Extension Period in which they will continue to 
receive ALXN1840. Patients may continue participation in the Extension Period and receive ALXN1840 until the product is registered and available to treat 
patients diagnosed with WD (in accordance with country specific regulations or for a maximum of 4 years, whichever comes first).  
 
a Unscheduled study visits may occur at any time during the study and may include any study procedures (including dispensing of ALXN1840) as deemed 
necessary by the Investigator. These visits may or may not be completed by a home healthcare nurse, where applicable, depending on the purpose of the 
unscheduled visit. 
b Assessments on Extension Period Day 1 and other study visit days where laboratory sampling is planned should be performed pre-dose. 
c Assessments at the Day 337 (Week 48) visit of the Treatment Period will be used as the Extension Period Day 1 assessments. 

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d Abbreviated physical examination consists of a body system relevant examination based upon Investigator judgment and patient symptoms. At least 1 body 
system must be checked for an abbreviated examination. 
e Vital signs include heart rate, blood pressure, respiration rate, temperature, height (Extension Period Day 1 only; without shoes), and weight. 
f Serum and urine pregnancy tests will only be performed for females of childbearing potential. Female patients of childbearing potential must not be pregnant 
and not breastfeeding, and must have a negative urine pregnancy test at each study visit. Positive urine pregnancy results will be confirmed by a serum 
pregnancy test. 
g The MELD and Nazer scores will be calculated by a central laboratory. 
h For the 24-hour urine sample, 500 mL will be considered the minimum acceptable sample size. Any amount < 500 mL will not be tested due to an insufficient 
sample collection. The container for 24-hour urine collection should be dispensed at the study visit immediately prior to the next expected collection. Urine 
containers should be dispensed on Extension Period Day 1 and at the visit on Days 85 (Week 12). 24-hour urine collection should be submitted by the patient at 
Extension Period Days 1, 169 (Week 24), and 337 (Week 48). 
i Plasma samples will be obtained from the blood samples collected pre-dose on the day of all study visits. Patients should be instructed not to take their dose of 
ALXN1840 on the morning of scheduled study visits so that PK/PD/Biomarker samples are collected at pre-dose trough: total and PUF Mo (PK), total and PUF 
Cu, NCC (PD), Cp, and CpC (biomarker). 
j The UWDRS is scheduled to be performed at Extension Period Day 1 and Day 337 (Week 48) only but can also be performed as appropriate if a neurological 
adverse event is reported. 
k ALXN1840 will not be dispensed or administered at the ET Visit. 
 
Abbreviations: BPRS = Brief Psychiatric Rating Scale-24; CGI-I = Clinical Global Impression-Improvement Scale; CGI-S = Clinical Global Impression-Severity 
Scale; CLDQ = Chronic Liver Disease Questionnaire; EOS = End of Study; EQ-5D = EuroQoL 5 Dimensions; ET = Early Termination; ICF = informed consent 
form; MELD = Model for End-Stage Liver Disease; MRE = magnetic resonance elastography; MR-PDFF = magnetic resonance-proton density fat fraction; PD = 
pharmacodynamic; NCC = non-ceruloplasmin bound copper; PK = pharmacokinetic; SF-36 = Short Form 36; TSQM-9 = Treatment Satisfaction Questionnaire 
for Medication-9; UNS = unscheduled; UWDRS = Unified Wilson Disease Rating Scare; WD = Wilson Disease 
 
 

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2. 
INTRODUCTION 
2.1. 
Study Rationale 
This study is being conducted to evaluate the change in liver copper (Cu) concentration at 
Week 48 compared with baseline in adult patients with Wilson Disease (WD) treated with 
ALXN1840 at doses up to 30 mg/day. 
Currently available standard of care (SoC) medications (ie, trientine, penicillamine, and zinc) 
control excess free Cu in the blood but have never been demonstrated prospectively to reduce Cu 
burden in the human liver. Conversely, tetrathiomolybdate (the active ingredient in ALXN1840), 
has been shown to reduce liver Cu stores in animal models (Suzuki, 1993; Suzuki, 1994; Suzuki, 
1995; Ogra, 1995a; Ogra, 1995b; Ogra, 1996). 
2.2. 
Background 
2.2.1. 
Wilson Disease 
Wilson Disease is an autosomal recessive disorder of impaired Cu transport. Mutations in the 
ATP7B gene result in deficient production of the Cu-transporter ATPase2, leading to impaired 
incorporation of Cu into ceruloplasmin (Cp), impaired biliary excretion of Cu, increased free and 
albumin-bound Cu, and Cu accumulation in liver, brain, and other tissues, with resulting organ 
damage and dysfunction (Pfeiffer, 2007). Ceruloplasmin is a serum ferroxidase, and in healthy 
humans, it contains greater than 95% of the Cu found in plasma (Hellman, 2002). 
The prevalence of genetic markers associated with WD is approximately one per 30,000 
population worldwide (Frydman, 1990; Reilly, 1993; Schilsky, 2002). Among people with an 
identified mutation, disease manifestation will be present in approximately 50%. The majority of 
patients are diagnosed before 30 years of age (Beinhardt, 2014). A recent nationwide, 
population-based epidemiological study based in France found the diagnosed prevalence of WD 
to be 1.5 per 100,000 population (Poujois, 2018). 
Typical clinical presentation of WD is in adolescence to early adulthood. Genetic screening and 
genotype-phenotype correlation is complicated by a multitude (˃ 500) of associated ATP7B 
mutations; most individuals with WD are compound heterozygotes. Initial signs and symptoms 
of WD are predominantly hepatic (~40%), neurologic (~40%), or psychiatric (~20%), but 
patients often develop combined hepatic and neuropsychiatric disease. Untreated or inadequately 
treated patients have progressive morbidity, and mortality is usually secondary to liver cirrhosis. 
Liver transplantation is the only effective therapy for WD-associated acute liver failure; other 
causes of death associated with WD include hepatic malignancy and neurologic deterioration 
with severe inanition (Pfeiffer, 2007; Roberts, 2008). 
The liver represents the primary Cu storage organ in humans. In healthy people, intracellular Cu 
homeostasis is tightly regulated. Copper is transported into cells by Cu transporter 1 (CTR1), and 
then transferred to Cu chaperones such as the Cu chaperones for antioxidant 1, cytochrome c 
oxidase, and superoxide dismutase. Copper accompanying the chaperone is delivered to a 
specific Cu-requiring enzyme. If excess amounts of Cu appear, the excess Cu is bound to 
metallothionein (MT) as monovalent Cu (Cu+) via Cu thiolate bridges by abundant cysteine 

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residues in MT, thus providing a stable storage mechanism limiting the potential for redox 
cycling (oxidative stress) and associated toxicity. 
In patients with WD, Cu is not removed from the tissue compartments due to the deficient 
activity of ATPase2. This results in an accumulation of Cu, mainly in the liver where the protein 
is highly expressed in hepatocytes and then in the brain, but also in other organs. Within the 
capacity of MT biosynthesis, no apparent toxicity of Cu exists because MT tightly binds Cu. 
However, beyond the Cu buffering capacity of MT, free Cu ions appear and this excessive 
amount of free intracellular Cu triggers pro-oxidant properties, leading to an increased risk of 
tissue/organ damages with clinical manifestations as a result. It is assumed that the toxicity of Cu 
in WD is mediated by the free Cu that is not bound to MT due to the Cu overload (Ogra, 1996). 
Copper is then increased in the circulation and is available for uptake into other organs where it 
may cause damage, in particular, in the brain. 
Treatment goals focus on compensating for impaired Cu metabolism, by reducing toxic free Cu, 
and maintaining normal Cu concentrations to improve organ function and patients’ symptoms. 
The current treatments for WD are general chelator therapies D-penicillamine (Cuprimine, 
Depen) and trientine (eg, Cufence, Cuprior, Syprine), which non-specifically chelate Cu and 
promote urinary Cu excretion. In addition, zinc, which blocks dietary uptake of Cu, is used 
mainly for maintenance treatment. Zinc impairs the absorption of Cu by the induction of MT and 
Cu sequestration within the enterocytes of the gastrointestinal tract, which ultimately get 
sloughed and excreted in stool. 
Disease control in patients with neurological symptoms at WD diagnosis is an area of particular 
concern. More than a third of patients presenting with neurological symptoms show no 
improvement after 4 years of treatment with chelators. In a recent study, approximately 50% of 
patients had residual neurological symptoms despite years of therapy on a Cu-modulating agent 
(Holscher, 2010). This failure to respond to chelation therapy with neurological presentation may 
reflect irreversible damage to the nervous system (Weiss, 2013). In addition, worsening of 
neurological symptoms on initiation of treatment has been reported in approximately 25% of 
patients initiated on penicillamine and trientine, and up to 50% of those patients never recover 
(Brewer, 1987; Brewer, 2006; Merle, 2007; Weiss, 2011; Kalita, 2014; Kalita, 2015). The 
mechanism behind this worsening is believed to be a mobilization of Cu from the liver leading to 
elevations in blood Cu associated with neurological progression (Brewer, 2009). This theory is 
supported by non-clinical data (Zhang, 2015; Chen, 2012). 
Currently available drugs have high rates of treatment discontinuation due to adverse events 
(AEs) and treatment failure. They also need to be dosed 2 to 5 times per day and must be taken 
in the fasted state. Their AE profiles and complicated dosing regimens lead to poor treatment 
compliance and high rates of treatment failure, a major concern in a disease that requires life-
long treatment such as WD (Maselbas, 2010; Dziezyc, 2014). 
2.2.2. 
ALXN1840 
ALXN1840 (bis-choline tetrathiomolybdate; formerly known as WTX101) is a novel, 
first-in-class, Cu-protein binding agent in development for the treatment of WD. 
ALXN1840 has been selected for development in WD due to its improved stability properties 
over ammonium tetrathiomolybdate, which has previously been studied in patients with WD and 

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other indications. Ammonium tetrathiomolybdate as well as bis-choline tetrathiomolybdate 
non-clinical and clinical data reported to date support the efficacy and safety of ALXN1840. 
ALXN1840 has been evaluated in 28 patients with WD in an open-label Phase 2 Study 
WTX101-201. Results from the main 24-week study showed that ALXN1840 monotherapy 
reduced mean serum non-ceruloplasmin-bound Cu (NCC) by 72% at Week 24 compared with 
baseline. ALXN1840 treatment also resulted in significant improvements in neurological status 
and disability measured as a change from baseline in Unified WD Rating Scale (UWDRS) 
Part III and Part II, respectively. In addition, liver status, as measured by the Modified Nazer 
Score and model for end-stage liver disease (MELD), was stabilized or improved in most 
patients. Treatment with ALXN1840 was generally well-tolerated, with most reported AEs being 
mild (Grade 1) to moderate (Grade 2). Reversible liver function test elevations were observed in 
39% of patients; these elevations were mild to moderate, asymptomatic, were associated with no 
notable increases in bilirubin (ie, no documented case of Hy’s Law), and normalized with dose 
reduction or treatment interruption. No paradoxical neurological worsening was observed upon 
treatment initiation with ALXN1840 (Weiss, 2017). All patients who completed the 24-week 
Initial Dosing Period were enrolled in a 36-month Extension Period to assess long-term efficacy 
and safety of ALXN1840. 
Preliminary PK data at 48 weeks from the Extension Period of the study were consistent with the 
24-week Dosing Period results. No clear dose-proportionality was observed in 
Study WTX101-201. This result may have been due to the small sample size and relatively high 
inter-patient variability. 
In total, tetrathiomolybdate (bis-choline or ammonium salt of tetrathiomolybdate) has been 
evaluated in nearly 600 patients in studies of WD, oncology, macular degeneration, and primary 
biliary cirrhosis indications using either the ammonium or the bis-choline tetrathiomolybdate salt 
forms, and in 60 healthy volunteers in Phase 1 studies. ALXN1840 has been generally 
well--tolerated, and the most frequently reported drug-related AEs were changes in 
hematological parameters, fatigue, sulphur eructations, and other gastrointestinal symptoms. 
Aminotransferase elevations were much less common in oncology patients than in patients with 
WD treated with ALXN1840. The reason for this difference is not known, but it should be noted 
that oncology patients are unlikely to have excess liver Cu. 
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of ALXN1840 are 
provided in the Investigator’s Brochure (IB).  
2.3. 
Benefit/Risk Assessment 
More information about the known and expected benefits and risks and expected AEs with 
ALXN1840 may be found in the current edition of the IB. 
2.3.1. 
Risk Assessment 
Details of the potential risks and mitigation strategy are provided in Table 3. Further information 
on ALXN1840 is available in the IB. 

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Table 3: 
Potential Risks and Mitigation Strategy 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
ALXN1840 
Anemia 
Anemia has been observed in patients 
with WD, attributed to overtreatment 
and resultant Cu depletion, see the IB 
Monitoring complete blood 
count 
Dose modification (Section 6.6) 
or discontinuation (Section 7) 
Dose-dependent elevations 
in transaminases (ALT and 
AST) 
Generally mild to moderate in 
severity, asymptomatic and reversible 
with dose adjustments were reported, 
usually after 3-6 weeks of treatment. 
Results obtained from studies of 
ALXN1840 and ammonium 
tetrathiomolybdate in patients with 
WD; see the IB  
Regular monitoring of liver 
function tests 
Dose modification (Section 6.6) 
or discontinuation (Section 7) 
Low white blood cell count 
(leukopenia, bone marrow 
toxicity)  
Leukopenia and bone marrow toxicity 
(myelosuppression) have been 
observed in patients with WD, 
attributed to overtreatment and 
resultant Cu depletion. 
Results obtained from studies of 
ALXN1840 and ammonium 
tetrathiomolybdate in patients with 
WD; see the IB 
Dose modification (Section 6.6) 
or discontinuation (Section 7) 
Study Procedures and Other 
Liver biopsy: bleeding, 
infection, liver laceration, 
pneumothorax, gallbladder 
injury  
Overall rate of serious complications 
is approximately 1% and mortality at 
0.2% 
Pain is most common complication 
with one quarter of patients 
experiencing right upper quadrant or 
shoulder pain, most common serious 
complication is bleeding with 
hemodynamic compromise occurring 
in 0.01% to 0.5% of cases and 
includes intraperitoneal hemorrhage, 
hematoma, and/or hemobilia. 
Additional complications include but 
are not limited to transient 
bacteremia, bile peritonitis, organ 
injury including pneumothorax 
(Reddy, 1997; Seeff, 2010; West, 
2010; Boyum, 2016) 
Abdominal ultrasound is 
required prior to biopsy to 
confirm adequate visualization 
of liver and adjacent structures 
(Section 5.1) 
Obese patients (BMI >30 kg/m2) 
will be excluded from 
participating in the study 
(Section 5.1) 
Restrictions on antiplatelet and 
anticoagulant medications 
(Section 5.3.2)  
Patients must have a PT-INR 
< 1.5 (Section 5.2 ) 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Neurological worsening 
Neurological worsening may occur 
due to disease progression or Cu 
mobilization 
Dose modification (Section 6.6) 
or discontinuation (Section 7) 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; Cu = 
copper; IB = Investigator’s Brochure; PT-INR = prothrombin time-international normalized ratio; WD = Wilson 
disease. 
2.3.2. 
Benefit Assessment 
The main objective of effective WD treatment is to provide: 
• Rapid and sustained control of Cu and clinical symptoms of WD through the 
formation of irreversible Cu-tetrathiomolybdate-protein complexes, leading to prompt 
Cu control without mobilizing free Cu that could cause tissue toxicity, including 
neurological deterioration that has been reported at the initiation of treatment with 
chelators. This hypothesis is supported by results from Study WTX101-201 in patients 
with WD (Weiss, 2017).  
• Improved compliance over current chelator therapy through improved tolerability and the 
convenience of a simplified dosing regimen (once daily) compared to current therapeutic 
options (multiple daily dosing).  
Potential benefits of study participation for patients include: 
• Participation in a clinical study increases the patient’s understanding of the 
pathophysiology and treatment of WD. 
• Removal of total body Cu as a definitive treatment for WD. 
• All patients will receive ALXN1840, ie, all patients will have access to a potentially more 
convenient and effective treatment for removing toxic free Cu from the blood and liver. 
• Patients who participate in the study will contribute to improved care for other patients 
with WD in the future. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Accounting for the measures taken to minimize risk to patients participating in this study, the 
potential risks identified in association with the administration of ALXN1840 and procedures 
performed in the study, including, but not limited to, liver biopsy are justified by the anticipated 
benefits that may be afforded to adult patients with WD. 

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3. 
OBJECTIVES AND ENDPOINTS 
The study objectives and corresponding endpoints are presented in Table 4. 
Table 4: 
Study ALXN1840-WD-205 Objectives and Endpoints 
Objectives 
Endpoints 
Treatment Period 
Primary 
To evaluate change in liver copper (Cu) 
concentration following treatment with ALXN1840 
at Week 48 in patients with Wilson disease (WD) 
Change from baseline to Week 48 in liver Cu 
concentration 
Secondary 
To assess change in liver histopathology following 
treatment with ALXN1840 
Change from baseline to Week 48 in steatosis, 
inflammation, and fibrosis  
To evaluate the safety of ALXN1840 in patients 
with WD 
Adverse events (AEs), vital signs, ECGs, clinical 
laboratory data, and physical examination data 
To evaluate pharmacokinetics (PK) of ALXN1840  
• 
ALXN1840 PK profiles in plasma at Week 6 
(Day 43) and Week 36 (Day 253), of which 
ALXN1840 PK are measured as total molybdenum 
(Mo) and plasma ultrafiltrate (PUF) Mo 
• 
Pre-dose trough ALXN1840 concentrations in plasma 
at each study site visit 
• 
ALXN1840 concentrations in the liver biopsy 
specimen.  
To evaluate the effects of ALXN1840 on clinical 
symptoms 
Change from baseline in Clinical Global Impression-
Improvement (CGI-I) Scale and the Clinical Global 
Impression-Severity (CGI-S) Scale  
Exploratory 
To explore the effects of ALXN1840 on hepatic 
status 
Change from baseline to Week 48 in: 
• 
Model for End Stage Liver Disease (MELD) score 
• 
Modified Nazer score  
To assess changes in liver fibrosis and steatosis 
using non-invasive techniques 
Liver stiffness by magnetic resonance (MR) elastography 
and transient elastography (Vibration-Controlled Transient 
Elastography/FibroScan), MR-proton density fat fraction 
(PDFF) 
To explore changes in mitochondrial ultrastructure 
of the liver at Week 48 
Change from baseline to Week 48 in mitochondrial 
ultrastructure by electron microscopy 
To explore the change in Cu deposition in the eye at 
Week 48 
Change from baseline to Week 48 in in Cu deposition in 
the eye by optical coherence tomography 
To explore the change in PD and biomarkers with 
ALXN1840 treatment at Week 48 
• 
Absolute and percent change in plasma total and PUF 
Cu and calculated non-ceruloplasmin-bound Cu 
(cNCC) concentrations, as well as directly measured 
NCC (dNCC), labile-bound Cu (LBC), ceruloplasmin 
(Cp) and Cp-bound Cu (CpC) from baseline to Week 
48 
• 
Daily mean area under the effect-time curve (AUEC) 
of dNCC from 0 to 48 weeks 
To explore the effects of ALXN1840 on quality of 
life at Week 48 
Change from baseline to Week 48 in quality of life 
measures of: 
• 
EuroQoL 5 Dimensions (EQ-5D) 
• 
Short form-36 (SF-36) 
• 
Chronic Liver Disease Questionnaire (CLDQ) 

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Objectives 
Endpoints 
To assess treatment satisfaction of ALXN1840 at 
Week 48 
Treatment Satisfaction Questionnaire for Medication-9 
(TSQM-9) 
To explore the effects of ALXN1840 on neurologic 
and psychiatric symptoms 
Change from baseline to Week 48 in: 
• 
Brief Psychiatric Rating Scale-24 (BPRS-24) 
• 
Unified Wilson Disease Rating Scale (UWDRS) 
Extension Period 
All patients will continue to receive ALXN1840 in the 48-week Extension Period. 
All safety and efficacy parameters will be measured as detailed above at Week 48 in the Extension Period, except 
for liver biopsy, which will not be performed in the Extension Period. 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2, open-label multicenter study designed to evaluate the change in liver Cu 
concentration following 48 weeks of treatment with ALXN1840 at doses up to 30 mg/day in 
adult patients with WD who have previously been treated for at least 1 year with SoC (ie, 
trientine, penicillamine, or zinc).  
On Day 1 of the Treatment Period, patients will receive ALXN1840. Patients will be initiated at 
15 mg once daily, then the dose will be increased to 30 mg once daily at Week 6. 
In case of drug tolerability issues, the dose of ALXN1840 may be reduced or temporarily 
interrupted. Such dose changes must be discussed with the Alexion Medical Monitor and 
documented in the study record. Any subsequent dose increases must be approved by Alexion. 
The planned study duration is approximately up to 100 weeks, including a 4-week Screening 
Period. A liver biopsy will be performed during the Screening Period within 14 days prior to the 
first dose of study drug, followed by a 48-week Treatment Period, which starts on the day of first 
dose of study drug. Patients who complete the 48-week Treatment Period will be offered the 
opportunity to participate in a 48-week Extension Period to evaluate the long-term safety and 
efficacy of ALXN1840.   
This study is pathologist-blinded for the assessments of liver histology samples. 
If additional clinical evaluation outside of the visit schedule is deemed necessary by the 
Investigator, or if the patient meets dose modification criteria, then unscheduled visits can occur. 
Additionally, if there is clear neurological deterioration, as demonstrated by signs or symptoms 
of neurological worsening, then additional neurological assessments will be performed at the 
discretion of the Investigator. 
An independent Data Monitoring Committee (DMC), comprising experts in relevant fields with 
no direct relationship to the study, will be appointed by Alexion to review and monitor study 
data for safety, effectiveness, and study conduct, and make recommendations regarding study 
continuation, changes to the study population, and/or modification to study procedures. Further 
details are provided in Section 9.5.  
An independent Hepatic Adjudication Panel, comprising experts in relevant fields will be 
appointed by Alexion. Details of the Hepatic Adjudication Panel are provided in Section 9.6.  
4.2. 
Scientific Rationale for Study Design 
Currently available SoC medications (ie, trientine, penicillamine, and zinc) control excess free 
Cu in the blood, but do not consistently reduce Cu overload in the liver. Accumulation of Cu in 
the liver leads to an increased risk of tissue and organ damage. Limited available data obtained 
from serial liver biopsies in patients with WD indicate that liver Cu concentration remains 
elevated, with no consistent reduction of liver Cu over time in patients treated with SoC beyond 
the first year (Medici, 2006; Scheinberg, 1987; Cope-Yokoyama, 2010; Gibbs, 1990). The 
impact of ineffective decoppering with SoC medications can be seen in patients with WD who 
discontinue treatment for WD, who are at risk for rapid progression to liver failure (Maselbas, 
2010; Dziezyc, 2014).  

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Preclinical data and results on thiomolybdates (bis-choline and ammonium tetrathiomolybdate) 
suggest that, unlike penicillamine or trientine, ALXN1840 may be able reduce liver Cu burden 
load in patients with WD. In vitro and preclinical data indicate that ALXN1840 may remove Cu 
from internal MT liver stores, promote mobilization of stable high affinity ALXN1840-Cu-
albumin complexes, and enhance elimination of Cu. ALXN1840 may promote elimination of Cu 
through excretion of Mo:Cu complexes into bile, promoting net negative excretion of Cu from 
the liver. In the Long-Evans Cinnamon rat model of WD, treatment with tetrathiomolybdate 
leads to rapid reduction in the liver Cu concentration (Suzuki, 1993; Suzuki, 1994; Suzuki, 1995; 
Ogra, 1995a; Ogra, 1995b; Ogra, 1996). 
While SoC treatment may promote elimination of Cu, no treatment has been demonstrated to 
result in a meaningful reduction of Cu in liver stores, which is thought to be key in reducing the 
risk of progression to liver failure.  
The principal aim of this study is to confirm in humans that ALXN1840 reduces liver Cu 
concentration by studying the effect of 48 weeks of ALXN1840 treatment in patients with WD 
who have been previously treated with SoC (ie, trientine, penicillamine, or zinc). 
To assess reduction in liver Cu concentration, liver biopsies will be taken prior to initiation of 
ALXN1840 and at Week 48 of treatment.  
Liver biopsy for Cu concentration is considered the most effective means to show reduction in 
liver Cu; no other non-invasive surrogate marker is available to fully explore the impact of 
ALXN1840 on liver Cu stores. Although WD impacts patients of all ages, because it is a chronic 
disease, most treatment-experienced (ie, have received treatment for at least 1 year) patients are 
≥ 18 years, therefore, including patients ≥ 18 years of age is representative of the population with 
WD. 
To better understand the mechanism by which ALXN1840 results in reduction of liver Cu 
concentrations, the liver biopsy specimen will also be assessed for total Mo and concentrations 
will be correlated to blood total Cu and Mo concentrations. 
In addition to evaluating liver Cu concentration, histology will be performed on the remaining 
liver tissue to assess the impact of ALXN1840 on liver inflammation and tissue injury, as well as 
progression in fibrosis. 
Imaging (ie, magnetic resonance imaging [MRI] and transient elastography) will be performed to 
evaluate changes by non-invasive assessment of the liver. Optical coherence tomography will 
also be performed as a measure of Cu reduction with respect to Kayser-Fleischer rings. 
4.3. 
Justification for Dose 
For this study, the term “dose” refers to the following: 
Dosing for ALXN1840 will be initiated at 15 mg once daily, then the dose will be increased to 
30 mg once daily at Week 6.  
A starting dose of 15-60 mg daily was shown to have an acceptable safety profile and was 
effective in reducing NCC in a Phase 2 study in patients with WD (Weiss, 2017). Elevation of 
hepatic transaminases and/or gamma glutamyl transferase occurred in 39% of patients in the 
Phase 2 study and were generally associated with higher doses of ALXN1840. Elevations of 

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liver enzymes were detected by routine laboratory monitoring and were managed by dose 
reduction or treatment interruption of ALXN1840. In this study, the starting dose will be 15 mg 
once daily for the first 6 weeks, then the dose will be titrated up to 30 mg once daily. Elevation 
of liver enzymes, if occurring, and management of other laboratory abnormalities or AEs, will be 
managed according to Table 6. Any change to dosing in response to laboratory results or AEs 
must be discussed with the Alexion Medical Monitor and documented in the study record. 
Subsequent dose increases must be approved by Alexion. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last patient last visit of the 48-week Extension 
Period. 

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria are met: 
Age 
1. Patients must be ≥ 18 years of age at the time of signing the informed consent. 
Type of Patient and Disease Characteristics 
2. Diagnosis of WD by Leipzig Criteria ≥ 4 documented by testing as outlined in the 2012 
European Association for the Study of Liver (EASL) WD Clinical Practice Guidelines 
(Ferenci, 2003; EASL, 2012) or by historical test results for WD including some or all of the 
following: 
• Presence of Kayser Fleischer rings, 
• Neurological symptoms, 
• Serum ceruloplasmin below reference range, 
• Coombs-negative hemolytic anemia, 
• Elevated liver or urinary copper, 
• Presence of mutations in the ATP7B gene, or 
• Other, as considered appropriate, may be used instead to confirm the diagnosis of WD. 
3. Continuous treatment for WD with penicillamine, trientine or zinc for at least 1 year in 
duration prior to screening 
4. Adequate venous access to allow collection of required blood samples 
5. Able to swallow intact ALXN1840 tablets 
6. Body mass index < 30 kg/m2 
7. Able to cooperate a percutaneous liver biopsy, including having the ability to lie flat and still 
throughout the procedure, and tolerate mild sedation, if required 
8. Adequately visualized landmarks on screening ultrasound without evidence of significant 
ascites, hemangiomas, or other findings that would put the patient at unnecessarily high risk 
of complications  
Sex 
9. Male Patients: 
• Male patients are eligible to participate if they agree to the following during the drug 
period and for at least 90 days after the end of systemic exposure:  
o Refrain from donating sperm 
o PLUS either: 
o Be abstinent from heterosexual intercourse with a woman of childbearing potential 
(WOCBP) as their preferred and usual lifestyle (abstinent on a long term and 
persistent basis) and agree to remain abstinent  

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o OR 
o Must agree to use contraception/barrier as detailed below  
− Agree to use a male condom with spermicide 
− No contraception/barrier is required for men with a male sexual partner. 
− No contraception/barrier is required for men with a female sexual partner who is 
not of childbearing potential. 
10. 
Female Patients:  
• A female patient is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
− Is not a WOCBP 
OR 
− Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as described 
in Section 10.4 starting at least one menstrual cycle before first study drug 
administration and continuing for at least 30 days after the end of systemic 
exposure of the study drug and agrees not to donate eggs (ova, oocytes) for the 
purpose of reproduction during this period. The Investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of study 
drug. 
− A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study drug 
(Table 1).  
− If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the patient must be excluded from 
participation if the serum pregnancy result is positive. 
• Additional requirements for pregnancy testing during and after study drug are located 
in Section 10.4. 
• The Investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Informed Consent 
11. Capable of giving signed informed consent as described in Section 10.1.3, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol 
5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
1. Decompensated cirrhosis or MELD score >13 

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2. Modified Nazer score > 7 (Dhawan, 2005) 
3. Clinically significant gastrointestinal bleed within past 3 months 
4. Alanine aminotransferase > 2 × upper limit of normal (ULN) 
5. History of bleeding abnormality or known coagulopathy, including platelet count 
< 100,000, and international normalized ratio for prothrombin time (PT-INR) ≥ 1.5; 
coagulopathy or bleeding risk due to medication is acceptable if medication can be safety 
discontinued for biopsy (see Section 5.3) 
6. Patient unwilling to accept blood products, if required 
7. Marked neurological disease requiring either nasogastric feeding tube or intensive 
inpatient medical care 
8. Hemoglobin less than lower limit of the reference range for age and sex 
9. Systemic disease or other illness, any disability acquired from trauma or another illness, 
or any deviation in laboratory values that are confirmed on re-examination to be 
clinically significant by the Investigator that would, in the opinion of the Investigator, 
compromise patient safety, interfere with evaluation of disability due to WD, or interfere 
with the collection or interpretation of study results 
10. Patients in renal failure, defined as in end-stage renal disease on dialysis (chronic kidney 
disease [CKD] 5) or creatinine clearance < 30 mL/min (as calculated by the Modification 
of Diet in Renal Disease formula) (Levey, 2006). 
11. Known sensitivity to ALXN1840, ALXN1840 excipients (anhydrous di-calcium 
phosphate, anhydrous sodium carbonate), or any of the ingredients contained in 
ALXN1840 or related compounds. 
12. History or presence of/significant history of or current cardiovascular, respiratory, renal, 
gastrointestinal, endocrinological, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; constituting a 
risk when taking the study drug; or interfering with the interpretation of data 
13. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or 
squamous epithelial carcinomas of the skin that have been resected with no evidence of 
metastatic disease for 3 years 
14. Current or chronic history of liver disease not associated with WD, or known hepatic or 
biliary abnormalities (with the exception of asymptomatic gallstones) 
15. Use of nonprescription/ over-the-counter medications, including herbal remedies, 
nutritional supplements, or mineral supplements containing Cu, zinc, iron or Mo after 
dosing on Day 1 through the end of the study. 
16. In the opinion of the Investigator, the patient and/or their legal guardian is likely to be 
non-compliant or uncooperative during the study 

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Prior/Concurrent Clinical Study Experience 
17. Participation in any other interventional study during the study or for 3 months (or 5 half-
lives of the administered investigational medicinal product, whichever is longer) prior to 
study start. 
Diagnostic assessments 
18. Presence of hepatitis B surface antigen or positive hepatitis C antibody or RNA test result 
at screening or within 3 months prior to first dose of study drug. NOTE: Patients with 
positive Hepatitis C antibody due to prior resolved disease can be enrolled if a 
confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtained. NOTE: The 
RNA test is optional and patients with negative Hepatitis C antibody test are not required 
to also undergo Hepatitis C RNA testing 
19. Positive human immunodeficiency virus (HIV) antibody test 
Other Exclusions 
20. Regular alcohol consumption within 6 months prior to the study defined as > 14 units for 
males or > 7 units for females per week. One unit is equivalent to 8 g of alcohol: a half 
pint (approx. 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. 
21. Abuse of illicit or prescribed drugs 
22. Sensitivity to any drug or other allergy that, in the opinion of the Investigator or Alexion 
Medical Monitor, contraindicates participation in the study 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
Patients should follow their study doctor's advice regarding adherence to a low Cu diet. 
ALXN1840 will be administered in the fasted state (1 hour before or 2 hours after meals) and 
will be taken with approximately 240mL of water. 
5.3.2. 
Restrictions Relating to the Liver Biopsy 
Prior to biopsy and following biopsy, the guidelines and restrictions apply (Rockey, 2009): 
• Antiplatelet medications should be discontinued a minimum of 10 days before liver 
biopsy.  
• Anticoagulant medications should be discontinued prior to liver biopsy. Warfarin 
should generally be discontinued at least 5 days prior to liver biopsy. Heparin and 
related products should be discontinued 12 to 24 hours prior to liver biopsy. Oral 
agents, including rivaroxaban, dabigatran, apixaban, and edoxaban, should be 
discontinued a minimum of 72 hours before liver biopsy (Douketis, 2019). 
• Antiplatelet therapy may be restarted 72 hours after liver biopsy.  
• Warfarin may be restarted 24 hours after liver biopsy. 

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5.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently assigned to study drug. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details (eg, failed 
eligibility criteria), and any serious adverse event (SAE) occurring during the Screening Period. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened up to 2 times after agreement on required repeated assessments with the Alexion 
Medical Monitor.  

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6. 
STUDY DRUG 
Study drug is defined as any investigational drug intended to be administered to a study patient 
according to the study protocol, ie, ALXN1840. 
6.1. 
Study Drugs Administered 
Details of the study drug to be administered in this study are detailed in Table 5. 
Table 5: 
Study Drugs Administered 
Drug Name 
ALXN1840  
Type  
Drug 
Dose Formulation 
White, round, delayed-release tablet 
Unit Dose Strength(s) 
15 mg 
Dosage Level(s) 
15 mg daily up to 30 mg daily 
Route of Administration 
Oral 
Use 
Experimental 
IMP and NIMP 
IMP 
Sourcing 
Provided centrally by Alexion 
Packaging and Labeling 
ALXN1840 will be provided in treatment kits that will each have a unique 
identification number and be packaged and labelled in accordance with all applicable 
regulatory requirements. At a minimum, the treatment kit label will provide the 
following information: study Sponsor identification, batch number, directions for 
use, required storage conditions, caution statements (including “New Drug-Limited 
by Federal Law to Investigational Use” language), study identification, and expiry 
date. 
Current/Former 
Name(s) or Alias(es) 
bis-choline tetrathiomolybdate 
Abbreviations: IMP = investigational medicinal product; NIMP = Noninvestigational medicinal product 
 
6.2. 
Preparation/Handling/Storage/Accountability 
• The ALXN1840 treatment kits must be stored at refrigerated conditions, 2°C to 8°C 
(36°F to 46°F). 
• The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study drug received and any discrepancies are 
reported and resolved before use of the study drug. 
• Only patients enrolled in the study may receive study drug. Appropriately trained 
employees of the study site will instruct patients on how to correctly dose themselves 
with ALXN1840 at home. 
• All study drug must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the Investigator and authorized site staff. 
• The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study drug accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 

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• Further guidance and information for the final disposition of unused study drug are 
provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
• There is no randomization and blinding of patients in this study, because it is a 
single-arm, open-label study. 
• This study is only pathologist-blinded for the assessments of liver histology samples.  
• Study drug will be dispensed at the study visits summarized in the SoAs (Table 1 and 
Table 2). 
6.4. 
Study Drug Compliance 
Compliance with ALXN1840 will be assessed by the study team at each study visit. Compliance 
will be assessed by direct questioning during the site visits and documented in the source 
documents and case report form (CRF) and checked against the medication returned by the 
patient. Any deviation from the prescribed dosing regimen including extra doses, missed doses 
and drug interruptions will be recorded in the electronic data capture (EDC) system.  
Patients who take 80% or more of the prescribed doses of ALXN1840 in the first 48 weeks of the 
study will be considered to have shown acceptable compliance.  
Reasons for not following study treatment administration as described in the protocol should be 
clearly recorded in the source documents. 
Once compliance with study drug has been calculated, patients will be dispensed new 
ALXN1840 to cover dosing requirements until the next in-clinic visit if required. 
A record of the number of ALXN1840 tablets dispensed to and taken by each patient must be 
maintained and reconciled with study drug and compliance records. Study drug start and stop 
dates, including dates for drug delays and/or dose reductions will also be recorded in the CRF. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) taken within 30 days prior to 
signing informed consent and throughout the duration of the study will be recorded in the source 
documents and on the appropriate CRF along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Medications specific for WD taken at any time prior to the study will also be recorded.  
Patients may continue medications required to treat existing medical conditions as long as they 
are not anticipated to interfere with the conduct or outcome of the study. Patients should avoid 
starting or stopping medications and all potential medication changes should be reviewed by the 
Investigator to ensure changes are not expected to interfere with the outcome of the study. 

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The guidelines provided below are to be used by the Investigator, the study staff, and the patient 
to safeguard patient safety while maintaining data integrity.  
Use of the following medications or contrast media is not prohibited; however, if used, this 
therapeutic change must be clearly documented as a concomitant medication. Please contact the 
Alexion Medical Monitor with questions. Refer to the current IB for potential inhibitory effect of 
ALXN1840 on the metabolism of certain drugs that are substrates of cytochrome P450 enzymes 
(eg, CYP2C9 and CYP2B6). 
• Gadolinium- and iodine-containing contrast media are known to interfere with PK/PD 
tests on Mo. Gadolinium- and iodine-containing contrast media are requested not to 
be used within the 96 hours prior to Mo testing. 
• Barium-containing contrast media are known to interfere with tests on Cu. 
Barium-containing contrast media are requested not to be used within the 96 hours 
prior to Cu testing. 
• Acetaminophen/paracetamol must be limited to ≤ 1 g per day. 
The following medications are prohibited during the study: 
• Estrogens may interfere with biliary Cu excretion. Patients must not initiate estrogen 
therapy or estrogen-containing contraception on or after the Day 1 visit. Detailed 
guidance on allowed contraceptive methods and medication are provided in 
Section 10.4. 
• Standard of care medications for WD (trientine, penicillamine, and zinc) must be 
discontinued prior to the start of the Treatment Period (Day 1) with ALXN1840 and 
should not be used throughout the duration of study treatment. 
• Vitamin E has been used as an adjunctive therapy in WD treatment regimens. Patients 
must not initiate use of vitamin E during the study. 
• Patients must not use vitamins and/or minerals containing Cu, zinc, iron, or Mo. 
6.6. 
Dose Modification 
Patients will be initiated on ALXN1840 at 15 mg once daily, then the dose will be increased to 
30 mg once daily at Week 6 (Day 43). 
The dose should be decreased or interrupted if any of the relevant Dose Modification Criteria are 
met (see Table 6). Deviation from the dose modification guidelines must be agreed with the 
Alexion Medical Monitor. Any subsequent dose increases must be approved by Alexion. 
All patients will continue to be treated with ALXN1840 in the Extension Period at the same dose 
they received at the last study visit in the Treatment Period and ALXN1840 administration 
during the Extension Period will follow the same procedures as for the Treatment Period. 
In case a dose modification is necessary for ALXN1840, it will be administered as per the details 
in Table 6. 
 

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Table 6: 
ALXN1840 Dose Modifications for Individual Patients  
Test 
Result 
Conditions 
Action with ALXN1840 Dosing 
Changes in Safety 
Monitoringa 
Re-Challengeb  
ALT 
> 5 × ↑ from 
baseline 
ALT above 
reference range 
at baseline 
Temporary interruption 
 
Contact patient within 48 hours 
to arrange repeat testing 
Weekly repeat testing 
At 15 mg QOD when 
ALT < 2 × ↑ from 
baseline. 
> 5 × ULN 
ALT within 
reference range 
at baseline 
Temporary interruption 
Contact patient within 48 hours 
to arrange repeat testing 
Weekly repeat testing 
At 15 mg QOD when 
ALT < 2 × ULN. 
> 2 × ↑ from 
baseline 
ALT above 
reference range 
at baseline 
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 15 mg QOD if on 15 mg QD. No 
further dose ↑ until resolution of 
abnormality. 
Weekly repeat testing 
Not applicable. 
> 2 × ULN 
ALT within 
reference range 
at baseline 
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 15 mg QOD if on 15 mg QD. No 
further dose ↑ until resolution of 
abnormality. 
Weekly repeat testing 
Not applicable. 
Increased 
triglycerides  
> 300 to 500 
mg/dL or > 3.4 
to 5.6 mmol/L  
None  
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 15 mg QOD if on 15 mg QD. No 
further dose ↑ until resolution of 
abnormality. 
Weekly repeat testing 
Not applicable  
> 500 mg/dL 
or 5.6 mmol/L  
Temporary interruption 
At 15 mg QOD when 
triglyceride 
concentrations return to 
baseline  
Increased 
total 
cholesterol  
> 300 to 400 
mg/dL or > 7.8 
to 10.3 
mmol/L  
None  
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 15 mg QOD if on 15 mg QD. No 
further dose ↑ until resolution of 
abnormality. 
Weekly repeat testing  
Not applicable  
> 400 mg/dL 
or 
> 10.3 mmol/L  
Temporary interruption 
At 15 mg QOD when 
cholesterol concentrations 
return to baseline 

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Test 
Result 
Conditions 
Action with ALXN1840 Dosing 
Changes in Safety 
Monitoringa 
Re-Challengeb  
Hemoglobin 
< 8 g/dL in the 
absence of 
bleeding 
None 
Temporary interruption 
Weekly repeat testing 
At 15 mg QOD when 
hemoglobin and other 
hematology parameters 
(neutrophils and platelets) 
are at baseline 
concentration. 
> 30% ↓ from 
baseline 
None 
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 15 mg QOD if on 15 mg QD. No 
further dose ↑ until resolution of 
abnormality. 
Weekly repeat testing 
Not applicable. 
Platelets 
< 30,000/µL 
None 
Temporary interruption 
Weekly repeat testing 
At 15 mg QOD when 
platelets and other 
hematology parameters 
(neutrophils and 
hemoglobin) are at 
baseline concentration. 
> 30% ↓ from 
baseline 
Platelets below 
reference range 
at baseline 
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 15 mg QOD if on 15 mg QD. No 
further dose ↑ until resolution of 
abnormality. 
Weekly repeat testing 
Not applicable. 
Neutrophils 
< 1.0 × 103/µL 
None 
Temporary interruption 
Weekly repeat testing 
At 15 mg QOD when 
neutrophils and other 
hematology parameters 
(hemoglobin and 
platelets) are at baseline 
concentration. 
> 30% ↓ from 
baseline 
Neutrophils 
below reference 
range at baseline 
Reduce dose to previous dose level if 
up-titration has occurred or reduce dose 
to 15 mg QOD if on 15 mg QD. No 
further dose ↑ until resolution of 
abnormality. 
Weekly repeat testing 
Not applicable. 

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Test 
Result 
Conditions 
Action with ALXN1840 Dosing 
Changes in Safety 
Monitoringa 
Re-Challengeb  
Bilirubin 
> 2 × ULN  
Accompanied 
by ALT > 3 × 
ULN, indicative 
of liver injury. 
Temporary interruption 
Weekly repeat testing 
At 15 mg QOD or less 
frequent, when bilirubin is 
below ULN. Re-challenge 
under these conditions 
requires approval of the 
Alexion Medical Monitor. 
UWDRS-III 
and clinical 
neurological 
assessment 
Increase in UWDRS-III score 
from baseline as follows, AND is 
deemed clinically significant by 
the Investigator: 
 
Baseline UWDRS-III score < 20: 
≥ 4-point increase 
OR 
Baseline UWDRS-III score ≥ 20: 
≥ 6-point increase 
Investigator and Alexion Medical 
Monitor will evaluate the need for dose 
modification (interruption, increase or 
decrease) based on Cu control 
parameters and relevant clinical data. 
Rationale for dosing decision must be 
documented in study record and re-
evaluated at the next study visit. 
Report neurologic adverse event 
of special interest and perform 
UWDRS Parts I, II and III. Re-
evaluate neurologic status, 
including complete UWDRS 
examination, no later than next 
study visit, even if not planned 
per the SoA. 
Discuss with the Alexion 
Medical Monitor. 
Psychiatric 
assessment 
Clinically significant signs of 
psychiatric worsening according 
to the BPRS 
Investigator and Alexion Medical 
Monitor will evaluate the need for dose 
modification (interruption, increase or 
decrease) based on Cu control 
parameters and relevant clinical data. 
Rationale for dosing decision must be 
documented in study record and re-
evaluated at the next study visit. 
Re-evaluate psychiatric status no 
later than next study visit, even if 
not planned per the SoA. 
Discuss with the Alexion 
Medical Monitor. 
a For changes in safety monitoring, weekly repeat testing for laboratory parameters may be completed by a home healthcare nurse, where applicable, if a routine 
study visit is not scheduled during this time period. 
b A maximum of 3 re-challenges will be allowed. For re-challenges, patients who were on 15 mg QOD should be re-challenged at the 15 mg QOD dose. The 
Investigator, in consultation with the Medical Monitor, may change dose and dose frequency in patients who require re-challenge. 
 
Abbreviations: ALT = alanine aminotransferase; BPRS = Brief Psychiatric Rating Scale-24; Cu = copper; QD = once daily; QOD = every other day; SoA = 
Schedule of Activities; ULN = upper limit of normal; UWDRS = Unified Wilson Disease Rating Scale. 
 
 
 

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6.7. 
Drug after the End of the Study 
ALXN1840 will not be provided after the end of the 48-week Extension Period of the study. 

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7. 
DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Drug 
If it becomes necessary for a patient to permanently discontinue (definitive discontinuation) 
study drug, the patient must complete an Early Termination (ET) visit. See the SoAs (Table 1 
and Table 2) for data to be collected at the time of discontinuation of study drug and follow-up, 
and for any further evaluations that need to be completed. 
Discontinuation of study drug for abnormal liver chemistry tests should be considered by the 
Investigator when a patient meets one of the conditions outlined in the Dose Modification criteria 
(see Table 6) or if the Investigator believes that it is in best interest of the patient. 
If a clinically significant finding is identified (including suicidality) after enrollment, the 
Investigator or qualified designee will determine if the patient can continue in the study and if 
any change in patient management is needed. Any new clinically relevant finding should be 
reported as an AE. 
For clinically significant findings from baseline in QT interval corrected using Bazett’s formula 
(QTcB) or Fridericia’s formula (QTcF), review of the ECG printed at the time of collection must 
be documented.  
For details relating to pregnancy, see Section 8.3.5 and Section 10.4. 
See the SoAs (Table 1 and Table 2) for samples and data to be collected at the time of drug 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.1.1. 
Temporary Discontinuation 
Dose modification and reasons for interruption or discontinuation of dosing are detailed in 
Section 6.6 for ALXN1840. 
7.1.2. 
Rechallenge 
See Table 6 for details of rechallenge for ALXN1840. 
7.2. 
Patient Discontinuation/Withdrawal from the Study 
• A patient may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an ET visit should be 
conducted, as shown in the SoAs. See the SoAs for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed (Table 1 and Table 2). 
• The patient will be permanently discontinued both from the study drug and from the 
study at that time. 

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• If the patient withdraws consent for disclosure of future information, Alexion may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a patient withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
Participation of a patient in this clinical study may be discontinued for any of the following 
reasons: 
• The patient or/legal guardian withdraws consent or requests discontinuation from the 
study for any reason, is lost to follow-up or dies. 
• Occurrence of any medical condition or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the 
protocol. 
• Occurrence of a decompensated cirrhosis event which is not responsive to standard 
treatment. 
− A decompensation cirrhosis event is defined as acute esophageal or gastric 
variceal bleeding, development of new overt hepatic encephalopathy, or 
substantive de novo ascites formation. 
• Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent 
illness, or other medical condition which indicates to the Investigator that continued 
participation is not in the best interest of the patient. 
• Patient becomes pregnant or is unwilling to comply with protocol requirements for 
highly effective contraception. 
• Requirement to take prohibited concomitant medication or enroll in a clinical study of 
an experimental or unapproved/unlicensed therapy. 
• Patient failure to comply with protocol requirements or study-related procedures. 
7.3. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule, and ascertain whether or not the patient wishes to and/or should continue in 
the study. 
• Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, 
if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the patient’s 
medical record. 

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• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoAs (Table 1 and Table 2). 
Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with Alexion immediately upon 
occurrence or awareness to determine if the patient should receive study drug. 
• Adherence to the study design requirements, including those specified in the SoAs, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Liver biopsy is the last pre-dose baseline procedure to be completed and must be 
completed within 14 days prior to the first dose of ALXN1840. 
• Procedures conducted as part of the patient’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA (Table 1). 
• Details of the maximum amount of blood to be collected from each patient over the 
duration of the study are provided in the laboratory manual and ICF. 
8.1. 
Efficacy Assessments 
The time points for all efficacy assessments are provided in the SoAs (Table 1 and Table 2). 
8.1.1. 
Liver Biopsy Copper Content and Histologic Assessment 
A percutaneous needle biopsy of the liver will be performed by a licensed trained expert as per 
standard of care and outlined in American Association for the Study of Liver Diseases (AASLD) 
guidelines (Rockey, 2009) at baseline and Week 48. 
Cu content: one biopsy sample will be taken for the assessment of liver Cu concentration. Tissue 
samples will be dried, weighed, and stored in a Cu-free tube. Cu concentration will be 
determined at a central laboratory by inductively coupled plasma mass spectrometry and 
expressed as µg Cu/g dry weight. 
The second biopsy sample will be used for histologic and electron microscopy assessment. If 
there is insufficient sample for all assessments, electron microscopy will be omitted.  
Assessments of steatosis, inflammation, and fibrosis will include morphometric quantitation of 
hepatic fat, collagen, and alpha-smooth muscle actin (details of the analysis will be provided 
separately) (Jayakumar, 2019). Disease activity and fibrosis will be scored according to 
METAVIR criteria (METAVIR, 1994).  
All biopsy specimens will be reviewed and scored by an independent expert hepatopathologist 
who is blinded to patient identity and biopsy order. Further details relating to the biopsies will be 
provided in a separate manual. 

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8.1.2. 
Non-Ceruloplasmin-Bound Copper 
Because measures of NCC control in the blood are an exploratory assessment for efficacy of 
treatment with ALXN1840, plasma samples will be collected to measure the cNCC 
concentration, as well as dNCC, LBC, Cp, and CpC concentrations in the blood.  
The LBC assay measures Cu in plasma that is not bound to either Cp or the tetrathiomolybdate-
Cu-albumin tripartite complexes. The dNCC assay measures NCC in plasma. During treatment 
with ALXN1840, dNCC includes tetrathiomolybdate-Cu-albumin tripartite complexes. 
8.1.3. 
Model for End-Stage Liver Disease 
The MELD is a scoring system for assessing the severity of chronic liver disease in adults and 
adolescents aged 12 years and older. The MELD score (range 6-40, with higher values indicating 
more advanced disease) uses the patient’s values for serum bilirubin, serum creatinine, and the 
PT-INR to predict survival. In patients with a MELD score > 11, the serum sodium value is also 
taken into account (UNOS, 2015). 
The MELD score will be calculated by a central laboratory. 
8.1.4. 
Modified Nazer Score 
The modified Nazer Score is an assessment of liver status and consists of a composite of 
5 laboratory parameters: aspartate aminotransferase, INR, bilirubin, albumin, and white blood 
cell count. The score has a total range of 0 to 20, and lower values indicate a healthier liver status 
(Dhawan, 2005).  
The modified Nazer score will be calculated by a central laboratory. 
8.1.5. 
Unified Wilson Disease Rating Scale (Parts I, II, and III) 
The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of 
WD that generally can be divided into 3 movement disorder syndromes: dystonic, ataxic, and 
Parkinsonian syndrome. The UWDRS comprises 3 parts: UWDRS Part I (level of consciousness, 
item 1), UWDRS Part II (a patient-reported review of daily activity items [disability], items 2 to 
11), and UWDRS Part III (a detailed neurological examination, items 12 to 34). 
The UWDRS Part I and Part III will be assessed by a qualified neurologist, while UWDRS 
Part II may be reported to a member of the study team by the patient, family member, or 
caregiver (Czlonkowska, 2007; Leinweber, 2008).  
8.1.6. 
Clinical Global Impression-Improvement Severity Scale and the Clinical Global 
Impression-Severity Improvement Scale 
The Clinical Global Impression (CGI) rating scales are commonly used measures of symptom 
severity, treatment response, and the efficacy of treatments in treatment studies of adult and 
pediatric patients with mental disorders. 
The CGI-Severity (CGI-S) scale is a 7-point scale that requires the clinician to rate the severity 
of the patient's illness at the time of assessment, relative to the clinician's past experience with 
patients who have the same diagnosis. Considering total clinical experience, a patient is assessed 

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on severity of illness at the time of rating as: 1, normal, not at all ill; 2, borderline ill; 3, mildly 
ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.  
The CGI-Improvement (CGI-I) scale is a 7-point scale that requires the clinician to assess how 
much the patient's illness has improved or worsened relative to a baseline state at the beginning 
of the intervention and rated as: 1, very much improved; 2, much improved; 3, minimally 
improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. 
8.1.7. 
Imaging Techniques 
Details of imaging techniques will be detailed in an Imaging Manual. 
Magnetic Resonance Elastography and MR-PDFF 
Baseline and follow-up MRI studies of the liver will be performed as detailed in the SoAs 
(Table 1 and Table 2) and read by a central radiologist with expertise in these methods. Hepatic 
steatosis will be quantified by magnetic resonance (MR)-proton density fat fraction (MR-PDFF). 
Hepatic stiffness will be quantitated by MR elastography (MRE) according to standard protocols. 
Transient Elastography  
Transient elastography (Fibroscan preferred) uses ultrasound and low-frequency elastic waves to 
quantify liver fibrosis. Vibration controlled transient elastography will be performed at visits as 
outlined in the SoAs (Table 1 and Table 2). 
Optical Coherence Tomography 
Optical coherence tomography uses light waves to map and measure the structures of the eye 
(Sridhar, 2017). Copper deposits in the anterior chamber of the eye will be photographed and 
quantitated at visits as outlined in the SoAs (Table 1 and Table 2). 
Electron Microscopy 
Electron microscopy enables examination of mitochondrial ultrastructure of the liver to 
determine whether hepatic mitochondrial function is affected negatively in WD (Einer, 2019). 
The glutaraldehyde-fixed liver biopsy specimen will be processed by a qualified central 
laboratory to permit examination of subcellular ultrastructure using transmission electron 
microscopy and a descriptive assessment of electron microscopic images will be performed by 
an expert. 
8.1.8. 
Quality of Life, Treatment Satisfaction, and Psychiatric Symptoms 
8.1.8.1. 
EuroQoL 5 Dimensions 
The EQ-5D consists of 2 different assessments – the EQ-5D-5L Descriptive System and the EQ 
Visual Analogue Scale (VAS). The descriptive system comprises measures of health-related 
quality of life state and consists of 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels of severity: no problems, 
slight problems, moderate problems, severe problems, or extreme problems. The EQ VAS 
records the patient’s self-rated health on a vertical visual analogue scale. Together, this can be 
used as a quantitative measure of health outcome that reflects the patient’s own judgement. 

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8.1.8.2. 
Short Form Health Survey (SF-36) 
The SF-36 is a 36-item survey that is used to assess the patient’s view of their health. It consists 
of 8 scaled scores that are weighted sums of the questions in each section. The lower the score, 
the greater the disability: 
• Vitality 
• Physical functioning 
• Bodily pain 
• General health perceptions 
• Physical role functioning 
• Emotional role functioning 
• Social role functioning 
• Mental health 
8.1.8.3. 
Chronic Liver Disease Questionnaire 
The Chronic Liver Disease Questionnaire (CLDQ) is a 29-item instrument with 6 domains that 
measures longitudinal change over time in patients with chronic liver disease. Each domain is 
scored from 1 (worst possible function) to 7 (best possible function). The scores obtained 
correlate with the severity of liver disease (Younossi, 1999): 
• Fatigue 
• Activity 
• Emotional function 
• Abdominal symptoms 
• Systemic symptoms 
• Worry 
8.1.8.4. 
Treatment Satisfaction Questionnaire for Medication 
The Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) is used to assess the 
overall level of satisfaction or dissatisfaction with medication patients are taking. This composite 
scale is comprised of 3 items on the TSQM-9 survey: 
• Overall, how confident are you that taking this medication is a good thing for you? 
• How satisfied are you that good things about this medication outweigh the bad 
things? 
• Taking all things into account, how satisfied or dissatisfied are you with this 
medication? 

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8.1.9. 
Brief Psychiatric Rating Scale-24 
The Brief Psychiatric Rating Scale-24 (BPRS-24) is a 24-item instrument that allows the rater to 
measure psychopathology severity. The BPRS-24 assesses the following psychiatric symptoms: 
• Somatic concern, Anxiety, Depression, Suicidality, Guilt, Hostility, Elated Mood, 
Grandiosity, Suspiciousness, Hallucinations, Unusual thought content, Bizarre 
behavior, Self-neglect, Disorientation, Conceptual disorganization, Blunted affect, 
Emotional withdrawal, Motor retardation, Tension, Uncooperativeness, Excitement, 
Distractibility, Motor hyperactivity, Mannerisms and posturing. 
The presence and severity of psychiatric symptoms are rated on a Likert scale ranging from 1 
(not present) to 7 (extremely severe).  
The BPRS-24 can be performed by a qualified person (eg, neurologist, psychiatrist, psychologist, 
licensed mental health practitioner, social worker). 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoAs (Table 1 and Table 2).  
8.2.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and 
weight will also be measured and recorded. 
• A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Note: A neurological examination will be conducted by a qualified neurologist for 
UWDRS Part III at the time points specified in the SoAs (see also Section 8.1.5). 
8.2.2. 
Vital Signs 
• Temperature, heart rate, respiratory rate, blood pressure, temperature, weight, and 
height (Day 1 only) will be assessed. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the patient in a quiet setting without distractions (eg, television, cell phones). 
• Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse, and respiratory rate. 
8.2.3. 
Electrocardiograms 
• Single 12-lead ECGs will be obtained, as outlined in the SoAs (Table 1 and Table 2) 
using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. Refer to Section 7 for QTc withdrawal criteria and any 
additional QTc readings that may be necessary. Note that QTcF is preferred, unless 
only QTcB is available. 

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• Patients must be supine for approximately 5 to 10 minutes before ECG collection and 
remain supine but awake during ECG collection. 
• The Investigator or designee will be responsible for reviewing the ECG to assess 
whether the ECG is within normal limits and determine the clinical significance of 
the results. These assessments will be indicated on the CRF. 
8.2.4. 
Clinical Safety Laboratory Assessments 
• See Section 10.2 for the list of clinical laboratory tests to be performed and to the 
SoAs for the timing and frequency (Table 1 and Table 2). 
• The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected 
for the patient's condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 4 weeks after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or Alexion Medical Monitor. 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and Alexion 
notified. 
− All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoAs (Table 1 and 
Table 2). 
− If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in patient 
management or are considered clinically significant by the Investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.  
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring 
Patients with WD may occasionally develop suicidal ideation or behavior. 
Patients being treated with ALXN1840 should be monitored appropriately and observed closely 
for suicidal ideation and behavior or any other unusual changes in behavior, especially at the 
beginning and end of the course of drug, or at the time of dose changes, either increases or 
decreases. Consideration should be given to discontinuing the study medication in patients who 
experience signs of suicidal ideation or behavior, following a risk assessment.  
Families and caregivers of patients being treated with ALXN1840 should be alerted about the 
need to monitor patients for the emergence of unusual changes in behavior, as well as the 
emergence of suicidal ideation and behavior and to report such symptoms immediately to the 
Investigator. 

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Baseline assessment of suicidal ideation and behavior/drug emergent suicidal ideation and 
behavior will be monitored during this study using the BPRS-24 at the time points specified in 
the SoAs (Table 1 and Table 2). 
8.3. 
Adverse Events and Serious Adverse Events 
AEs will be reported to the Investigator or qualified designee by the patient (or, when 
appropriate, by a caregiver, surrogate, or the patient's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study drug or study procedures, or that caused 
the patient to discontinue the study drug (see Section 7). 
Definitions and procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are 
outlined in Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All AEs will be collected from the signing of the informed consent until the follow-up visit at the 
time points specified in the SoAs (Table 1 and Table 2). 
All SAEs will be recorded and reported to Alexion or designee within 24 hours, as indicated in 
Section 10.3. The Investigator will submit any updated SAE data to Alexion within 24 hours of it 
being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has exited the study, and he/she considers the event to be reasonably related to the study 
drug, the Investigator must promptly notify Alexion Global Drug Safety (GDS). 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Section 10.3. 

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8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to Alexion of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of 
a study drug under clinical investigation are met. 
• Alexion has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study drug under clinical investigation. 
Alexion will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRBs)/Independent 
Ethics Committees (IECs), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Alexion policy 
and forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from Alexion will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Pregnancy 
• Pregnancy data will be collected during this study for all female patients and female 
spouses/partners of male patients. Exposure during pregnancy (also referred to as 
exposure in utero) can be the result of either maternal exposure or transmission of 
drug product via semen following paternal exposure. Female patients who become 
pregnant during the study must withdraw from the study. 
• For all Alexion products in development, exposure during pregnancy must be 
recorded and the pregnancy followed until the outcome of the pregnancy is known 
(ie, spontaneous miscarriage, elective termination, normal birth, or congenital 
abnormality), even if the patient discontinues study drug or withdraws from the study.  
• If a female patient becomes pregnant from the first dose of study drug up to 30 days 
after the end of systemic exposure or a male patient’s female partner becomes 
pregnant from the first dose of study drug up to 90 days after the end of systemic 
exposure, the Investigator must submit the “Pregnancy/Breastfeeding Reporting and 
Outcome Form” to Alexion GDS via email or fax (Section 10.4). When the outcome 
of the pregnancy becomes known, the form should be updated and submitted to 
Alexion GDS. If additional follow-up is required, the Investigator will be requested to 
provide the information.  
• Exposure of an infant to an Alexion product during breastfeeding must also be 
reported (via the “Pregnancy/Breastfeeding Reporting and Outcome Form”) and any 
AEs experienced by the infant must be reported to Alexion GDS or designee via 
email or fax. 
• Pregnancy in and of itself is not regarded as an AE unless there is a suspicion that the 
study drug may have interfered with the effectiveness of a contraceptive medication. 
However, complications of pregnancy and abnormal outcomes of pregnancy are AEs 

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and may meet the criteria for an SAE (eg, ectopic pregnancy, spontaneous abortion, 
intrauterine fetal demise, neonatal death, or congenital anomaly). Elective abortions 
without complications should not be reported as AEs. 
8.3.6. 
Adverse Events of Special Interest  
No adverse events of special interest have been defined for this study.  
8.4. 
Treatment of Overdose 
For this study, any dose of ALXN1840 greater than the amount of study drug that exceeds the 
protocol required dose on a given dosing day or within a 24-hour time period will be considered 
an overdose. Alexion does not recommend specific treatment for an overdose of ALXN1840. 
 Overdoses are medication errors that are not considered AEs unless there is an untoward 
medical occurrence resulting from the overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Alexion Medical Monitor immediately. 
2. Closely monitor the patient for any AE/SAE and laboratory abnormalities. 
3. Obtain a plasma sample for PK/PD analysis as soon as possible within 10 days from the 
date of the last dose of study drug if requested by the Alexion Medical Monitor 
(determined on a case-by-case basis).  
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Alexion Medical Monitor based on the clinical evaluation of the patient. 
8.5. 
Pharmacokinetics 
• Blood samples will be collected for measurement of total and PUF Mo in plasma at 
the time points specified in the SoAs (Table 1 and Table 2). 
• A maximum of 5 samples may be collected at additional time points during the study 
if warranted and agreed upon between the Investigator and Alexion. The timing of 
sampling may be altered during the course of the study based on newly available data 
(eg, to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring.  
• Instructions for the collection and handling of biological samples will be provided by 
Alexion. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
• Samples will be used to evaluate the PK of ALXN1840. Samples collected for 
analyses of total and PUF Mo may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study. 

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• Samples will be used for diagnostic biomarker development and research to 
understand the pathways associated with disease states and the mechanism of action 
of ALXN1840. 
8.6. 
Pharmacodynamics 
Blood samples will be collected for measurement of total and PUF Cu, cNCC, LBC, and dNCC 
in plasma at study visits indicated in the SoAs (Table 1 and Table 2).  
A part of the liver tissue sample collected for biopsy within 14 days prior to Day 1 and again at 
Week 48 will be allocated for the measurement of total Mo and Cu concentrations in the liver 
tissue. 
A maximum of 5 samples may be collected at additional time points during the study if 
warranted and agreed upon between the Investigator and Alexion. The timing of sampling may 
be altered during the course of the study based on newly available data (eg, to obtain data closer 
to the time of peak plasma concentrations) to ensure appropriate monitoring. 
8.7. 
Genetics 
A blood sample for DNA isolation will be collected from patients who have consented to 
participate in the genetic analysis component of the study. Participation is optional and requires 
specific informed consent for this procedure. Patients who do not wish to participate in the 
genetic research may still participate in the main study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the patient. Signed informed consent will be required to obtain a replacement sample unless 
it was included in the original consent. 
See Section 10.5 for information regarding genetic research and details on processes for 
collection and shipment and destruction of these samples. 
8.8. 
Biomarkers 
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all patients in this study 
as specified in the SoAs (Table 1 and Table 2): 
• Blood samples will be collected to measure Cp and CpC 
• Urine samples will be collected for analysis of urine creatinine, Cu and Mo 
8.9. 
Immunogenicity Assessments 
Not applicable. 
8.10. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The hypothesis to be tested for the primary endpoint is: 
𝐻𝐻0: µALXN1840 ≥ 0 vs 𝐻𝐻1: µALXN1840 < 0  
where µALXN1840 is the mean change from baseline in liver Cu concentration (µg Cu/g dry liver) 
at Week 48.  
9.2. 
Sample Size Determination 
Cope-Yokoyama et al (Cope-Yokoyama, 2010) reviewed 6 previous liver biopsy studies on 
patients with WD before and after treatment with various SoC medications. From this review, 
data from 37 patients were available to calculate a weighted average of Cu concentration after 
treatment of 570 µg Cu/g dry liver. In addition, 13 individual patient data were available for both 
before and after treatment, with a standard deviation of paired difference of 319. It is expected 
that 48 weeks of treatment with ALXN1840 will reduce Cu concentration by 40%, from 570 to 
342, for a reduction of 228. Using a t-test statistic, 24 patients in ALXN1840 will provide 92% 
power at a one-sided significance level of 0.025 to detect a reduction of 228, with a standard 
deviation of paired difference of 319, in Cu concentration. 
Approximately 28 patients will be enrolled to accommodate a 15% dropout rate, such that 
approximately 24 evaluable patients complete the study. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined in Table 7. 
Table 7: 
Populations for Analyses 
Population 
Description 
Enrolled  
All patients who sign the informed consent form 
Safety Analysis Set in 
Treatment Period  
All patients who receive at least 1 dose of treatment in the Treatment Period 
Full Analysis Set in Treatment 
Period 
All patients who receive at least 1 dose of treatment in the Treatment Period 
and have at least baseline liver Cu value 
Per Protocol Set in Treatment 
Period 
All patients who receive at least 1 dose of treatment in the Treatment Period 
and have both baseline and Week 48 liver Cu values. Patients with major 
protocol deviations that are likely to impact the primary efficacy endpoint 
analysis will be excluded from the Per Protocol Set. Major protocol 
deviations, and the Per Protocol Set, will be defined, documented, and agreed 
within Alexion prior to database lock. 
Safety Analysis Set in 
Extension Period  
All patients who receive at least 1 dose of ALXN1840 in the Extension Period 
Full Analysis Set in Extension 
Period 
All patients who receive at least 1 dose of ALXN1840 in the Extension Period 
and have at least baseline liver Cu value 
Abbreviation: Cu = copper. 

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9.4. 
Statistical Analyses 
All statistical analyses will be performed by Alexion or under the authority of Alexion. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan (SAP), which will be 
finalized prior to the data cut for the primary analysis at 48 weeks in the Treatment Period. Any 
deviations from the planned analysis as described in the SAP will be justified and recorded in the 
final study report. In general, descriptive statistics for continuous variables will include number 
of non-missing values, mean, standard deviation, median, minimum, and maximum. Categorical 
variables will be summarized using percentages and frequency counts.  
All variables will be listed on a patient level. Baseline for all assessments will be defined as the 
last assessment yielding non-missing valid values taken prior to first dose of ALXN1840. 
Data will be analyzed separately and sequentially for the Treatment Period and Extension Period.  
All statistical analyses will be conducted using SAS® for Windows® Version 9.3 or higher (SAS 
Institute, Cary, North Carolina, USA). 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Treatment Period 
The primary objective of this study is to evaluate change in liver Cu concentration following 
treatment with ALXN1840 at 48 weeks in patients with WD. The primary analysis will be 
performed using the Full Analysis Set in the Treatment Period. 
The change in liver Cu concentration will be evaluated using a paired samples t-test. For the 
primary analysis, a multiple imputation method will be used for missing data imputation. 
Missing values for each patient will be imputed multiple times based on the estimated means 
from patients with similar baseline liver Cu concentration values. This approach will be used for 
all missing data at Week 48 due to any reason including, but not limited to, loss to follow-up and 
withdrawal of consent. The details of implementing this multiple imputation approach are as 
follows: 
• Step 1: Missing values at Week 48 will be imputed 20 times via SAS PROC 
MI, using MCMC statement, including baseline and Week 48 liver Cu value; imputed 
values at Week 48 will be retained in the imputed datasets. 
• Step 2: Apply paired samples t-test analysis for each of the 20 imputed datasets and save 
the mean and standard error at Week 48 from each of the 20 analyses. 
• Step 3: Combine the 20 sets of analysis results via SAS PROC MIANALYZE. The 
combined treatment effect, confidence interval, and p-value will be estimated. 
Sensitivity analyses will be performed to assess the robustness of the analysis result and will 
include: 
• Use baseline value carried forward to impute missing Week 48 data 
• Analyze primary endpoint using the Per Protocol Set, multiple imputation will be used to 
impute missing Week 48 data 

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Secondary and exploratory analyses will be performed using the Full Analysis Set in the 
Treatment Period.  
For continuous endpoints that are measured multiple times between baseline and Week 48, data 
will be analyzed using mixed model repeated measures (MMRM) analysis. Fixed-effect terms 
will include visit and baseline value as covariates. An unstructured covariance will be used to 
model within-patient error.  
For exploratory endpoints, data will be analyzed as observed, for endpoints that are only 
measured at baseline and Week 48, an analysis of covariance (ANCOVA) model will be used to 
analyze continuous endpoints, and a non-parametric ANCOVA model will be used to analyze 
ordinal outcomes. Baseline value will be included in the model. 
9.4.1.2. 
Multiplicity Adjustment 
No adjustments will be made for multiplicity of multiple endpoints. 
9.4.2. 
Safety Analyses 
Safety analyses will include all AEs, ECGs, clinical laboratory data, physical examinations, and 
vital sign measurements using descriptive statistics. 
Safety analyses will be performed using the Safety Analysis Set in the Treatment Period. 
The verbatim terms as reported in the CRF by Investigators to identify AEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA), Version 20.0 or higher and 
summarized by primary System Organ Class and Preferred Term. 
Summary tables will include patient counts and percentages and will present separate tabulations 
for all AEs, SAEs, AEs leading to treatment discontinuation or withdrawal, and AEs leading to 
death. 
Laboratory data will be summarized by laboratory parameter and by scheduled time point. 
Summary statistics will be applied for continuous laboratory parameters, and categorical 
laboratory parameters will be summarized by absolute and relative frequencies. Reference ranges 
will be used in the summary of laboratory data. Changes in laboratory parameters from the 
baseline over time will be summarized via summary statistics and shift tables to allow detection 
of clinically relevant changes. 
Vital sign results will be evaluated by means of descriptive statistics and frequency tabulations. 
These tables will include shifts from baseline values to allow detection of clinically relevant 
changes. Abnormal vital sign results will be tabulated. 
Physical examination results will be tabulated; abnormalities will be listed. 
9.4.3. 
Other Analyses 
The PK, PD, and biomarker analyses will be described in the SAP (or the PK/PD data analysis 
plan, as applicable), and finalized before database lock. 

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9.4.4. 
Interim Analyses  
Regulatory submission(s) may be performed before all patients complete the Treatment Period. 
Interim analyses of safety and efficacy data may be performed to support theses submission(s). 
These analyses will be descriptive; they will not include formal hypothesis testing and will not 
be used to adapt the study. Consequently, no adjustments to control Type I error will be 
performed for the Treatment Period primary analysis.  
Full details will be provided in interim and final SAPs. 
9.4.5. 
Extension Period Analyses 
Efficacy endpoints will be analyzed using descriptive summary statistics. Efficacy analyses will 
be performed using the Full Analysis Set in the Extension Period. 
Safety analyses will include all AEs, ECGs, clinical laboratory data, physical examinations, and 
vital sign measurements using descriptive statistics. Safety analyses will be performed using the 
Safety Analysis Set in the Extension Period. 
9.5. 
Data Monitoring Committee 
An independent DMC, comprising experts in relevant fields with no direct relationship to the 
study, will be appointed by Alexion. As detailed in the DMC Charter (maintained separately 
from the study protocol), the DMC will review and monitor study data for safety, effectiveness, 
and study conduct, and make recommendations regarding study continuation, changes to the 
study population, and/or modification to study procedures. The activities of the DMC will be 
ongoing before, during, and after the Treatment Period, and through the end of the Extension 
Period. The specific responsibilities of the DMC are described in the DMC Charter.  
Final decisions regarding the conduct of the study will be made by Alexion after consultation 
with the DMC. All appropriate regulatory authorities and ethics committees will be notified of 
significant actions taken as a result of DMC recommendations.  
Each member of the DMC is required to sign an agreement, including confidentiality and 
financial disclosure statements, assuring no conflicts of interest as a condition for membership on 
the committee.  
9.6. 
Hepatic Adjudication Panel 
A separate independent Hepatic Adjudication Panel, comprising experts in hepatology and drug 
induced liver injury, will be appointed by Alexion. As detailed separately in the Hepatic 
Adjudication Panel charter (maintained separately from the study protocol), the Hepatic 
Adjudication Panel will review and monitor study data for abnormalities of liver tests and liver 
function that may impact safety, effectiveness, and study conduct, and make recommendations 
regarding study continuation, changes to the study population, and/or modification to study 
procedures. The specific responsibilities are described in the Hepatic Adjudication Panel charter. 
 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC and, where applicable, 
competent authority approval, before implementation of changes made to the study 
design, except for changes necessary to eliminate an immediate hazard to study 
patients.  
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to the 
requirements of ICH guidelines and the IRB/IEC, all regional and national 
regulations as applicable (eg, CFR Title 21, Regulation [EU] No 536/2014 for 
clinical studies on medicinal products for human use, Directive 2001/20/EC), and 
all other applicable local regulations. 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide Alexion with sufficient, accurate financial 
information as requested to allow Alexion to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the study and for 1 year after 
completion of the study. 

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10.1.3. 
Informed Consent Process 
• It is the responsibility of the Investigator to obtain signed (written or electronic 
signature) informed consent from all patients prior to any study-related procedures 
including screening assessments. 
• The Investigator or his/her representative will explain the nature of the study to the 
patient or his/her legally authorized representative and answer all questions regarding 
the study.  
• Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative, defined according to local and country regulations where 
the study is taking place, will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that signed (written or electronic) 
informed consent was obtained before the patient was screened in the study and the 
date the consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF(s). 
• Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the patient or the patient’s legally 
authorized representative.  
Patients who are rescreened are required to sign a new ICF (see Section 5.4). 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The Investigator or authorized designee will explain to each 
patient the objectives of the exploratory research. Patients will be told that they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the storage 
period. A separate signature will be required to document a patient’s agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate in 
this optional research will not provide this separate signature. 
10.1.4. 
Data Protection 
• Patients will be assigned a unique identifier by Alexion. Any patient records or 
datasets that are transferred to Alexion will contain the identifier only; patient names 
or any information which would make the patient identifiable will not be transferred.  
• The patient must be informed that his/her personal study-related data will be used by 
Alexion in accordance with local data protection law. The level of disclosure must 
also be explained to the patient who will be required to give consent for their data to 
be used as described in the informed consent. 
• The patient must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 

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Alexion, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on publically accessible clinical study 
databases (eg, the US website www.clinicaltrials.gov or the EU website 
www.clinicaltrialregister.eu), as appropriate, and in accordance with national, regional, and local 
regulations. 
10.1.6. 
Data Quality Assurance 
• All patient data relating to the study will be recorded on a CRF unless transmitted to 
Alexion or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Alexion or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of patients are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for 2 years after the last marketing 
application approval, or if not approved, 2 years following the discontinuance of the 
test article for investigation, unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period 
without the written approval of Alexion. No records may be transferred to another 
location or party without written notification to Alexion.  
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the patient and substantiate 
the integrity of the data collected. The Investigator or designee will prepare and 
maintain adequate and accurate source documents (eg, medical records, ECGs, AE 
and concomitant medication reporting, raw data collection forms) designed to record 
all observations and other pertinent data for each patient.  
• Data reported on the CRF or entered in the CRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 

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explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
Source documents are filed at the Investigator’s site. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the first patient is consented.  
Alexion or designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of Alexion. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Alexion or Investigator may include but are not 
limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, Alexion 's procedures, or GCP guidelines 
• Inadequate recruitment of patients by the Investigator 
• Discontinuation of further study drug development 
If the study is prematurely terminated or suspended, Alexion shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the patient and 
should assure appropriate patient therapy and/or follow-up 
10.1.9. 
Publication Policy 
The full terms regarding publication of the results of this study are outlined in the applicable 
Clinical Study Agreement. 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
• Pregnancy testing should be conducted in accordance with the SoAs (Table 1 and 
Table 2). 
• Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure plus an additional 30 days and 
correspond with the time frame for female patient contraception in Section 5.1. 
• Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the Investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the patient's participation in the study. 
• The tests detailed in Table 8 will be performed by a central laboratory, except for any 
ad hoc tests performed, eg, if an AE occurs. 
• Protocol-specific requirements for inclusion or exclusion of patients are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
Table 8: 
Protocol-Required Safety Laboratory Assessments 
Clinical Chemistry 
Blood urea nitrogen (BUN) 
Alanine aminotransferase 
Potassium 
Alkaline phosphatase 
Creatinine 
Urea 
Creatine kinase 
Magnesium 
Sodium 
Iron 
Chloride 
Zinc 
Potassium 
Total and direct bilirubin 
Glucose 
Total protein 
Total carbon dioxide 
Albumin 
Aspartate aminotransferase 
Calcium 
Gamma glutamyltransferase 
Phosphate 
Total cholesterol 
Triglycerides 
LDL cholesterol 
HDL cholesterol 
Hematology 
Hematocrit 
Red blood cell count (including nucleated red blood cells) 
Platelets 
Mean corpuscular volume 
White blood cell count 
Mean cell hemoglobin concentration 
Mean cell hemoglobin 
Lymphocytes 
Neutrophils 
Eosinophils 
Monocytes 
Prothrombin time 
Basophils 
International Normalized Ratio 
Hemoglobin 
Partial Thromboplastin Time 

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Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocytes 
Microscopy 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Red blood cells 
Bacteria 
White blood cells 
Other Tests 
HIV, hepatitis B, and hepatitis C screen 
Total Cu and total Mo 
Ceruloplasmin 
24-hour urine 
Serum and urine pregnancy testa 
24-hour urine creatinine, Cu and Mo 
NCC 
 
a Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
Abbreviations: Cu = Copper; HDL = high density lipoprotein; IEC = Independent Ethics Committee; IRB = 
Institutional Review Board; LDL = low density lipoprotein; Mo = Molybdenum; NCC = non ceruloplasmin-bound 
Cu; PTH = parathyroid hormone. 
 
Investigators must document their review of each laboratory safety report. 

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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
 
Adverse Event Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study patient, temporally associated 
with the use of study drug, whether or not considered related to the study drug. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of 
study drug. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the Investigator (ie, 
not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
Signs, symptoms, or the clinical sequelae, regardless of whether a suspected drug-drug interaction. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or 
SAE if they fulfil the definition of an AE or SAE.  
• 
Overdose per se will not be reported as an AE/SAE unless it is an intentional overdose taken with 
possible suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae. 
• 
Pre-existing conditions that are detected after administration of study drug with an onset date prior to 
administration should be considered medical history. 
 
Events NOT Meeting the AE Definition  
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen.  
• 
A medication error (including intentional misuse, abuse, and overdose of the product) or use other than 
what is defined in the protocol is not considered an AE unless there is an untoward medical occurrence 
as a result of a medication error.  
• 
Cases of pregnancy that occur during maternal or paternal exposure to investigational product are to be 
reported within 24 hours of Investigator/site awareness. Data on fetal outcome and breastfeeding will 
be collected for regulatory reporting and safety evaluation.  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the patient’s condition. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
Serious Adverse Event Definition 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 

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An SAE is defined as an AE that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient was at risk of death 
at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were 
more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
4. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in 
other situations such as important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require medical or surgical drug to prevent 
one of the other outcomes listed in the above definition. These events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event 
Adverse Event and Serious Adverse Event Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE or SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the patient’s medical records to Alexion in 
lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by Alexion. In this 
case, all patient identifiers, with the exception of the patient number, will be redacted on the copies of the 
medical records before submission to Alexion. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and assign 
it to 1 of the following categories from National Cancer Institute CTCAE v5.0, published 27 Nov 2017:  
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated.  
• 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental activities of daily living.  
• 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living.  
• 
Grade 4 Life-threatening consequences; urgent intervention indicated.  
• 
Grade 5 Death related to AE. 

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Adverse Event and Serious Adverse Event Recording 
Increases in the severity of an AE should be documented to allow an assessment of the AE duration at each level 
of intensity to be evaluated. Adverse events characterized as intermittent require documentation of onset and 
duration of each episode, if the severity of the intermittent event changes. 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between the study drug and each occurrence of each 
AE or SAE. An Investigator causality assessment must be provided for all AEs (both nonserious and 
serious). This assessment must be recorded in the CRF and on any additional forms, as appropriate. The 
definitions for the causality assessments are as follows: 
o Not related (unrelated): There is no causal association with study drug  
o Related: There is causal (temporal) association to the study drug. Other conditions (concurrent 
illness, concurrent medication reaction, or progression/expression of disease state) do not appear to 
explain the event; the event corresponds with the known pharmaceutical profile; improvement on 
discontinuation; reappearance on rechallenge. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study intervention administration will be considered and investigated. 
• 
The Investigator will also consult the IB and/or Product Information, for marketed products, in his/her 
assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the Investigator has minimal information to 
include in the initial report to Alexion or its designee. However, it is very important that the Investigator 
always makes an assessment of causality for every event before the initial transmission of the SAE data to 
Alexion or its designee. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and send a SAE 
follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting requirements.  
 
 
Follow-up of Adverse Events and Serious Adverse Events 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by Alexion to elucidate the nature and/or causality of the 
AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a patient dies during participation in the study or during a recognized follow-up period, the Investigator 
will provide Alexion with a copy of any post-mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to Alexion within 24 hours of receipt of the information. 
Reporting of Serious Adverse Events 
Serious Adverse Event Reporting to Alexion or designee via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to Alexion GDS will be the RAVE Safety Gateway. 
• 
If the electronic system is unavailable at the time that the Investigator or site becomes aware of an SAE, the 
site will use the paper Contingency Form for SAE reporting via email or fax. Email or facsimile 
transmission may be used in the event of electronic submission failure. Once the system becomes available 
again, the SAE report must be forwarded via the RAVE Safety Gateway. 
• 
Email: 
 or Fax: 
 The site will enter the SAE data into the EDC 
system as soon as it becomes available. 

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Serious Adverse Event Reporting to Alexion or designee via an Electronic Data Collection Tool 
• 
When further information becomes available, the EDC system should be updated with the new information 
and an updated SAE report should be submitted to Alexion GDS via the RAVE Safety Gateway.  
• 
After the study is completed at a given site, the EDC tool will be taken off-line to prevent the entry of new 
data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data on a previously 
reported SAE after the electronic data collection tool has been taken off-line, then the site can report this 
information on the paper Contingency Form for SAE Reporting. 
• 
If applicable, additional information such as relevant medical records should be submitted to Alexion GDS 
via the email address or fax number noted above.  
• 
All paper forms and follow-up information submitted to Alexion outside of the RAVE Safety Gateway (eg, 
discharge summary) should be kept in the appropriate section of the study file and MUST be accompanied 
by a cover page signed by the Investigator.  
• 
Paper source documents and/or reports should be kept in the appropriate section of the study file. 
 

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10.4. 
Appendix 4: Pregnancy Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
• For individuals with documented permanent infertility due to an alternate medical 
cause other than the above, (e.g., mullerian agenesis, androgen insensitivity), 
Investigator discretion should be applied to determining study entry. 
• Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy. However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  
Contraception Guidance: 
Guidance for Female Patients  
Female patients of non-childbearing potential are exempt from contraception requirements.  
Female patients of child-bearing potential must have a negative highly sensitive pregnancy test 
(urine or serum as required by local regulations) within 24 hours before the first dose of study 
drug.  
The Investigator is responsible for the review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
Female patients of child-bearing potential must use a highly effective method of contraception, 
including at least one of the following, starting at least one menstrual cycle before first study 
drug administration and continuing for at least 30 days after the end of systemic exposure of the 
study drug, including at least one of the following:  

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a. Intrauterine device (without Cu)  
b. Progestogen-only hormonal contraception (either oral, injectable, or implantable) 
associated with inhibition of ovulation 
c. Intrauterine progestogen releasing system  
d. Bilateral tubal occlusion  
e. Combined (estrogen and progestogen containing) hormonal contraception (either oral, 
intravaginal, or transdermal) associated with inhibition of ovulation. Estrogen-
containing hormonal contraception is acceptable only if it has been used for at least 6 
weeks immediately prior to the Day 1 visit. Estrogen-containing hormonal 
contraception may not be initiated during the study period. 
f. Surgical sterilization of the male partner (medical assessment of azoospermia is 
required if vasectomy was performed within the prior 6 months)  
Sexual abstinence for female patients  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse. In this study, abstinence is only acceptable if consistent with the 
patient’s preferred and usual lifestyle. Abstinent female patients who wish to initiate a highly 
effective method of contraception during the study must refrain from heterosexual intercourse for 
at least 28 days.  
Periodic abstinence (e.g. calendar, symptothermal, or post-ovulation methods) is not considered 
a highly effective method of contraception for female patients.  
Other methods of contraception that are not considered highly effective for female patients  
Barrier methods, such as male or female condoms, diaphragm, or cervical cap, used alone or in 
combination, are not acceptable.  
Spermicides or spermicidal sponges, used alone or in combination with barrier methods, are not 
acceptable.  
Withdrawal (coitus interruptus) is not acceptable.  
Lactational amenorrhea is not acceptable.  
Guidance for male patients with a partner who is a woman of childbearing potential 
Male patients must use a condom and spermicide during heterosexual intercourse from the first 
dose of study intervention until at least 90 days after their final dose of study intervention. 
Female partners of male patients who are of childbearing potential must use highly effective 
contraception as defined above, starting one menstrual cycle before (the male patient’s) first 
study intervention administration and continuing until at least 90 days after the end of their male 
partner’s systemic exposure to the study intervention. 
Male patients must not donate sperm from the first dose of study intervention until at least 90 
days after their final dose of study intervention. 

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Sexual abstinence for male patients  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse. In this study, abstinence is only acceptable if consistent with the 
patient’s preferred and usual lifestyle. Abstinent male patients who become heterosexually active 
with a WOCBP must use a condom and spermicide during intercourse.  
Periodic abstinence (e.g. calendar, symptothermal, or post-ovulation methods for a female 
partner) is not considered a highly effective method of contraception for male patients.  
Collection of Pregnancy Information 
Pregnancy data will be collected during this study for all female patients and female partners of 
male patients. Exposure during pregnancy (also referred to as exposure in utero) can be the result 
of either maternal exposure or transmission of drug product via semen following paternal 
exposure. If a female patient becomes pregnant from the first dose of study drug up to 30 days 
after the end of systemic exposure or a male patient’s female partner becomes pregnant from the 
first dose of study drug up to 90 days after the end of systemic exposure, the Investigator must 
submit the “Pregnancy/Breastfeeding Reporting and Outcome Form” to Alexion GDS via email 
or facsimile. When the outcome of the pregnancy becomes known, the form should be updated 
and submitted to Alexion GDS. If additional follow-up is required, the Investigator will be 
requested to provide the information.  
Exposure of an infant to an Alexion product or other study drug during breastfeeding must also 
be reported (via the “Pregnancy/Breastfeeding Reporting and Outcome Form”) and any AEs 
experienced by the infant must be reported to Alexion GDS or designee via email or facsimile.  
Pregnancy in itself is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication. However, complications of 
pregnancy and abnormal outcomes of pregnancy are AEs and may meet the criteria for an SAE 
(eg, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or 
congenital anomaly). Elective abortions without complications should not be reported as AEs.  
Any female patient who becomes pregnant while participating in the study will be discontinued 
from study drug and withdrawn from the study.  
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies to male participants who receive ALXN1840. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
“Pregnancy/Breastfeeding Reporting and Outcome Form” and submit it to Alexion 
within 24 hours of obtaining the consent. The female partner will also be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to Alexion. Generally, the follow-up will be no longer than 3 
months following the delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
the procedure.  

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Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to Alexion within 24 hours of 
learning of a participant's pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate, and 
the information will be forwarded to Alexion. Generally, follow-up will not be 
required for longer than 3 months beyond the delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. A spontaneous abortion (occurring at < 22 weeks 
gestational age) or still birth (occurring at > 22 weeks gestational age) is always 
considered to be an SAE and will be reported as such. Any post-study pregnancy 
related SAE considered reasonably related to the study intervention by the 
Investigator will be reported to Alexion as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting. 

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10.5. 
Appendix 5: Genetics  
Use/Analysis of DNA 
• Genetic variation may impact a patient’s response to study drug, susceptibility to, and 
severity and progression of disease. Variable response to study drug may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting patients. 
• DNA samples will be used for research related to ALXN1840 or WD and related 
diseases. They may also be used to develop tests/assays including diagnostic tests 
related to ALXN1840 and WD. Genetic research may consist of the analysis of one or 
more candidate genes or the analysis of genetic markers throughout the genome or 
analysis of the entire genome (as appropriate). 
• DNA samples will be analyzed for variants in the coding and regulatory sequences of 
the ATP7B gene. 
• Additional unspecified analyses may be conducted in the future if it is hypothesized 
that this may help resolve issues with the clinical data. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to ALXN1840 or study drugs of this class to understand 
study disease or related conditions. 
• The results of genetic analyses may be reported in the clinical study report or in a 
separate study summary. 
• Alexion will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The DNA samples will be retained while research on ALXN1840 continues but no 
longer than 15 years or other period as per local requirements. 
 

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10.6. 
Appendix 6: Abbreviations 
 
Abbreviation 
Definition 
AASLD 
American Association for the Study of Liver Diseases 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate transaminase 
AUEC 
Area under the effect-time curve 
BMI 
Body mass index 
BPRS 
Brief Psychiatric Rating Scale-24; 
CGI 
Clinical Global Impression 
CGI-I 
Clinical Global Impression-Improvement Scale 
CGI-S 
Clinical Global Impression-Severity Scale 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
Chronic kidney disease 
CLDQ 
Chronic liver disease questionnaire 
cNCC 
Calculated non-ceruloplasmin-bound Cu 
CONSORT 
Consolidated Standards of Reporting Trials 
Cp 
Ceruloplasmin 
CpC 
Ceruloplasmin bound Cu 
CRF 
Case report form 
Cu 
Copper 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
dNCC 
Directly measure non-ceruloplasmin bound Cu 
EASL 
European Association for the Study of the Liver 
EDC 
Electronic data capture 
EOS 
End of Study 
EQ-5D 
EuroQoL 5 Dimensions 
EQ VAS 
EuroQol visual analog scale 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GDS 
Global Drug Safety 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
IEC 
Institutional Ethics Committee 
INR 
International normalized ratio for prothrombin time 

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Abbreviation 
Definition 
IRB 
Institutional Review Board 
LLT 
Lowest level term 
LS 
Least-squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-Stage Liver Disease 
MMRM 
Mixed model repeated measures 
Mo 
Molybdenum 
MR(E) 
Magnetic resonance (elastography) 
MRI 
Magnetic resonance imaging 
MT 
Metallothionein 
NCC 
Non-ceruloplasmin-bound Cu 
NIMP 
Non-investigational medicinal product 
PD 
Pharmacodynamic(s) 
PDFF 
Proton density fat fraction 
PK 
Pharmacokinetic(s) 
PT-INR 
Prothrombin time-international normalized ratio 
PUF 
Plasma ultrafiltrate 
QOD 
Once every other day 
QD 
Once a day 
SAE 
Serious adverse event 
SoA 
Schedule of Activities 
SoC 
Standard of care 
SUSAR 
Suspected unexpected serious adverse reaction 
TSQM-9 
Treatment Satisfaction Questionnaire for Medication-9 
ULN 
Upper limit of normal 
UNS 
Unscheduled 
UWDRS 
Unified Wilson Disease Rating Scale 
WD 
Wilson disease 
WOCBP 
Woman of childbearing potential 
 
 

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10.7. 
Appendix 7: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Original Protocol 
20 Dec 2019 
Amendment 1 (Austria) 
07 May 2020 
Amendment 2 (Germany) 
03 Aug 2020 
Amendment 3 (Denmark) 
10 Aug 2020 
Amendment 4 (United Kingdom) 
23 April 2021 
Amendment 1 (07 May 2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
This amendment was prepared to add information on monthly pregnancy testing for female 
patients of childbearing potential who are enrolled in an interventional clinical study. This is a 
legal requirement in Austria, according to Article 30 of the Austrian Drug Law. This amendment 
applies only to Austria. 
Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or 
Clarifications 
Section 1.2 Schedule of 
Activities, Tables 1 and 2 
Section 5.1, Inclusion Criteria 
Section 10.4 Appendix 4: 
Pregnancy Information 
Addition of requirement for 
female subjects of childbearing 
potential to perform monthly 
pregnancy testing at their home 
throughout the study 
It is a legal requirement in Austria 
to include monthly pregnancy tests 
in clinical studies 
Figure 1 
Figure corrected to remove 
mention of treatment-naïve 
patients 
Treatment-naïve patients are not 
included in the study. 
All sections 
Minor editorial updates and 
corrections 
For clarification, and to ensure 
accuracy and consistency 
throughout the protocol 
 
Amendment 2 (03 Aug 2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
This amendment was prepared to update exclusion criterion relating to clinical study experience 
and to add information on prohibited concomitant medication in response to a request by the 
Federal Institute for Drugs and Medical Devices in Germany (BfArM). Additional changes are 
included in the table below. This amendment only applies to Germany. 

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Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or 
Clarifications 
Section 5.2, Exclusion 
Criteria 
Prior clinical study experience 
limited to 3 months (or 5 half-
lives of the administered 
investigational medicinal 
product, whichever is longer) 
prior to study start. 
More detailed language regarding 
exclusion of patients who 
participated in any interventional 
study prior to initiation of Study 
ALXN1840-WD-205. 
Section 6.5, Concomitant 
Therapy 
Standard of care treatment for 
Wilson disease added as 
prohibited medication during 
the treatment period. 
Standard of care treatment for 
Wilson disease and ALXN1840 
should not be administered 
concomitantly. 
Figure 1 
Figure corrected to remove 
mention of treatment-naïve 
patients 
Treatment-naïve patients are not 
included in the study. 
All sections 
Minor editorial updates and 
corrections 
For clarification, and to ensure 
accuracy and consistency 
throughout the protocol 
 
Amendment 3 (10 Aug 2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
This amendment was prepared to add information on pregnancy testing for female patients of 
childbearing potential who are enrolled in an interventional clinical study in response to a request 
from the Danish Health Authority. Additional minor editorial updates were made for clarification 
and consistency. This amendment only applies to Denmark. 
Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or 
Clarifications 
Section 1.2, Schema, Figure 1 
Figure corrected to remove 
mention of treatment-naïve 
patients 
Treatment-naïve patients are not 
included in the study. 
Section 1.1, Synopsis 
Section 1.3, Table 1, and 
Table 2 
Section 4.1, Overall Design 
Monthly pregnancy testing will 
be performed for 90 days after 
the last dose of ALXN1840. 
Monthly pregnancy testing, 
according to the Clinical Trial 
Facilitation Group (CTFG) 
guideline on contraception in 
clinical trials, has been extended 
based on relevant exposure of 
ALXN1840. 
Section 10.4, Appendix 4, 
Pregnancy Information 
Contraception guidance 
updated to include duration of 
use and type. 
To further define contraception 
requirements 

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All sections 
Minor editorial updates and 
corrections 
For clarification, and to ensure 
accuracy and consistency 
throughout the protocol 
 
Amendment 4 (23 April 2021) 
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The main reason for preparation of this amendment was to add information regarding the 
coronavirus disease 2019 (COVID-19) vaccine risk assessment, as requested by the UK 
Medicines and Healthcare products Regulatory Agency (MHRA) in its updated guidance on 
managing clinical trials during the COVID-19 pandemic. This amendment only applies to the 
United Kingdom. 
Changes to the Protocol 
Section # and Name 
Description of Change 
Brief rationale and/or 
clarifications 
Section 2.3.1.1, 
Coronavirus Disease 
2019; Section 10.6 
Appendix 6: COVID-19 
Vaccine Risk 
Assessment 
Text on the COVID-19 vaccine risk 
assessment performed with respect 
to ALXN1840 added. 
To comply with the request by the 
MHRA for studies performed in the 
UK. 
All sections 
Minor editorial updates and 
corrections 
For clarification, and to ensure 
accuracy and consistency throughout 
the protocol 
Abbreviations: COVID-19 = coronavirus disease 2019; MHRA = Medicines and Healthcare products Regulatory 
Agency; UK =United Kingdom. 
 
 

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11. 
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